cardiology - cims

Cardiology TODAY

VOLUME XXII No. 5SEPTEMBER-OCTOBER 2018

PAGES 145-188

Rs. 1700/- ISSN 0971-9172 RNI No. 66903/97

www.cimsasia .com

MANAGING DIRECTOR & PUBLISHERDr. Monica Bhatia

EDITOR IN CHIEFOP Yadava

SECTION EDITORSSR Mittal (ECG, CPC), David Colquhou n (Reader’s Choice)

NATIONAL EDITORIAL ADVISORY BOARDArun K Purohit, Arun Malhotra, Ashok Seth, Ashwin B Mehta, CN Manjunath, DS Gambhir, GS Sainani, Harshad R Gandhi, I Sathyamurthy, Jagdish Hiremath, JPS Sawhney, KK Talwar, K Srinath Reddy, KP Misra, ML Bhatia, Mohan Bhargava, MR Girinath, Mukul Misra, Nakul Sinha, PC Manoria, Peeyush Jain, Praveen Jain, Ramesh Arora, Ravi R Kasliwal, S Jalal, S Padmavati, Satyavan Sharma, SS Ramesh, Sunil Kumar Modi, Yatin Mehta, Yogesh Varma, R Aggarwala.

INTERNATIONAL EDITORIAL ADVISORY BOARDAndrew M Tonkin, Bhagwan Koirala, Carlos A Mestres, Chuen N Lee, David M Colquhoun, Davendra Mehta, Enas A Enas, Gerald M Pohost, Glen Van Arsdell, Indranill Basu Ray, James B Peter, James F Benenati, Kanu Chatterjee, Noe A Babilonia, Pascal R Vouhe,Paul A Levine, Paul Simon, P K Shah, Prakash Deedwania, Salim Yusuf, Samin K Sharma, Sanjeev Saxena, Sanjiv Kaul, Yutaka Imoto.

DESK EDITORGandhali

DESIGNER A run Kharkwal

OFFICES CIMS Medica India Pvt Ltd(Previously known as UBM Medica India Pvt Ltd.)Registered OfficeMargosa Building, No. 2, 3rd Floor, 13th Cross, Margosa Road, Malleshwaram, Bengaluru -560 003 Karnataka, IndiaTel: +91-80-4346 4500Fax: +91-80-4346 4530

Corporate OfficeBoomerang (Kanakia Spaces), Wing-B1, 403,4th Floor, Chandiwali Farm Road, ChadiwaliPowai, Mumbai - 400 072Tel.: +91-22-6612 2600 Fax : +91-22-6612 2626

Regional Off ice709, 7th Floor, Devika Tower, Nehru Place, New Delhi-110 019, India. Tel: +91-11-4285 4300Fax: +91-11-4285 4310

EDITORIALHealthy Diet - Watch Press ! 149OP YADAVA

REVIEW ARTICLEPCSK9 Inhibitors 151NITIN AGGARWAL, HARSH WARDHAN

REVIEW ARTICLECardiovascular Disease, Obesity, MetS, T2DM and Aging, and Benefits of Calorie Restriction and Calorie Restriction Mimetics 158VINOD NIKHRA

REVIEW ARTICLEProsthetic Heart Valve Thrombosis: How to Manage? 169YK ARORA

Cardiology Today VOL.XXII NO. 5 SEPTEMBER-OCTOBER 2018 145

FOR MARKETING QUERIESAparna Mayekar: +91-9930937020+91-22-6612 [email protected]

FOR EDITORIAL QUERIESDr Gandhali : +91-22-6612 [email protected]

©2018 CIMS Medica India Pvt Ltd (Previously known as UBM Medica India Pvt Ltd) Copyright in the material contained in this journal (save for advtg. and save as otherwise indicated) is held by CIMS Medica India Pvt Ltd Margosa Building, No. 2, 3rd Floor, 13th Cross, Margosa Road, Malleshwaram, Bengal uru-560 003, Karnataka, India. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright owner.

The products and services advertised are those of individual advertisers and are not necessarilty endorsed by or connected with the publisher or with Cardiology Today or CIMS Medica India Pvt Ltd. Cardiology Today does not guarantee, directly or indirectly, the quality or efficacy of any product or services described in the advertisements in this issue, which are purely commercial in nature.

The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions.

For reprints (minimum order: 500) contact the production Department. Further copies of Cardiology Today are available from CIMS Medica India Pvt Ltd, 709, Devika Tower, Nehru Place, New Delhi-110 019, India.

Cardiology Today is Published and Printed by CIMS Medica India Pvt Ltd, Margosa Building, No. 2, 3rd Floor, 13th Cross, Margosa Road, Malleshwaram, Bengaluru - 560 003, IndiaTel: +91-80-4346 4500 (Board); Fax: +91-80-4346 4530

Printed at Modest Print Pack (P) Ltd., C-52, DDA Sheds Okhla Industrial Area, Phase-I, New Delhi-110 020.

REVIEW ARTICLENutraceuticals: The New Age Therapeutics and Its Effect on Heart Health 174SHIKHA SHARMA, REENA RAWAT, AASTHA JESSICA

ECG OF THE MONTHQT Interval 179SR MITTAL

PICTORIAL CMEUnusual Dominant Left Circumflex Artery 187MONIKA MAHESHWARI

146 Cardiology Today VOL.XXII NO. 5 SEPTEMBER-OCTOBER 2018

CORRIGENDUM“We regret the author sequence errors in the article “Challenges in Heart Failure Management” authors

name was wrongly published in the Cardiology Today March-April 2018 (Vol. XXII, No.2) issue. The sequence of the author names is as follows Mohit Bhagwati, Vidushi Rathi Ish, Pranav Ish, Rajeev Rathi. Dr. Mohit Bhagwati is Senior Resident, Cardiology, Max Super Specialty Hospital Saket New Delhi; Dr. Vidushi Rathi Ish is Senior Resident, Department of Pulmonary Medicine and Critical Care, Safdarjung Hospital, New Delhi and Dr. Pranav Ish is Assistant Professor Department of Pulmonary Medicine and Critical Care, Safdarjung Hospital, New Delhi.”

Cardiology Today VOL.XXII NO. 5 SEPTEMBER-OCTOBER 2018 149

Healthy Diet – Watch Press !

EDITORIAL

Dime a dozen dietary plans and recommendations for health has left the medical community, as also the laity, bemused and confused as to what to eat and what not. Something which was considered a total pariah, and therefore to be shunned in totality, has now become the elixir of life. The recently published Population Urban Rural Epidemiology (PURE) study1 has endorsed eating dairy products, including full- fat ones at lib. It was shown that consumption of at least two servings of dairy products daily was linked with a much lower risk of mortality or major adverse cardiovascular events (MACE) of nonfatal myocardial infarction (MI), stroke or heart failure (Hazard ratio 0.84, P - 0.0004) - (Ref Fig 1). When they specifically looked for whole-fat versus low-fat dairy products, they found that whole-fat products had lower risk of mortality and MACE than limited consumption of dairy products and there was no difference from even low-fat diets. The association was at best modest for major cardiovascular outcomes, but there was a strong association with overall mortality and non-cardiovascular outcomes like malignancies and respiratory events. Surprisingly consumption of even unprocessed red meat was associated with improved outcomes!

Looking at individual components of the dairy products the authors found that the composite endpoints were lower with more than one serving per day of milk (p-0.0529) and yoghurt (0.0051), but that was not significant for cheese (p-0.1399) and butter (0.4113). The authors, Dehghan et al try to explain these beneficial aspects of dairy products based on their containing potentially beneficial compounds like amino acids, medium and odd chain saturated fats, natural trans fats, vitamin K1 and K2 and calcium, besides fermented ones containing even probiotics influencing health outcomes.

DR. OP YADAVACEO and Chief Cardiac Surgeon

National Heart Institute,New Delhi

Endpoint No Dairy Intake (%)

High Dairy Intake (>2 Servings/ Day) (%)

Hazard Ratio (95% Confidence Interval)

P Value for Trend

Composite outcome 8.7 6.6 0.84 (0.75 - 0.94) .0004

Total mortality 5.6 3.4 0.83 (0.72 - 0.96) .0052

Non-cardiovascular mortality 4.0 2.5 0.86 (0.72 - 1.02) .046

Cardiovascular mortality 1.6 0.9 0.77 (0.58 - 1.01) .029

Major CVD 4.9 3.5 0.78 (0.67 - 0.90) .0001

Stroke 2.9 1.2 0.66 (0.53 - 0.82) .0003

MI 1.6 1.9 0.89 (0.71 - 1.11) .163

Heart failure 0.3 0.5 1.06 (0.71 - 1.57) .90

Table 1: PURE Study - Dairy Intake Vs Outcomes1

150 Cardiology Today VOL.XXII NO. 5 SEPTEMBER-OCTOBER 2018

Study was conducted across five continents and the results were consistent across all of them. However the results were strongest and most glaring in geographical locations with lowest mean intake of dairy foods like Asia and Africa. This therefore becomes all the more relevant and important to a country like India, which has high prevalence of cerebro-vascular atherosclerotic disease and where milk and milk products are easily available, especially in rural areas.

Should the study be taken as the gospel truth and we make radical changes to a diet? Obviously wisdom dictates - No. The evidence is compelling because of the large data mass covering 1,36,384 individuals across 21 countries, however it is not confirmatory. The authors themselves acknowledge,” Our study is an observational study and we report association between exposure and outcome, but we cannot prove any causality”. Though the ACC/AHA guidelines still recommend fat free and low-fat diet,s we should evolve our own guidelines and may be allow consumption of these products. The conventional wisdom of reducing LDL-cholesterol is not challenged and the importance of lifestyle interventions in terms of regular exercise, stress relief, yoga and meditation and basic tenets of good and healthy living still reign supreme.

The focus now seems to be shifting from individual nutrients to food in generic terms. As Andrew Mente, a leading nutrition expert from McMaster University quipped in a commentary on Medscape,” If you look at trials like the Women’s Health Initiative trial, where the focus was on nutrients, the effect was completely neutral. The PREDIMED trial, which focused on certain functional foods, had a much larger effect – about a 30% lower risk for major cardiovascular events and mortality compared with the control diet. We think the focus should be on foods instead of nutrients. When you are at a restaurant, you are not ordering nutrients, you are ordering food. This is easy for the public to translate into diet”. Even the recent brouhaha against carbohydrate is just as unjustified as the one against fats in the 1960s and 70s. Major part (55%) of the total calorie intake should come from the carbohydrates and diet should be balanced in its composition of carbohydrates, fats and proteins. It is therefore very important that we inform the masses against processing of the food and the risks associated with using refined carbohydrates, simple sugars and trans fats rather than scaring them by using generic terms like carbohydrates and fats. As the proverb goes, “God sent food, the devil sent the cook”, the public should be sensitised to the harm caused by food handling and cooking. Further they should be exhorted to follow the path of moderation and to consume diversified and balanced food, including oils.

Mantra : Shun nothing, consume nothing in excess.

Healthy eating in the ‘Festive Season’.

REFERENCE1. Dehghan M, Mente A, Rangarajan S et al Association of dairy intake with cardiovascular disease and mortality in 21

countries from five continents (PURE): A Prospective cohort study Lancet 2018; DOI: 10. 1016/S0140 – 6736(18) 31812 – 9.

Cardiology Today VOL. XXII NO. 5 SEPTEMBER-OCTOBER 2018 151

PCSK9 Inhibitors

REVIEW ARTICLE

NITIN AGGARWAL, HARSH WARDHANKeywords z 3-methylglutarylcoenzyme z PCSK 9 z humanized monoclonal antibody z statin monotherapy z LDL-C

Dr. Nitin Aggarwal is Senior Interventional Cardiologist, Rajiv Gandhi Cancer Institute and Research Centre Rohini, Sri Balaji Action Hospital Paschim Vihar Delhi, FIMS Hospital, Sonepat and Dr. (Prof) Harsh Wardhan is Head of Department of Cardiology, Primus Super Speciality Hospital, Chanakyapuri, New Delhi

AbstractAtherosclerotic cardiovascular disease (ASCVD) is associated with significant morbidity and mortality worldwide. Increased serum levels of low-density lipoprotein cholesterol (LDL-C) is an independent risk factor for ASCVD and clinical trial data have shown that lowering LDL-C generally reduces cardiovascular risk. Until recently, 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors (statins) have been the main therapy for lowering LDL-C. However, some statin-treated patients have persistently elevated residual cardiovascular risk due to the inadequate lowering of LDL-C levels or non-LDL-related dyslipidemia and in addition, the adverse effects of statins mainly statin-associated muscle symptoms (SAMS), may limit their tolerability and therefore the ability to attain effective doses in some patients. A new class of drugs that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed to treat hyperlipidemia. This review will explore the biology of PCSK 9, clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9.

LDL-CHOLESTEROL METABOLISMLDL-C has been the target of therapy for improving outcomes in patients at high risk for developing CVD and has been considered a surrogate endpoint for clinical events by the FDA.1 Reviewing LDL cholesterol metabolism is therefore important in understanding therapeutic approaches to treat hyperlipidemia.

The lipid cycle begins with the release of immature very low-density

lipoprotein (VLDL) or nascent VLDL from the liver. Nascent VLDL contains apolipoprotein-B100 (apoB-100), apolipoprotein E (apoE), apolipoprotein C1 (apoC1), cholesteryl esters, cholesterol, and triglycerides. While circulating in blood, high-density lipoprotein (HDL) donates apolipoprotein C-II (apoC-II) to nascent VLDL that leads to its maturation. Mature VLDL interacts with lipoprotein lipase (LPL) in the

152 Cardiology Today VOL. XXII NO. 5 SEPTEMBER-OCTOBER 2018

capillary beds of adipose tissues, cardiac muscle and skeletal muscle cells, which leads to extraction of triglycerides from VLDL for storage or energy production in these tissues. VLDL combines with HDL again and an interchange occurs where apoC-II is transferred back to HDL along with phospholipids and triglycerides in exchange for cholesteryl esters via cholesteryl ester-transfer protein (CETP). This exchange and removal of triglycerides leads to conversion of VLDL to intermediate-density lipoprotein (IDL).2 Half of IDLs are recognized and endocytosed by liver cells due to apoB-100 and apoE. The remaining IDL lose apoE, and with an increased concentration of cholesterol compared to triglyceride, transform into low-density lipoproteins (LDL). LDL particles thus formed contain apoB-100, which acts as a ligand for binding to LDL receptors (LDLR). Once LDL binds to LDLR, LDL/LDLR complex is internalized by endocytosis into clathrin-coated vesicles. In the cytosol, LDL and LDLR separate with recycling of LDLR to the cell surface. LDLR recycling is a continuous process and each receptor recycles up to 150 times after which they are endocytosed and metabolized.3 Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is involved in intracellular production of cholesterol. This lowers the levels of intracellular cholesterol leading to increased expression of LDLR on cell surfaces causing a reduction in serum LDL cholesterol.

Seidah and colleagues discovered that proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDLR degradation and could potentially be a target for modulating LDLR expression and consequently LDL-C levels.4,5 PCSK9 is a hepatic protease that attaches to and internalizes LDLR into lysosomes hence promoting their destruction.6 Clinical studies have shown that PCSK9 gain of function (GOF) mutation is associated with familial hypercholesterolemia and premature CVD, while individuals with loss of function (LOF) mutations in PCSK9 have been observed to have lower lifetime levels of LDL-C and lower

prevalence of CVD.7,8

Since the discovery of PCSK9, results from preclinical mice studies demonstrated that sterol regulatory element binding protein-2 (SREBP-2) plays a key role in regulating cholesterol metabolism. Low level of intracellular cholesterol activates SREBP-2 and leads to LDLR gene expression. This increases LDLR concentration thus enhancing LDL clearance from circulation.5,9 SREBP-2 also induces the expression of PCSK9, which promotes LDLR degradation. Thus, the coordinated interplay of SREBP-2 induced transcription of both LDLR and PCSK9 regulates circulating LDL levels.10 These discoveries resulted in the exploration and development of therapeutic agents to lower LDL levels by targeting PCSK9 activity.

PCSK9 STRUCTURE AND FUNCTIONThe gene for PCSK9 is located on chromosome 1p32 and codes for a 692-amino-acid serine protease10. PCSK9 is primarily expressed in the liver, but lower levels of protein expression have also been found in the intestine, kidney, and central nervous system. Transcription of PCSK9 is primarily regulated by sterol regulatory element-binding protein-2. In the hepatocyte,

PCSK9 is synthesized as a zymogen, requiring activation by another enzyme; it is composed of a signal peptide, a prosegment, a catalytic domain, and a C-terminal domain.11 In the endoplasmic reticulum, PCSK9 undergoes cleavage of its signal peptide and undergoes cotranslational autocatalytic cleavage into a prosegment and a mature protein, the latter of which is required for secretion from the endoplasmic reticulum to the Golgi body. Unique to PCSK9, the prosegment remains associated with the mature protein, facilitating protein folding, preventing enzyme activity by blocking access to the catalytic site, and chaperoning PCSK9 through the secretory pathway.

PCSK9 INHIBITORS – HOW THEY ACT?Multiple strategies of PCSK9 inhibition are currently under investigation.12 1. The first approach prevents binding

of PCSK9 to the LDL-R. Examples of this approach include monoclonal antibodies or adnectins, also termed monobodies (Figure 1). Monoclonal antibody therapeutic agents include Evolocumab, Alirocumab and Bococizumab. These bind the catalytic domain and prodomain

Figure 1. The role of PCSK9 in LDL-R metabolism. When PCSK9 levels are high, the degradation of the LDL-R through extracellular and intracellular pathways is enhanced, resulting in increased degradation of the PCSK9–LDL-R complex in lysosomes. Low surface LDL-R levels lead to greater levels of circulating LDL-C. Conversely, if PCSK9 levels are low, then cell surface LDL-R levels are high, and LDL-R can be recycled to the cell surface after delivery of LDL-C particles to endosomes, resulting in lower circulating LDL-C levels. PCSK9 activity via the extracellular pathway can be inhibited by monoclonal antibodies (mAb) or adnectins

REVIEW ARTICLE


of PCSK9, blocking interaction with the LDL-R and neutralizing PCSK9 activity. Studies have shown maximal suppression of circulating unbound PCSK9 within 4–8 h after administration of the monoclonal antibody,13 with reductions in LDL-C of ~65% in healthy subjects and ~60–80% in patients with hypercholesterolemia.14

2. The second major strategy for PCSK9 inhibition is directed toward PCSK9 synthesis and processing. Small interfering RNAs (siRNAs) are molecules that can be used to target PCSK9mRNA and arrest translation, leading to mRNA degradation. In a phase I clinical trial, the anti-PCSK9 siRNA ALN-PCS reduced free PCSK9 levels by 70% and LDL-C levels by 40%.15

3. Another approach to silence mRNA is the use of antisense oligonucleotides, which are short nucleic acid sequences that bind to mRNA. The data from animal studies demonstrated reductions in circulating PCSK9 and LDL-C levels.

LIPID EFFECTS OF PCSK9 INHIBITORSPCSK9inhibitioncansignificantlylowerLDL-C concentrations in humans, even on a background of statin therapy. Pa-tient populations studied in clinical trials range from those at low CV risk to the very-high-CV-risk population of indi-viduals homozygous for familial hyper-cholesterolemia (HoFH). Utilization of monoclonal antibodies has been the most effective approach thus far in inhibit-ing PCSK9 and reducing LDL levels. Currently, at least six monoclonal an-tibodies (mAb) have been or are being developed and tested: Alirocumab (for-merly called SAR236553/ REGN727), Evolocumab (formerly called AMG145), RG7 652[45], LGT209 (NCT01979601, NCT01859455), 1B20[46] and Bococi-zumab (formerly called RN316/PF-049 50615).

The FDA approved Evolocumab (Repatha) and Alirocumab (Praluent) in 2015 for adult patients with heterozygous familial hypercholesterolemia, homozy-

gous familial hypercholesterolemia or in patientswithclinicallysignificantathero-sclerotic CVD requiring additional LDL lowering after being on diet control and maximally tolerated statin therapy.

EVOLOCUMABEvolocumab has been tested in multiple randomized controlled trials, including several 12-week trials involving >3,000 patients, one 52-week trial involving 901 patients,16 and the recently published, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial.17 The lipid-lowering effects ofEvolocumab were consistent in these trials except for lesser LDL-C reductions in the HoFH population than expected, given its mechanism of action requiring the presence of LDL receptors.

Evolocumab was initially studied as monotherapy in patients at low CV risk,18 in patients on statin therapy,19 in “statin-intolerant” patients,20 in patients with heterozygous familial hypercholesterolemia (HeFH) and LDL ≥100 mg/dl,21 and in HoFH patients.22 The range of LDL-C lowering in these trials was −48% to −66.1%, with anabsolute reduction in LDL-C of up to −90.8 mg/dl from baseline. Thelongest of these trials was the Durable Effect of PCSK9 Antibody Comparedwith Placebo Study (DESCARTES), a randomized double-blind placebo-controlled trial that compared the effectof evolocumab with placebo in patients with hyperlipidemia.16 Patients received the study drug for 52 weeks after a run-in period of 4–12 weeks of background lipid-lowering therapy which could consist of diet alone, Atorvastatin 10 mg or 80 mg, or Atorvastatin 80 mg with Ezetimibe 10 mg daily. The mean LDL-C concentration in study drug at baseline was 104.2 mg/dl, and the mean LDL-C concentration at week 52 was 50.9 (±1.4) mg/dl,, representing a mean reduction of 50.1% (±1.2), while there was an increase in 57% LDL-C in the placebo group by week 52.

Additional support for durable LDL-C lowering with Evolocumab came from the Open-Label Study of “Long-Term

Evaluation Against LDL-C” (OSLER) Randomized Trial, which lasted 52 weeks.23 In OSLER, a total of 1,104 (81%) patients agreed and were randomized 2:1 to receive open-label subcutaneous (SC) evolocumab 420 mg every four weeks with standard of care (SOC) (N=736) or SOC alone (N=368), regardless of treatment assignment in the parent study. Patients without prior evolocumab exposure had a mean reduction in LDL-C of 52.3% at week 52 (p < 0.0001). Patients who received one of six dosing regimens of Evolocumab in the parent studies and received Evolocumab plus SOC in OSLER had a mean reduction in LDL-C of 50.4% at the end of the parent study and a persistent reduction of 52.1% at 52 weeks (p=0.31). Patients who were on evolocumab when they entered OSLER and were randomized to SOC alone exhibited a return of LDL-C levels to near baseline levels.

Evolocumab has also been shown to be efficacious in patientswith heterozygous and homozygous familial hypercholesterolemia. In the RUTHERFORD-2 trial,21 329 patients with heterozygous familial hypercholesterolemia were randomized to receive Evolocumab (140 and 420 mg respectively) or placebo at two weekly and monthly regimens. Evolocumab showed a significant reduction in LDLwith both regimens: 140 mg every 2 week led to 59.2% reduction and 420 mg once a month led to LDL reduction by 61.3% as compared to placebo after 12 week (p < 0.001 for all). The TESLA trial22 examined 50 patients with homozygous familial hypercholesterolemia on stable lipid lowering therapy and evaluated monthly Evolocumab (420 mg) vs. placebo therapy for 12 wk. Addition of Evolocumabledtoasignificantreductionin LDL-C by up to 31% (p < 0.0001).

The recent FOURIER trial17 enrolled 27,564 patients with prior ASCVD with an additional high risk feature who were receiving maximally tolerated statin (two-thirds were being treated with a high intensity statin) but who still had an LDL-C>70 mg/dl or a non-HDL cholesterol >100 mg/dl. Patients were randomized to receive subcutaneous


proved to be significant, including non-HDL-C, apoB, Lp(a), fasting triglycerides , and HDL-C all p < 0.001 versus placebo control.

Clinical outcomes after treatment with alirocumab were studied in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) in patients after acute coronary syndrome treated with maximally tolerated statin therapy.26 In this trial, 18,924 patients were randomized to treatment with either Alirocumab or placebo. This trial used a novel treat-to-target design, with all patients receiving 75 mg of Alirocumab every 2 weeks, and the dose was increased to 150 mg every 2 weeks if the LDL-C did not fall <50 mg/dl. A total of 1,955 patients experienced a primary endpoint (CHD death, nonfatal MI, fatal and nonfatal ischemic stroke, or unstable angina requiring hospitalization), 903 (9.5%) and 1,052 (11.1%) in those assigned Alirocumab and placebo, respectively, for an absolute risk reduction of 1.6% (p< 0.0003). Secondary efficacy endpointsthatwere significantly reduced includedmajor CHD event, cardiovascular event, MI, or ischemic stroke. Although it could not be evaluated as part of hierarchical testing, all-cause mortality was lower with alirocumab at 3.5% versus 4.1% (p < 0.026).

Alirocumab has also been studied in >800 patients with HeFH27,28 including those with very high LDL-C of 160 mg/dl or above, causing a least squares mean change in calculated LDL-C at week 24 ranging from −39.1% to −57.9%compared with placebo and an absolute change in LDL-C from baseline of up to −75.3mg/dlcomparedwithplacebo.

BOCOCIZUMABBococizumab is a humanized monoclonal antibody that retains ~3% murine sequences. The murine component has been shown to stimulate the production of high titers of antidrug antibodies in some patients, which directly attenuates the LDL-C lowering response and duration.

The SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular

injections of Evolocumab (either 140 mg every 2 weeks or 420mg every month based on patient preference) or matching placebo. Evolocumab reduced LDL-C by 59% from a median of 92 mg/dl to 30 mg/dl. After an average 2 years of follow-up, the composite of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for angina, or revascularization occurred in 11.3% versus 9.8% of the placebo group, a 15% relative risk reduction (p <0.001). The endpoint of cardiovascular death, MI, or stroke was reduced by 20%, from 7.4% to 5.9% (p < 0.001).

ALIROCUMABAlirocumabwasthefirstPCSK9inhibitorapproved by the US Food and Drug Administration (FDA), in July 2015, for use in addition to diet and maximally tolerated statin therapy in adult patients with HeFH or patients with clinical ASCVD who require additional lowering of LDL cholesterol.24

“The Long-Term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy” (ODYSSEY LONG TERM) trial was a large phase III randomized double-blind placebo controlled parallel-group multinational study conducted at 320 sites in 27 countries throughout Africa, Europe, and North and South America.25 This trial enrolled 2,341 patients at high-risk for CV events with LDL-C levels of at least 70 mg/dl while receiving treatment with statins at the maximum tolerated dose, with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo SC every two weeks for 78 weeks. The primary efficacy endpointwas the percentage change in calculated LDL-C from baseline to week 24. The baseline LDL-C was ~122 mg/dl in each group and decreased to 48.3 mg/dl in the alirocumab group and 118.9 mg/dl in the placebo group, representing a percentage changeof−61%and0.8%, respectively(p < 0.001). The least squares mean differences in other lipid elements also

Events) program consisted of 2 clinical trials (SPIRE-1 and SPIRE-2) that were terminated early. These trials evaluated ASCVD in 27,438 patients scheduled to receive Bococizumab (at a dose of 150 mg SC) every 2 weeks or placebo.29 The primary endpoint included nonfatal MI, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. The mean group difference inLDL-C between the treatment groups was 59.0% (p < 0.001). In a trial of lower-risk patients with baseline LDL-C level of >70 mg/dl and a shorter median follow-up of 7 months, there were no differences in major ASCVD events (p = 0.94). In the trial of higher-risk patients with a baseline LDL-C >100 mg/dl and a longer median follow-up of 12 months, major ASCVD events were reduced (p = 0.02). The HR for the primary endpoint in the combined trials was 0.88 (p = 0.08). Injection-site reactions were more frequent in the Bococizumab group than in the placebo group (10.4% vs. 1.3%; p < 0.001).

The major limitation of SPIRE was development of high-titer antidrug antibodies, which markedly diminished the magnitude and durability of the reduction in LDL-C levels.30 Because of the frequent antidrug antibodies, the sponsor terminated the clinical development program with Bococizumab.

PHARMACOKINETICS AND PHARMACODYNAMICSThe pharmacokinetic and pharmaco-dynamic parameters of PCSK9 inhibitors are described below.31,32

ALIROCUMABThe time taken to reach maximum serum concentration is 3-7 day with similar serum concentration - time profilesbetween abdomen, upper arm or thigh as the sites of injection. Steady state concentrations are reached at an average of 3 to 4 doses. The volume of distribution following intravenous administration is 0.04 to 0.05 L/kg. The median half-life (t 1/2) observed was between 17 to 20 day at 75 or 150 mg dosing every 2 week. Alirocumab is eliminated in two phases

REVIEW ARTICLE


Familial Hypercholesterolemia (FH) is a common autosomal genetic disorder, with prevalence of - 1 in 250 people for heterozygote and 1 in 300,000 for homozygote. Before the PCSK9 inhibitor era, the standard of care for heterozygous FH was statin drugs, often in combination with oral nonstatin agents and extracorporeal apheresis of LDL particles, performed weekly or biweekly. FH is an FDA-approved indication for both PCSK9 inhibitors.34-36 When given with standard therapies to heterozygous FH patients, Evolocumab and Alirocumab further reduced LDL-C by 51% to 61% compared with placebo. Studies with both PCSK9 inhibitors have shown that between 60% and 80% of FH patients could attain the strict guideline recommended LDL-C targets compared with <5% of patients randomized to placebo. The TAUSSIG trial (NCT01624142) is evaluating Evolocumab therapy in 300 patients with severe familial hypercholesterolemia to determine its efficacy and side effectprofile. The results of this study areanticipated by March 2020. PSCK9 inhibitors improve other clinical endpoints in FH, including regression of tendinous xanthomas37 and reduced frequency of apheresis treatments.38

Statin-associated muscle symptoms (SAMS)-. Muscle intolerance is the most common reason why patients discontinue statin treatment. Statin down titration or discontinuation increases the risk of cardiovascular events in patients previously hospitalized for an MI and of mortality in other high-risk patients.39 Several trials have evaluated the safety and efficacyofPCSK9 inhibitors inpatientswho report statin associated muscle symptoms (SAMS).40-41 GAUSS-2 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects- 2) included 307 patients at high cardiovascular risk who reported SAMS with least 2 different statins.40 This trial compared the efficacy of Evolocumab140 mg every 2 weeks or 420 mg monthly, with or without Ezetimibe. None of the participants discontinued the study drug because of muscle-related adverse events. Although it confirmed a potent LDLC–

depending upon its plasma concentration. The predominant mode of elimination at lower concentrations is via saturation of the targets (PCSK9) bound to the antibodies; however, at higher concentrations it is primarily through photolytic pathways.21 The maximum reduction in free plasma PCSK9 levels and LDL was observed within 3 and 15 day respectively, after drug administration with no differencenoted between different sites. No doseadjustment is needed for patients with mild or moderately impaired renal or hepatic function. No data are available in patients with severe renal and hepatic impairment.

EVOLOCUMABThe pharmacokinetic and pharmacodynamic properties of Evolocumab23 demonstrate non-linear pharmacokinetics in absorption at doses below 140 mg; however, between doses of 140 to 420 mg linear pharmacokinetics is observed. The time to reach maximum concentration is 3 to 4 d after a single dose. After a single 420 mg dosage, its volume of distribution has been estimated to be 3.3 L ± 0.5 L. A steady state in serum is observed after about 12 wk of dosing. The t1/2 of Evolocumab is between 11 to 17 d. The maximum reduction of LDL after therapy was similar after dosing of 140 mg every 2 week or 420 mg once a monthwitheffectwithin14day.Clinicalstudies have not revealed a differencein pharmacokinetics of Evolocumab in mild or moderate renal and hepatic impairment. However, subjects with severe renal and hepatic impairment have not been studied.

ADVERSE EFFECTS AND CONTRAINDICATIONSThe most common adverse effectsobserved include nasopharyngitis, injection site reactions (erythema, itchiness, swelling, pain or tenderness) ,influenza, urinary tract infection,diarrhea, bronchitis, myalgia, muscle spasms, sinusitis, cough, contusion and musculoskeletal pain. The most common adverse events that lead to drug discontinuation were allergic reactions and elevated liver enzymes. Other serious

adverse events noted were cardiac disorders in 2.4% including palpitations (0.6% vs 0.3% in placebo), angina pectoris (0.3% vs 0.2% in placebo), and ventricular extra systoles (0.3% vs 0.1% in placebo). Both the drugs are contraindicated in patients who develop serious hypersensitivity reactions like hypersensitivity vasculitis or allergic reactions requiring hospitalization with its usage. In addition, data from trials evaluating Evolocumab and Alirocumab have shown a higher incidence of cognitive adverse events in patients treated with PCSK9 inhibitors (0.9% vs 0.3%) for Evolocumab compared to standard care23 and (1.2% vs 0.5%) for Alirocumab compared to placebo.

CLINICAL EFFECTS OF PCSK9 INHIBITORSAtherosclerotic Cardiovascular Disease (ASCVD) - Although statins have a long history of providing clinical benefit,not all drugs that lower LDL-C using other mechanisms have shown similar results. The effect of PCSK9 inhibitionon atherosclerosis was studied in the GLAGOV (Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound) trial.33 In GLAGOV, 968 patients with coronary artery disease were treated with the PCSK9 inhibitor Evolocumab or placebo monthly for 1.5 years. On serial intravascular ultrasound, the lower LDL-C levels in the evolocumab group versus placebo (36.6 mg/dl vs. 93.0 mg/dl) were associated with a reduction in percent atheroma volume (-0.95% vs. +0.05%; p < 0.001), and a greater percentage of treated patients showed plaque regression (64.3% vs. 47.3%; p < 0.001). This trial demonstrated that LDL-C lowering with the addition of Evolocumab to statin therapy induced atheroma regression.

Most recent data from large CV outcome trials for alirocumab25,26 and Evolocumab,17 have shown significantreduction in the composite CV endpoint included death from CHD, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.


loweringeffectwithgoodtolerability,theduration of this study was only 12 weeks. ODYSSEY ALTERNATIVE compared Alirocumab with Ezetimibe in patients at moderate to high cardiovascular risk with SAMS because of the inability to tolerate statins, including one at the lowest approved starting dose.41 Despite a history of statin-intolerance, 66% of patients in the Atorvastatin and Ezetimibe arms completed the double-blind treatment, compared with 76% in the alirocumab group.

HOW MUCH LOW IS LOW LDL-C!!!There has been ongoing extensive debate on whether a target LDL-C level should be used in practice. In the CTT (Cholesterol Treatment Trialists) meta-analysis, a 38.6 mg/dl (1 mmol/l) reduction in LDL-C was associated with a 21% reduction in ASCVD events, regardless of baseline LDL-C.42 This prompted the 2013 ACC/ AHA guideline to recommend against the use of absolute target levels.1 With the benefits seen in the PCSK9 trials,some have questioned whether there should be an even lower LDL-C target. This reasoning is supported by 3 large RCTs, which tested 3 different classesof LDLC– lowering drugs in statin-treated patients. In each case, additional reduction in CVD events was seen in patients with achieved LDL-C levels <55 mg/dl. The IMPROVE-IT trial added Ezetimibe to statins, achieving an LDL-C of 54 mg/dl compared with 69 mg/dl for statin only.43 In the FOURIER trial,17 evolocumab reduced the LDL-C to 30 mg/dl compared with 90 mg/dl with statin only and most recently, the REVEAL (RandomizedEvaluationoftheEffectsofAnacetrapibThroughLipidModification)trial44 showed that Anacetrapib reduced LDL-C to <50 mg/dl compared with 61 mg/dl in the statin monotherapy group. All3trialsshowedsignificantreductionsin ASCVD events with treatment over statin alone, which suggests that further benefit can be achieved, evenamong patients whose baseline LDL-C is near 70 mg/dl. These trials provide evidence for a lower LDL-C target of <50 mg/dl., for primary prevention, National Cholesterol Education Program

guidelines have generally had a target about 30 mg/dl higher, so a target LDL-C range could be <100 mg/dl. This latter target is supported by the most recent primary prevention trial, HOPE 3 (Heart Outcomes Prevention Evaluation–3),45 in which baseline LDL-C was 127 mg/dl and was reduced to 90 mg/dl in the statin therapy group.

CONCLUSIONSPCSK9 drugs represent a novel approach to achieving substantial reductions in LDL-C concentrations in a variety of patient populations at high CV risk even on a background of maximally tolerated statin therapy. PCSK9 therapy is a welcome treatment option for statin intolerant patients who require treatment of their hyperlipidemia. It is important that patients should not be under-prescribed statins nor be dissuaded from attempting tofindadoseof statinagentthat is well tolerated by them, because PCSK9 inhibitors are available. The net clinical benefitof the class also appearsfavorable, without major safety signals regarding neurocognition or an increased risk of diabetes. Despite these obstacles, PCSK9 inhibitors are an exciting agent for reducing LDL-C hyperlipidemia and have ushered in a new era of lipid-lowering therapy.

REFERENCES1. Stone NJ, Robinson JG, Lichtenstein AH,et .al. 2013 ACC/

AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63: 2889-2934

2. Shelness GS, Sellers JA. Very-low-density lipoprotein assembly and secretion. Curr Opin Lipidol 2001; 12: 151-157

3. Goldstein JL, Brown MS, Anderson RG, et.al . Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol 1985; 1: 1-39

4. Seidah NG, Benjannet S, Wickham L, et.al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 2003; 100: 928-933

5. Abifadel M, Varret M, Rabès JP, et.al . Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154-156

6. Lambert G, Sjouke B, Choque B, et.al . The PCSK9 decade. J Lipid Res 2012; 53: 2515-2524

7. Tibolla G, Norata GD, Artali R, et.al.. Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition. Nutr Metab Cardiovasc Dis 2011; 21: 835-843

8. Davignon J, Dubuc G, Seidah NG. The influence of

PCSK9 polymorphisms on serum low-density lipoprotein cholesterol and risk of atherosclerosis. Curr Atheroscler Rep 2010; 12: 308-315

9. Denis M, Marcinkiewicz J, Zaid A, et.al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 2012; 125: 894-901

10. Horton JD, Shah NA, Warrington JA,et .al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo controlled, phase 1 trial. Lancet 2014; 383: 60-68

11. Bergeron N, Phan BA, Ding Y, et al. Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. Circulation. 2015 132:1648–66

12. Burke AC, Dron JS, Hegele RA, et al. PCSK9: Regulation and target for drug development for dyslipidemia. Annu. Rev. Pharmacol. Toxicol 2017. 57:223–44

13. Sible AM, Nawarskas JJ, Anderson JR.. PCSK9 inhibitors: an innovative approach to treating hyperlipidemia. Cardiol. Rev 2016. 24:141–52

14. Stein EA, Mellis S, Yancopoulos GD, et al.. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med 2012. 366:1108–18

15. Fitzgerald K, Frank-KamenetskyM, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014 . 383:60–68

16. Blom DJ, Hala T, Bolognese M, et al.. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med 2014. 370:1809–19

17. Sabatine MS, Giugliano RP, Keech AC, et al.. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med 2017. 376:1713–22

18. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012, 380:1995–2006

19. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012, 380:2007–17

20. Sullivan D, Olsson AG, Scott R, et al.. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012, 308:1–10

21. Raal FJ, Stein EA, Dufour R, et al.. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015,385:331–40

22. Raal FJ, Honarpour N, Blom DJ, et al.. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015, 385:341–50

23. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014, 129:234–43

24. Food and Drug Administration. 2015. FDA approves Praluent to treat certain patients with high cholesterol: first in a new class of injectable cholesterol-lowering

REVIEW ARTICLE


drugs. News release.https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm455883.htm. Accessed Apr. 8, 2015

25. Robinson JG, Farnier M, Krempf M, et al. 2015. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372:1489–99

26. Steg P. Cardiovascular outcomes with alirocumab after acute coronary syndrome: results of the ODYSSEY Outcomes Trial. Presented at: American College of Cardiology Annual Scientific Sessions; March 10, 2018; Orlando, FL

27. Kastelein JJ, Ginsberg HN, Langslet G, et al. 2015. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart J. 36:2996–3003

28. Ginsberg HN, Rader DJ, Raal FJ, et al. 2016. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc. Drugs Ther. 30:473–83

29. Ridker PM, Revkin J, Amarenco P, et al., for the SPIRE Cardiovascular Outcome Investigators. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376: 1527–39.

30. Ridker PM, Tardif JC, Amarenco P, et al., for the SPIRE Investigators. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med 2017;376:1517–26.

31. Lunven C, Paehler T, Poitiers F, et al. A randomized study of the relative pharmacokinetics, pharmacodynamics, and safety of alirocumab, a fully human monoclonal antibody to PCSK9, after single subcutaneous administration at three different injection sites in healthy subjects. Cardiovasc Ther 2014; 32: 297-301

32. Cicero AF, Colletti A, Borghi C. Profile of evolocumab and

its potential in the treatment of hyperlipidemia. Drug Des Devel Ther 2015; 9: 3073-3082

33. Nicholls SJ, Puri R, Anderson T, et al. 2016. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 316:2373–84

34. Cuchel M, Bruckert E, Ginsberg HN, et al., European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management: a position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146–57.

35. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016;68:92–125.

36. Santos RD, Gidding SS, Hegele RA, et al., International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol 2016;4:850-61

37. Bea AM, Perez-Calahorra S, Marco-Benedi V, et al. Effect of intensive LDL cholesterol lowering with PCSK9 monoclonal antibodies on tendon xanthoma regression in familial hypercholesterolemia. Atherosclerosis 2017;263:92–6.

38. Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J 2016;37:3588–95

39. Serban MC, Colantonio LD, Manthripragada A, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol 2017;69:1386–95.

40. Stroes E, Colquhoun D, Sullivan D, et al., for the GAUSS-2 Investigators. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541–8.

41. Moriarty PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014;8: 554–61.

42. Baigent C, Blackwell L, Emberson J, et al., Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81.

43. Cannon CP, Blazing MA, Giugliano RP, et al., for the IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97.

44. The HPS3/TIMI55–REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217–27.

45. Yusuf S, Bosch J, Dagenais G, et al., for the HOPE-3 Investigators. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2021–31


Cardiovascular Disease, Obesity, MetS, T2DM and Aging, and Benefits of Calorie Restriction and Calorie Restriction Mimetics

REVIEW ARTICLE

VINOD NIKHRA

Keywords z calorie restriction z calorie restriction with adequate

nutrition z cardiovascular aging z cardiovascular disease z metabolic syndrome z neuro-degenerative disorders z reactive oxygen species z SIRT gene z type 2 diabetes mellitus

Dr Vinod Nikhra is Senior Consultant (Physician) and the Teaching Faculty at Hindu Rao Hospital, Delhi

AbstractLCR - THE CONCEPT: The energy needs are determined by the body composition, especially the fat-free lean mass and level of physical activity, and there is a change in nutritional needs during the middle age and later. The diet-gene interaction is a major determinant of health and illness, and the amount and type of food ingestion and caloric intake, in general, influence the health and lifespan. The excess calorie intake causes overnutrition and nutritional overload leading to increased adipose stores culminating as weight gain and obesity, which lead to insulin resistance (IR), metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and other metabolic alterations. At the subcellular and cellular level, there is increased potentially damaging exposure to reactive oxygen species (ROS). The Calorie restriction (CR) is a dietary intervention that reduces calorie intake without malnutrition or a deficiency of essential nutrients. CR MECHANISMS AND PATHWAYS: There have been identified several metabolic and genetic pathways that govern food ingestion, metabolism and lifespan. Experimentally, the CR has been shown to achieve increased lifespan in a broad spectrum of life forms from yeast, nematode, fruit fly, rodents and primates, including Homo sapiens, endorsing that a diet adequately fulfilling nutritional needs, but low in calories, may improve health, prevent many late-onset diseases and extend the life span. But, the benefits of CR are not a passive result of lower caloric intake but the consequence of an active regulatory


CALORIE RESTRCTION: THE CONCEPTALTERED NUTRTIONAL NEEDS DURING MIDDLE AGE AND LATERThe energy needs of individuals are determined by their body composition, especially the fat-free lean mass and level of physical activity. Most older adults lose fat-free mass as they age, with skeletal muscle being lost at a rate of approximately 1% per year in the over 70s1 and many are less physically active.2 Therefore, older adults have lower requirements for energy which may contribute to a reduction in appetite. Itisvariesbetweenindividualsreflectingdifferencesintheirbodycompositionandlevels of physical activity. Further, there is a change in nutritional needs during the middle age and later, when no actual growth is taking place, though there is an increased need of nutrients to take care of increased wear and tear with age, but overall calorie requirements are less because of a sedentary nature of activity of daily living (ADL).

The diet-gene interaction is a major determinant of health and illness.3 The amount and type of food ingestion and caloric intake influence the generalhealth and lifespan.4 The extra calorie intake due to availability of palatable food and increased consumption causes overnutrition and nutritional overload,5 giving rise to excess stores in adipose tissue reservoirs culminating as weight gain and obesity, which lead to insulin resistance (IR), metabolic syndrome

(MetS), type 2 diabetes mellitus (T2DM) and other metabolic alterations. At the subcellular and cellular level there is increased potentially damaging exposure to reactive oxygen species (ROS). The calorie restriction, or caloric restriction, or energy restriction, is a dietary intervention that should reduce calorie intake without incurring malnutrition or a reduction in essential nutrients.6

The calorie restriction (CR) has been generally defined as consumption of anutritious diet that is about 40% less in calories compared to ad libitum diet. Optimal food intake and calorie restriction with adequate nutrition (CRAN) promote health, metabolic homeostasis, disease protection and long life, in general. The focus of positive lifestyle changes is often on a healthy diet and adequate exercise to minimize the risk of diseases like diabetes, hypertension and cardiovascular disease especially during the middle age and older years. The modality, CR is like going a step further.

PHYSIOLOGICAL EFFECTS OF CALORIE RESTRICTED DIETSeveral metabolic and genetic pathways have been identified that govern foodingestion, metabolism, and lifespan.7 Various studies in yeast, fruit fly,nematodes like C elegans, rodent models and primates (including Homo sapiens) endorsethatadietisadequatelyfulfillingnutritional needs, but low in calories may improve health and extend the lifespan.8 Experimentally, the food restriction has

been shown to achieve increased lifespan in a broad spectrum of life forms from yeast9 to primates.10 The early nutritional studies in rodents indicated that the number of calories in the diet was the key factor, thus the term calorie restriction.11 Atthephysiological level, theeffectsofCR are very well characterized, beginning with an acute phase upon imposition of the diet followed by an adaptive period of several weeks to reach a stable, altered physiological state.12 A lower body temperature, lower blood glucose and insulin levels, and reduced body fat and weight characterize this modified state.The CR animals also appear to be more resistant to external stressors, including heat and oxidative stress.13

Evolutionarily, CR may represent an adaptation to food scarcity. Any organism that could slow aging and reproduction in times of scarcity and remain able to reproduce when food reappeared would enjoy an advantage.14 In lower organisms, this strategy may lead to the building of specialized body forms for survival, for example, spores in microbes and dauer larvae in C. elegans.15 The animals have reduced energy stores, i.e., glycogen and fat. About the change in metabolic rate, the initial studies reported a reduction in metabolic rate in CR animals. This finding fits well with the theory thatoxidative damage from reactive oxygen species (ROS) is reduced, and a reduction in metabolic rate would decrease ROS production during electron transport and respiration. However, other studies found

intervention, mimicking certain food scarcity activating genetic and metabolic programs that result in various vital beneficial effects. The genetic and molecular studies in model organisms, in fact, suggest that CR is a regulated process, in which the SIRT (Silent Information Regulator 2) gene plays an important role.IMPACT OF CR ON HEALTH AND DISEASE: CR has long been identified for its ability to extend lifespan and mitigate aging and disease processes in various tissues. The data from animal and human studies indicate that CR affects several metabolic and molecular factors that modulate age-related cardiovascular alterations including cardiac and arterial stiffness and heart rate variability. Cardiac function parameters including the diastolic function were found to be better in subjects who practiced CR for 3–15 years than that in healthy age- and sex-matched controls. The CR subjects had less ventricular stiffness and less viscous loss of diastolic recoil, both of which are consistent with less myocardial fibrosis. These effects, in combination with other benefits of calorie restriction, such as protection against obesity, T2DM, hypertension, and cancer, suggest that the CR may have a major beneficial effect on health status, quality of life and lifespan in humans.


that the metabolic rate, when normalized to the lean body mass of the animals, did not decrease during CR.16 In the studies, the CR animals enjoyed a higher metabolic activity adjusted for body weight over their lifetimes than did the ad libitum controls.17 In budding yeast, as well as the nematode C. elegans, CR has been shown to actually to result in an increase in respiration.18,19

One of the most striking features of CR is that it appears to forestall or prevent many late-onset disorders and diseases. For example, CR extends lifespan in certain lab strains of mice which usually would die of cancer. Thus, CR extends the shortened lifespan of p53−/−micewhichotherwisedieofearlycancers that appear in the absence of the tumor suppressor.20,21 CR also extends lifespan in Fischer rats, which usually die of kidney disease. Further, CR has been shownefficacious inmousemodelsofavariety of diseases.22,23

CR MECHANISMS AND PATHWAYS THE SIRTUINS AND ALLIED PATHWAYSIt is important to understand that the benefitsofCRarenotapassiveresultoflower caloric intake but the consequence of an active regulatory intervention mimicking the food scarcity activating certain genetic and metabolic programs that result in beneficial vital effects.Various genetic and molecular studies in model organisms, in fact, suggest that CR is a regulated process, in which the SIRT (Silent Information Regulator 2) gene plays an important role. The SIR2 gene wasfirstidentifiedandso-namedbecauseit mediates gene silencing in yeast.24 The findings suggest that theSIR2ortholog,SIRT1 in mammals may mediate a broad array of physiological effects that occurin animals on a CR diet. Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein encoded by the SIRT1 gene.

The elevated activity of SIRT1 orthologs has been shown to extend lifespan in yeast (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans) and fruit flies (Drosophila

melanogaster). The CR also increases SIRT1 levels in mice, rats, non-human primates and humans. The regulation of SIRT1 activity by CR is complex, being tissue-specific aswell as region-specificin nonhomogeneous tissues, such as the brain.25 The activity of the sirtuin in the liver is reduced by CR and correlates with the reduced fat synthesis and is activated by a high-caloric diet. The SIRT1, thus figures prominently in the redistributionof resources during CR from growth, metabolism and reproduction to maintenance and survival.

The related genes in S. cerevisiae, C elegans and D. melanogaster called sirtuins, encode NAD-dependent deacetylases and appear to promote longevity in the organisms.26 In the mammals, there are at least seven sirtuins (SIRT1-7), each sirtuin influencingdiverse aspects of the metabolism and characterized by differences insubcellular localization, substrate preference, and biological function. In the study models ranging from yeast to mice, sirtuins have also been associated with the salutary effects of CR. Themammalian Sir2 ortholog SIRT1 targets numerous regulatory factors affectingstresseffectstometabolism.27 The levels of SIRT1 increase in rodent and human tissues in response to CR leading to favorable changes in metabolism and stress tolerance.28 The SIRT1 promotes oxidation of fatty acids in liver and skeletal muscle, cholesterol metabolism in the liver, and lipid mobilization in white adipose tissue.29 SIRT1 may also regulate CR by sensing low calories and triggering physiological changes linked to health and longevity.30 The gene, SIR2, encodes a NAD-dependent deacetylaseandmaymediate theeffectsof CR, as shown by experiments in the lower organisms, yeast and Drosophila. Further, the small-molecule activators of SIRT1 have been shown to protect mice fromtheadverseeffectsofahigh-fatdiet.

THE CR MECHANISMSThe CR appears to work through the following mechanisms:1. CR lowers the core body temperature:

An adaptive response to reduce

energy expenditure when nutrients availability is curtailed. Lowering the temperature may prolong the lifespan of cold-blooded animals. Mice, which are warm-blooded, have been geneticallymodified to have areduced core body temperature which increases the lifespan independently of calorie restriction.

2. Hormesis: The CR is low-intensity biological stressor. The CR diet imposes a low-intensity biological stress on the organism to elicit a defensive response that helps to protect from disorders of aging. The CR places the organism in a defensive state to survive in adverse life situations, resulting in improved health and longer life through activation of longevity genes. In C. elegans, the CR extends lifespan primarily by increasing oxidative stress to stimulate the organism into having an increased resistance to further oxidative stress.

3. Hormonal alterations: Prolonged severe CR lowers total serum and free testosterone while increasing sex hormone binding globulin concentrations in humans. Calorie restriction has been shown to increases DHEA in primates, but not in post-pubescent primates. These effects are independent of adiposity.Lowering the concentration of insulin and insulin-like growth factor 1 and growth hormone, has been shown to up-regulate autophagy, the repair mechanism of the cell. The CR works by decreasing insulin levels and up-regulating autophagy.

4. CR reduces production of ROS and damage by ROS. The free radicals may induce an endogenous response culminating in effective adaptationsto protect against exogenous radicals. The sublethal mitochondrial stress with ROS may initiate beneficialalterations in cellular physiology produced by CR. The CR is related to chromatin function. In C. elegans, the gene PHA-4 is responsible for the increased lifespan. Whereas, in rodents, CR slows aging, decreases ROS production and reduces the

REVIEW ARTICLE


accumulation of oxidative DNA damage in multiple organs. These results are linked to reduced oxidative DNA damage.

The CR also decreases 8-OHdG damages in the DNA of mice heart, skeletal muscle, brain, liver and kidney.12 The levels of 8-OHdG in the DNA of these organs were reduced to than that in the DNA of mice fed an unrestricted diet. Also, in rats, CR retarded the onset of age-related increases in 8-OHdG in nuclear DNA of brain, heart, liver, and kidney. The level of 8-OHdG in these organs of the calorie-restricted rats at 30 months averaged 65% of the level in rats fed an unrestricted diet.

5. Sirtuins: Sir2 has been implicated in the aging of S. cerevisiae and is a highly conserved, NAD+-dependent histone deacetylase. Sir2 homologs havebeenidentifiedinawiderangeoforganisms from bacteria to humans. Yeast has 3 SIR genes - SIR2, SIR3, and SIR4. Although all three genes are required for the silencing of mating type loci and telomeres, only SIR2 has been implicated in the silencing of rDNA. In addition, SIR2 related genes also regulate the formation of some specialized survival forms, such as spores in S. cerevisiae and Daher larvae in C. elegans. A study done by Kaeberlein et al. (1999) in yeast found that deletions of Sir2 decreased lifespan and its additional copies increased lifespan.

6. CR Mimetics: the results akin to CR, can be achieved with pharmacologic approaches, such as rapamycin, via mTOR signaling blockade, resveratrol, by activating SIRT1 activity, and metformin, which seems to be a stimulator of AMPK activity. The polyphenol resveratrol partially mimics CR by activating SIRT1 to inducebeneficialeffectsonhealth.31,32

THE CR STUDIES IN ANIMAL MODELSCR in S. cerevisiae and C. elegansThe classic experiments, diluting the energy source in growth media, namely glucose, extended the replicative lifespan

of yeast mother cells.33 This intervention extended the lifespan, by mutating genes for glucose utilization (hexokinase) and/or signaling components of the protein kinase A pathway. The major genetic determinant of replicative lifespan in yeast is SIR2 and its increased activity extended it.34 The SIR2 ortholog in C. elegans was also found to be the key determinant of lifespan.35 The evolutionary studies highlight that S. cerevisiae and C. elegans diverged from a common ancestor about a billion years ago and ratify that all descendants of that common ancestor, including mammals, have conserved the SIR2-related genes involved in regulating lifespan.

The phylogenetically conserved enzymatic activity of the SIR2 and its homologs is determined by NAD-dependent protein deacetylases.36 The studies show that the mammalian Sirt1 enzyme deacetylates many histone and nonhistone substrates, and NAD is cleaved to produce nicotinamide (NA) and acetyl-ADP-ribose each reaction cycle.37 The sudies suggest that Sir2 senses the metabolic state of cells and sets the lifespan accordingly.38 Further, the SIR2-related genes regulate the formation of the specialized survival forms in lower organisms, spores in yeast39 and Dauer larvae in C. elegans.40 Several studies suggest that CR in yeast is regulated by SIR241 and CR increased the silencing activity of SIR2 in vivo.42 Also, CR did not extend the lifespan when SIR2

was deleted. Further, an activator of the Sir2 enzyme, resveratrol, has been shown to extends yeast replicative lifespan.43 Resveratrol requires the SIR2 gene for thislongevityeffect.

Activating SIRT1 pathway might be beneficial in preventing somemanifestations of aging (Figure 1). But, resveratrol and CR did not synergize to extend the lifespan, suggesting that CR and resveratrol act through the same pathway. Resveratrol is a plant-derived polyphenol that appears to activate SIRT1 apart from having antioxidant, anti-inflammatory,and antitumorigenic properties. Through activation of SIRT1, resveratrol may function as a CR mimetic and resveratrol treatment has been shown to increase lifespan in several organisms, including, high-fat–fed mice, in which it improved insulin sensitivity, mitochondrial function, and survival. More recently, treatment of obese mice with SRT1720, a synthetic activator of SIRT1, resulted in similar improvements in survival as were observed in resveratrol-treated mice.

The mechanism by which CR activates the Sir2 enzyme is not fully understood, though a molecular pathway could be traced from caloric intake. In S. cerevisiae, the fermentation is a way for cells to generate ATP and to store excess energy in the form of ethanol when glucose is abundant. NADH itself is a competitive inhibitor of SIR2 and its reduction during CR upregulates the enzyme to extend the lifespan. The CR

Figure 1. CR, SIRT1 and Lifespan: Projected Metabolic Pathways

CR

PI3K

AktmTOR

SIRT1

AutophagyProtein

synthesis

ROS and inflammation

Lipid Metabolism

Cell Integrity

LONGEVITY


triggers a more efficient use of glucosevia an increase in respiration, analogous to a known metabolic shift that occurs in mammals during CR, in whom there is a transition in muscle cells from using glucose towards the use of fatty acids. This metabolic shift spares glucose for the brain and correlates with the characteristic enhancement of insulin sensitivity in muscle and liver. But, this model for activation of Sir2p by CR in yeast, however, is not established.

Instead, the NAD salvage pathway may play a key role in CR. The CR upregulates levels of an enzyme, Pnc1p, that synthesizes NAD from its cleaved products, NA and ADP-ribose. Since NA has also been shown to inhibit the SIR2 enzyme, it has been suggested that CR extends lifespan by reducing NA in cells, thereby upregulating Sir2p. Consistent with this model, deleting PNC1 reduced or eliminated the ability of CR to extend lifespan.44 As the synthesis of the two theories, it is possible that the NAD salvage pathway functions in parallel to changes in NADH to regulate Sir2. To validate this, NA levels are in fact altered in CR cells. However, that NA functions as the mediator of CR, since the regimen wascompletelyeffectiveincellsdeletedfor PNC1 if the excess NA was depleted from cells.45 In another study, it was reported that CR is independent of SIR2 inadifferent,unrelatedstrainofyeast.46 Thisfindingendorsesthattherearethanone pathway that mediate CR in yeast.

CR in DrosophilaThe lifespan in Drosophila can be extended by diluting the fruit fly’s dietcomprising of yeast along with glucose.47 This form of food restriction, works by activating the SIR2 ortholog, Sir2, and increasing levels of Sir2 mRNA in Drosophila. These observations suggest the role of SIR2 as a mediator of CR for lifespan, which has been conserved in metazoans. The SIR2 activator, resveratrol also extends the lifespan in Drosophila48 but does not further extend thelongerlifespanofCRflies,indicatingthat Sir2 works in the same pathway as CR.49

In study models, certain mutations

in the insulin/IGF-1 signaling pathway appear to extend the lifespan in C. elegans, flies and mice.50 The CR does not extend the lifespan of Sir2 mutant flies. But, the long-lived dwarf mice,with missing the growth hormone-IGF-1 axis and other pituitary hormones due to a mutation in the pit-1 gene, shows further extension in their lifespan on a low-calorie diet.51 This finding leads toinference that CR and IGF-1 may extend lifespan by independent mechanisms. Thus, the effect of CR in mammalsis more complex than C. elegans and Drosophila, involving various organs and physiological axes. Thus, the metabolic pathways do not stand alone but are interconnected and merge at various levels. In mammals, the CR appears to affect metabolism and studies suggestthat it may be advantageous to increase metabolism during CR, at least in some tissues to promote a longer lifespan in mammals.

CR AND METABOLIC ALTERATIONS UPREGULATION OF MITOCHONDRIAL UNCOUPLING PROTEINSThe mice are suitable models for mammalian studies concerning the effect of CR andmetabolic and geneticalterations on lifespan. The fat insulin receptor knock-out mice (FIRKO) lacking insulin signaling, have low-fat deposits in white adipose tissue (WAT). These mice eat more than weight-matched wild-type mice yet have lower body weight, indicating that they have a higher than normal metabolic rate. Further, these mice live longer than controls.52 Another group of genetically engineered mice having their C/EBPαgene replaced with a second copy of C/EBPβ are also hypermetabolic due toincreased metabolism in WAT. These mice also live longer than controls.53

Another study in mice showed a positive correlation between oxygen consumption, i.e., metabolic rate, and lifespan.54 In this study, the variation in metabolism was due to differences inthe degree to which electron transport was coupled to ATP synthesis in mitochondria. The longer-lived mice had

mitochondria that were more uncoupled. Also, the CR mice have more uncoupled mitochondria than controls, perhaps due to upregulation of mitochondrial uncoupling proteins by CR. CR reduces the size of animals, likely creating a higher surface area and potentially greater heat loss, and thus the lower body temperature. The CR mice may increase uncoupling proteins in metabolic tissues, muscle, liver, and brown adipose tissue. It appears that the extra electron transport dissipated by uncoupling may activate a regulatory pathway to extend lifespan. Because of proton leakage down the gradient, uncoupled mice would avoid hyperpolarization of the mitochondrial membrane and partially uncoupled electron transport may generate a lower level of ROS.

CR AND STRESS RESISTANCECR is known to increase the resistance to oxidative stress,55 which leads to longer lifespan by a greater ability to detoxify ROS and repair oxidative damage, and slow down cellular decay.56 The genetic regulators of mammalian lifespan can also increase resistance to stress. Absence of the protein p66 shc causes an increase in stress resistance and the KO mice and cells from KO mice are more resistant to oxidative stress, and the p66 KO mice live longer than wild-type. Experimentally, in vitro, the CR serum triggers a higher level of the mammalian SIR2 ortholog, Sirt1,inthefibroblasts,whichispartiallyreversed by adding IGF-1 and insulin to the serum.

Further, the connection between Sirt1 and stress resistance appears to be extensive. The Sirt1 is a NAD-dependent deacetylase and appears to target many proteins that are not histones and an important one, p53, which is shown to be deacetylated and downregulated by Sirt1.57 Thus, Sirt1 negatively regulates p53-dependent apoptosis in response to cellular damage.58 Another family of regulators targeted by Sirt1 are Foxo or forkhead proteins, which, like p53, can respond to stress and trigger apoptosis. The Sirt1 was shown to deacetylate and downregulate Foxo1, 3, and 4 and thus repress Foxo-mediated apoptosis.59 Sirt1

REVIEW ARTICLE


also deacetylates and downregulates the Foxo coactivator p300. In addition, Sirt1 deacetylates the DNA repair protein Ku70, allowing it to bind to and inactivate the proapoptotic factor Bax60. Thus, Sirt1 appears to target numerous cellular factors, thereby resulting in a higher threshold for apoptosis.61

CR AND FAT REGULATIONThere is increasing evidence that mammalian aging is regulated in part by adiposity.62 The WAT stores fat as triglycerides when food is abundant. When food is scarce, as in CR animals, cells shed their fat from adipose tissue. The WAT can sense nutritional status and sends appropriate signals to coordinate aging in all organs, and in addition, WAT is an endocrine organ and secretes hormones such as leptin and adiponectin.63 The idea that WAT regulates aging is strengthened by the findingsthattheFIRKOmiceandC/EBPknockin mice stay lean and live long. The WAT also mediates many age-associated metabolic disorders such as T2DM and dyslipidemiawhichcannegativelyaffectthe lifespan.64 The Sirt1, thus, regulates WATbyrepressingp53.Itexertseffectson hormones, including growth factors, which override cell-autonomous effects

on apoptosis. Such changes may permit or even mandate raising the threshold for apoptosis in hormone-responsive cells. The combined effect of changesin hormones and a higher threshold for apoptosis in responsive cells is an advantage for the survival.

The WAT, muscle, liver and pancreatic β cells are integrated with a regulatorycircuit and an important hormonal axis during CR comprises WAT, metabolic organs (muscle and liver) and pancreatic β cells producing insulin. Chronic highfood intake triggers an increase in blood glucose. The surges in blood glucose will activateβcellstoproducemoreinsulin,inthelongrunleadingtoβcellproliferationand ultimately failure. Insulin signals WAT to store fat as triglycerides. The triglycerides store influences the levelsof hormones produced by the WAT cells, primarily increase in leptin and a decrease in adiponectin.65 These hormonal changes influence the insulin sensitivity ofmetabolic organs. Adiponectin increases sensitivity to insulin in metabolic organs and its decrease exacerbates insulin resistance and rises in blood glucose.66 This vicious cycle initiated by adiposity and culminating as T2DM (Figure 2), is antagonized by CR by lowering blood glucose and insulin, reducing fat stores,

increasing adiponectin and improving insulin sensitivity.

In WAT, Sirt1 is expressed and represses the key regulator of WAT, the nuclear receptor PPARγ, which slowsdownthedifferentiationofprecursorcellsinto white adipocytes and downregulates fat storage in existing WAT.67 Sirt1 is bound directlytothePPARγ-negativecofactors,NCoR and SMRT, and associated with PPARγDNAbinding sites in promotersof fat-specific genes, and functions as anegative regulator of PPARγ. The CRcauses the lipolysis of triglycerides in WAT and the release of free fatty acids, which are taken up and oxidized by metabolic organs. Further, CR induces thebindingofSirt1 to thePPARγDNAbinding region of the promoters of fat-specificgenestoexertrepressiveeffects.The CR, thus, increases levels of Sirt1,68 which modulates the genes concerned with fat storage and hormones. The changes in Sirt1 during long-term CR, by increasingβoxidationoffattyacidsandlowering free fatty acids, improve insulin sensitivity, and working in a coordinated way lead to the slowing of aging. The Sirt1-PPARγ connection is important inother tissues as well. It controls many biological processes in the vessel wall, such as smooth muscle cell proliferation ordifferentiationandlipidaccumulationin macrophages,69 playing an active role in age-related atherosclerosis.

CR AND NEURODEGENERATIONIn certain mouse models of neurodegenerative diseases, such as Parkinson’s or Alzheimer’s, CR hasbeen reported to reduce age-associated neuronal loss.70 CR has also been reported to slow declines in psychomotor and special memory tasks, preserve dendritic spines involved in learning, and improve the plasticity and ability of self-repair of the brain.71 The repression of p53- and FOXO-mediated apoptosis by Sirt1 may be of special importance for the long-term maintenance of postmitotic cells such as neurons. There appears to be a connection between Sirt and the preservation of neuronal integrity.72 In the neuronal cell body, Sirt1 regulates genes whose products travel down the axon

Figure 2. Metabolic changes triggered by adiposity - The links between aging, visceral fat, inflammation and MetS. Visceral fat increases with age and its increase induces inflammation. Inflammation accelerates process of aging. The aging, visceral fat and inflammation increase risk of metabolic diseases like obesity, IR, T2DM, CVD and HTN.

Insulin

b-CellsActivation & Proliferation

Blood Glucose

Body Fat Stores

WAT

T2DM

Obesity IR

CVD HTN

Body Weight Gain

& Adiposity

Metabolic Syndrome


and mediate axonal survival in event of injury.

IMPACT OF CR ON HEALTH AND DISEASECR has long been recognized for its ability to extend lifespan and to mitigate aging and disease processes in various tissues.TheeffectsofCRwithadequatenutritionseemtopossessmanybeneficialeffects in retarding numerous diseasestates.73 The studies related to calorie restriction mimetics (CRMs), number of phytochemicals that biochemically mimic the effects of CR, prove that both CRand CRMs trigger an adaptive response similar to mild-stress or a low-dose response, referred to as hormesis.74 Both CRandCRMsaffectacommonpoolofbiochemical pathways that are involved in an organism's survival and longevity.75 The two bio-metabolic pathways, sirtuin pathway and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, also referred to as the Keap1/Nrf2/ARE pathway are concerned with an organism's longevity and upregulation of cytoprotective genes essential for cell survival respectively.76

STUDIES OF CR EFFECTS IN ANIMAL MODELSDuring 1935, based on his classical animal studies at Cornell University, Clive McCay proved that a 40% calorie reduced diet prolonged the life in mice.77 The

findingshavesincebeenexperimentedinother animals and there exists a possibility of parallel physiological links in non-human primates and humans.78 In a 2017 collaborative report on rhesus monkeys by scientists of the US National Institute on Aging and the University of Wisconsin, CR in the presence of adequate nutrition was effective in delaying the effects ofaging.79 The older age, female sex, lower body weight and fat mass, reduced food intake, diet quality, and lower fasting blood glucose levels were factors associated with fewer disorders of aging and improved survival. The reduced food intakewas beneficial in adult and olderprimates, but not in younger monkeys. Because rhesus monkeys are genetically similar to humans, the benefits andmechanisms of CR may apply to human health and aging. Earlier, the NIA rhesus macaque calorie restriction study in 1987 had shown that CR did not extend years of life or reduce age-related deaths in rhesus monkeys. It did improve certain measures of health but did not have any significanteffectonlifespan.

The CR represents an important intervention to extend both mean and maximum lifespan in various organisms. This is due to numerous metabolic alterations following CR (Figure 3). The CR preserves muscle tissue in nonhuman primates and rodents. Mechanisms include reduced muscle cell apoptosis andinflammation,protectionagainstage-related mitochondrial abnormalities and preserved muscle stem cell function.80

Laboratory rodents placed on a CR diet tend to exhibit increased activity levels at feeding time. Monkeys undergoing CR also appear more restless immediately before and after meals, and have demonstrated an increase in licking, sucking, and rocking behavior. The CR regimen may also lead to increased aggressive behavior in animals.81

THE CR AND CARDIOVASCULAR RISK Data from animal and human studies indicate that the effects of CR andespecially CRAN on the aging heart and vasculature may have additional beneficial effects on several metabolicand molecular factors that modulate cardiovascular aging alterations including cardiac and arterial stiffness and heartrate variability.82 The risk factors for atherosclerosis are substantially improved in a manner consistent with experimental studies in rodent models of atherosclerosis and nonhuman primates. The risk factors such as c-reactive protein, serum triglycerides, low-density lipoprotein, high-density lipoprotein, blood pressure and fasting blood sugar, are substantially more favorable with CR than with unrestricted dietary schedule and comparable with the long-term endurance exercise plan.

The risk factors for atherosclerosis are substantially improved in a manner consistent with experimental studies in rodent and nonhuman primate models of atherosclerosis. Other risk factors for CVD also become substantially more favorable.Similareffectswerealsoseenduring a natural experiment in Biosphere 2, andeffectsonbloodpressure,cholesterollevel, and resting heart rate were seen in subjects in the Minnesota Starvation Experiment, during World War II.84 The cardiac function parameters including the diastolic function were found to be better in subjects who practiced CR for 3–15 years than that in healthy age- and sex-matched control subjects. The CR subjects had less ventricular stiffnessand less viscous loss of diastolic recoil, both of which would be consistent with less myocardial fibrosis. These effects,in combination with other benefits of

Activation of

SIRT1, PI3K/Akt signaling

and Erk1/2 signaling

Adiposity, Cytokine, IIS

Signaling, Thyroid Hormone

Adiponectin

Figure 3. CR and cellular pathways for longevity promotion - various metabolic alterations in body fat mass, cytokines, IIS signaling, thyroid hormones and adiponection levels, accompanied by activation of SIRT1, PI3K/Akt and Erk ½ signaling, and activation of stress defence plus survival pathways and attenuation of proinflammatory mediators.

CR Longevity

Promotion

Activation of Stress Defense and

Survival Pathways/Attenuation

of Proinflammatory Mediators

REVIEW ARTICLE


calorie restriction, such as protection against obesity, diabetes, hypertension, and cancer, suggest that CR may have amajorbeneficialeffectonhealthspan,quality of life and lifespan in humans. Further, a detailed review of the effectsof CR on the aging heart and vasculature concluded that the data from animal and human studies indicate that beyond the effects of implementation of healthierdiets and regular exercise, CRAN may have additional beneficial effects onseveral metabolic and molecular factors that are modulating cardiovascular aging including cardiac and arterial stiffnessand heart rate variability.83

CONCLUSION: CR IN PRACTICEMETABOLIC STRATEGY TO DELAY AGING PROCESSBiological characteristics of animals following CR include numerous changes in the transcriptome, metabolome, and proteome, as well as increase in stress hormones. CR leads to decline in insulin, thyroid hormone, reproductive hormones and GH/IGF-1 levels. Some of these effects represent restoration to levelssimilar to that in younger age, such as lower insulin and glucose concentrations, whereas other changes resemble those in older age, such as low GH/IGF-1. Because CR modulates a remarkable number of biologic systems and it appears that the thelongevity-promotingeffectsofCRareelicited by concurrent interplay of several mechanisms. The Akt activation of NF-κB may be mTOR-dependent, whereasSIRT1 may be a direct stimulator of AMPK activity and autophagy.

THE CR STUDIES ACROSS THE SPECIESMost CR studies have been conducted in rats and mice, but CR experiments in other mammalian species as well as taxonomically distant organisms suggest the universality of its beneficial effecton lifespan. In nonhuman primates, CR decreases the risk of T2DM and other age-related diseases and appears to extendlifespan.MostoftheeffectsofCRin animal studies have been reproduced in middle-aged humans and it is capable of reducing disease-specific mortality risk,

though the issue about lifespan extension in humans remains un-resolved. The possiblebenefitsofCRshouldbecarefullyweighed against the QOL concerns. The middle-aged individuals subjected to rigorous CR may experience issues with low bone density and muscle mass, and feel hungry, muscular pains, lethargic and cold.85 Thus, CR as a late-life intervention will be counterproductive in frail, sarcopenic individuals in whom adequate caloric and protein intake are essential to maintaining bone and muscle mass. Some of these concerns can be overcome by using a more moderate CR regimen with adequate essential vitamins and minerals supplementation, and a suitable exercise program. Such a strategy has been shown to improve several health indices while simultaneously preserving bone mineral density, lean body mass, strength, and aerobic capacity.

THE CR AND ROLE OF GENETICSThe Somatotropic SignalingThe GH/IGF-1 axis declines with aging. Lifespan extension has also been demonstrated in mutant mice with reduced function of the somatotropic axis, including Ames and Snell dwarf mice and mice lacking the GH receptor, all of which have decreased plasma IGF-1 concentrations. The extended longevity isduetoGHdeficiency,asrestorationofGH levels in Ames dwarf mice reverted their longevity to that of nonmutant controls. In addition, functional mutations havebeenidentifiedinthehumanIGF-1Rgene that result in altered IGF-1 signaling and are common in centenarians. Both animal and human studies have also linked reduced IGF-1 levels/signaling per se with reduced risk of many cancers as well as improved longevity, but the low IGF-1 concentration in humans carries an increased risk for CVD, stroke, T2DM, and osteoporosis.

Sirtuins, Ampk Activators And Mtor SignalingThe sirtuin family of proteins is a seven-member group (SIRT1–7) of highly conserved, nicotinamide adenine dinucleotide-dependent protein deacetylases that function in the regulation

of various metabolic and biological processes. The mammalian SIRT1 shares the closest similarity to Sir2, plays an important role in regulating glucose metabolism, insulin action, fat storage, and nutrient sensing. It deacetylates the inflammatory regulator nuclear factor-κB(NF-κB),whichisakeyplayerinIRand the MetS. Activating SIRT1 pathway through CRMs may be beneficial inpreventing several manifestations of aging including improved insulin sensitivity, mitochondrial function, and cell integrity and survival.

AMPK plays a critical role in regulating whole-body energy balance and is activated by various interventions such as exercise or CR. In the hypothalamus, AMPK activation in agouti-related peptide or pro-opiomelanocortin neurons stimulates food intake, whereas activation of AMPK in muscle promotes glucose transport, fatty acid oxidation, and mitochondrial biogenesis. The AMPK activators can serve as exercise or CR mimetics. In sedentary mice, the 4 weeks of treatment with the AMPK agonist, AICAR, substantially enhanced running endurance. Similarly, metformin, which is an AMPK activator, increases lifespan in yeast and mice, though not in rats. Further, there are no data to support a role for metformin in human aging, which is well-tolerated and have anti-diabetic and anticancer property, as well. The mechanism by which AMPK activation modulates aging and disease risk is not established.

The mTOR signaling pathway is highly conserved and integrates energy and growth factor signaling to cell growth and basic cellular processes such as RNA translation, stress resistance, and autophagy. It is closely linked to components of IIS pathways, energy metabolism and glucose homeostasis. The inhibition of mTOR signaling pathway by genetic or pharmacological intervention extends lifespan in yeast, nematodes, andfruitflies.Also,theinhibitionofthedownstream effector of mTOR, S6K,increases lifespan in worms and fliesand protects against diet-induced obesity and enhances insulin sensitivity in mice. The pharmacologic inhibition of mTOR


with rapamycin has also been shown to extend lifespan in mice. In mice, the specific deletion of raptor, a componentof mTOR complex in adipose tissue, protects against diet-induced obesity, whereas deletion of raptor in skeletal muscle results in muscular dystrophy. The inhibition of mTOR in the pancreas decreases insulin production by islets, and increased mTOR activity in the brain or the hypothalamus leads to decreased appetite via modulation of leptin and ciliary neurotrophic factor. The human skeletal muscle from older adults has been shown to have impaired mTOR complex 1 activation and systemic blockade of the mTOR complex 1 pathway eliciting an aging skeletal muscle phenotype, sarcopenia and frailty.

FOOT NOTES1. Affiliation – Senior Consultant and

Faculty, Department of Medicine, Hindu Rao Hospital and NDMC Medical College, New Delhi, India. Email: [email protected]

2. Disclosures – None.3. The Figures 1-3 in this Review Article

are subject to Copyright by Dr Vinod Nikhra.

REFERENCES1. Goodpaster B, Park S, Harris T, et al. 2006. The loss of

skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 61; 1059–64.

2. Taylor A, Cable N, Faulkner G, et al. 2004. Physical activity and older adults: a review of health benefits and the effectiveness of interventions. Journal of Sports Sciences, 22; 703–25.

3. McKay JA, Mathers JC. 2011. Diet induced epigenetic changes and their implications for health. Acta Physiol. (Oxf.), 202; 103–18.

4. Koubova J, Guarente L. 2003. How does calorie restriction work? Genes & Dev, 17; 313–21.

5. James PT, Rigby N, Leach R, et al. 2004. The obesity epidemic, metabolic syndrome and future prevention strategies. Eur. J. Cardiovasc. Prev. Rehabil. 11, 3–8.

6. Wolf G. 2006. Calorie restriction increases life span: a molecular mechanism. Nutrition reviews, 64:2.1;89-92.

7. Kenyon C. 2005. The plasticity of aging: Insights from long-lived mutants. Cell, 120; 449–60; Sinclair DA. 2005. Toward a unified theory of calori c restriction and longevity regulation. Mech. Ageing Dev, 126; 987–1002.

8. Weindruch R, Walford RL. 1988. The retardation of aging and disease by dietary restriction. Charles C. Thomas; Springfiled, IL: 1988.

9. Lin SJ, Defossez PA, Guarente L. 2000. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000; 289; 2126–28.

10. Ingram DK, Anson RM, de Cabo R, et al. 2004.

Development of calorie restriction mimetics as a prolongevity strategy. N Y Acad. Sci. 1019; 412–23.

11. Masaro EJ. 1984. Nutrition as a modulator of the aging process. Physiologist, 27; 98–109.

12. Sohal RS, Weindruch R. 1996. Oxidative stress, caloric restriction, and aging. Science, 273: 59–63.

13. Harrison D.1989. Natural selection for extended longevity from food restriction. Growth Dev. Aging, 53; 3–6.

14. Holliday R. 1989. Food, reproduction, and longevity: is the extended life span of calorie-restricted animals an evolutionary adaptation? Bioessays, 10; 125–27.

15. McCarter R, Masoro EJ, Yu BP. 1985. Does food restriction retard aging by reducing the metabolic rate? Am. J. Physiol, 248; E488–E490.

16. McCarter RJ, Palmer J. 1992. Energy metabolism and aging: a lifelong study of Fischer 344 rats. Am. J. Physiol, 263; E448–E452.

17. Lin SJ, Kaeberlein M, Andalis AA, et al. 2002. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature, 418; 344–48.

18. Houthoofd K, Braeckman BP, Lenaerts I, et al. 2002. No reduction of metabolic rate in food restricted Caenorhabditis elegans. Exp. Gerontol, 37; 1359–69.

19. Hulbert AJ, Clancy DJ, Mair W, et al. 2004. Metabolic rate is not reduced by dietary-restriction or by lowered insulin/IGF-1 signalling and is not correlated with individual lifespan in Drosophila melanogaster. Exp. Gerontol, 39; 1137–43.

20. Hursting SD, Lavigne JA, Berrigan D, et al. 2003. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu. Rev. Med. 2003; 54: 131–152.

21. Berrigan D, Perkins S, Haines DC, Hursting S. 2002. Carcinogenesis Adult-onset calorie restriction and fasting delay the spontaneous tumorigenesis in p53-deficient mice. 23; 817–22.

22. Lane MA, Ingram DK, Roth GS. 1999. Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicol. Sci, 52; 41–48.

23. Stern JS, Gades MD, Wheeldon CM, Borchers AT. 2001. Calorie restriction in obesity: prevention of kidney disease in rodents. J. Nutr, 131; 913S–17S.

24. Rine J, Herskowitz I. 1987. Four genes responsible for a position effect on expression from HML ANS HMR in Saccharomyces cerevisiae. Genetics, 116; 9–22.

25. Chen D, Bruno J, Easlon E, et al. 2008. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev, 22:13; 1753–57.

26. Chen D, Guarente L. 2007. SIR2: A potential target for calorie restriction mimetics. Trends Mol. Med,13; 64–71.

27. Sinclair DA. 2005. Toward a unified theory of caloric restriction and longevity regulation. Mech. Ageing Dev, 126; 987–1002.

28. Civitarese AE, Carling S, Heilbronn LK, et al. 2007. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med, 4:e76, doi: 10.1371/journal.pmed.0040076.

29. Lomb DJ, Laurent G, Haigis MC.2010. Sirtuins regulate key aspects of lipid metabolism. Biochimica et biophysica acta, 1804:8; 1652-7.

30. Guarente L, Picard F. 2005. Calorie restriction--the SIR2 connection. Cell, 120:4; 473-82.

31. Baur JA, Pearson KJ, Price NL, et al. 2006. Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 444; 337–42.

32. Lagouge M, Argmann C, Gerhart-Hines Z, et al. 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α Cell, 127;1109–22.

33. Lin SJ, Defossez PA, Guarente L. 2000. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science, 289; 2126–28.

34. Kaeberlein M, McVey M, Guarente L. 1999. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 13; 2570–80.

35. Tissenbaum HA, Guarente L. 2001. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410; 227–30.

36. Tanny JC, Moazed D. 2001. Coupling of histone deacetylation to NAD breakdown by the yeast silencing protein Sir2: evidence for acetyl transfer from substrate to an NAD breakdown product. Proc. Natl. Acad. Sci. USA. 2001; 98: 415–420.

37. Tanner KG, Landry J, Sternglanz R, Denu JM. 2000. Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc. Natl. Acad. Sci. USA, 97: 4178–82.

38. Guarente L. 2000. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev, 14; 1021–26.

39. Margolskee JP. 1988. The sporulation capable (sca) mutation of Saccharomyces cerevisiae is an allele of the SIR2 gene. Mol. Gen. Genet, 211; 430–34.

40. Tissenbaum HA, Guarente L. 2001. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410; 227–30.

41. Lin SJ, Defossez PA, Guarente L. 2000. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science, 289; 2126–228.

42. Lin SJ, Kaeberlein M, Andalis AA, et al. 2002. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature, 418; 344–48.

43. Howitz KT, Bitterman KJ, Cohen HY, et al. 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425; 191–96.

44. Anderson RM, Bitterman KJ, Wood JG, et al. 2003. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature, 423; 181–85.

45. Lin SJ, Ford E, Haigis M, et al. 2004. Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev, 18; 12–16.

46. Kaeberlein M, Kirkland KT, Fields S, Kennedy BK. 2004. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol, 2; e296.

47. Clancy DJ, Gems D, Harshman LG, et al. 2001. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science, 292; 104–06.

48. Wood JG, Rogina B, Lavu S, et al. 2004. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature, 430; 686–89.

49. Rogina B, Helfand SL. 2004. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA, 101; 15998–16003.

50. Kenyon C. 2005. The plasticity of aging: Insights from long-lived mutants. Cell, 120.

51. Bartke A. Wright CJ, Mattison JA, et al. 2001. Extending the lifespan of long-lived mice. Nature, 414; 412.

52. Blüher M, Kahn BB, Kahn CR. 2003. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science, 299; 572–74.

53. Chiu CH, Lin WD, Huang SY, Lee YH. 2004. Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev, 18; 1970–75.

54. Speakman JR, Talbot DA, Selman C, et al. 2004. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell, 3: 87–95.

55. Sohal RS, Weindruch R. 1996. Oxidative stress, caloric restriction, and aging. Science, 273; 59–63.

56. Ristow M, Zarse K. 2010. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Experimental Gerontology, 45:6; 410–8.

REVIEW ARTICLE


57. Langley E, Pearson M, Faretta M, et al. 2002. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J, 21; 2383–96.

58. Luo J, Nikolaev AY, Imai S, et al. 2001. Negative control of p53 by Sir2α promotes cell survival under stress. Cell, 107; 137–48.

59. Motta MC, Divecha N, Lemieux M, et al. 2004. Mammalian SIRT1 represses forkhead transcription factors. Cell, 116; 551–63.

60. Cohen HY, Miller C, Bitterman KJ, et al. 2004. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science, 305; 390–92.

61. Wang Y. 2014. Molecular Links between Caloric Restriction and Sir2/SIRT1 Activation. Diabetes & metabolism journal, 38:5; 321-29.

62. Bertrand HA, Lynd FT, Masaro E, Yu BP. 1980. Changes in adipose mass and cellularity through the adult life of rats fed ad libitum or on a life prolonging restricted diet. J. Gerontol, 35; 827–35.

63. Kershaw EE, Flier JS. 2004. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab, 89; 2548–56.

64. Barzilai N, Gabriely I. 2001. The role of fat depletion in the biological benefits of caloric restriction. J. Nutr, 131; 903S–906S.

65. Combs TP, Berg AH, Rajala MW, et al. 2003. Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin. Diabetes, 52; 268–76.

66. Pajvani UB, Scherer PE. 2003. Adiponectin: systemic contributor to insulin sensitivity. Curr. Diab. Rep, 3; 207–13.

67. Picard F, Kurtev M, Chung N, et al. 2004. Sirt1 promotes

fat mobilization in white adipocytes by repressing PPARγ. Nature, 429; 771–76.

68. Cohen HY, Miller C, Bitterman KJ, et al. 2004. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science, 305; 390–92.

69. Lee CH, Evans RM. 2002. Peroxisome proliferator-activated receptor-γ in macrophages lipid homeostasis. Trends Endocrinol. Metab, 13; 331–35.

70. Mattson MP. 2003. Gene-diet interactions in brain aging and neurodegenerative disorders. Ann. Intern. Med, 139; 441–44.

71. Mattson MP, Duan W, Lee J, Guo Z. 2001. Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms. Mech. Ageing Dev, 122; 757–78.

72. Araki T, Sasaki Y, Milbrandt J. 2004. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science, 305; 1010–13.

73. Omodei D, Fontana L. 2011. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 585:11; 1537–42.

74. Ghosh HS. 2008. The anti-aging, metabolism potential of SIRT1. Curr Opin Investig Drugs, 9:10; 1095-1102.

75. Chaudhary N, Pfluger PT. 2009. Metabolic benefits from Sirt1 and Sirt1 activators. Current opinion in clinical nutrition and metabolic care, 12:4; 431-7.

76. Kensler TW, Wakabayashi N, Biswal S. 2007. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol, 47; 89–116.

77. Everitt AV, Heilbronn LK, Le Couteur DG. 2010. Ch. Food Intake, Life Style, Aging and Human Longevity. In Everitt AV, Rattan S, Le Couteur DG, de Cabo R. Calorie

Restriction, Aging and Longevity. New York: Springer. ISBN 978-90-481-8555-9.

78. Schäfer D. 2005. Aging, Longevity, and Diet: Historical Remarks on Calorie Intake Reduction. Gerontology. 51 (2): 126–30.

79. Mattison JA, Colman RJ, Beasley TM, et al. 2017. Caloric restriction improves health and survival of rhesus monkeys. Nature Communications, 8; 14063. doi:10.1038/ncomms14063.

80. Cerletti M, Jang YC, Finley LW, et al. 2012. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell. 10:5; 515–9. doi:10.1016/j.stem.2012.04.002.

81. Vitousek KM, Manke FP, Gray JA, Vitousek MN. 2004. Caloric Restriction for Longevity: II--The Systematic Neglect of Behavioural and Psychological Outcomes in Animal Research. European Eating Disorders Review. 12:6; 338–60.

82. Marzetti E, Wohlgemuth SE, Anton SD, et al. 2012. Cellular mechanisms of cardioprotection by calorie restriction: state of the science and future perspectives. Clin. Geriatr. Med, 25:4; 715–32.

83. Weiss, EP; Fontana, L (Oct 2011). Caloric restriction: powerful protection for the aging heart and vasculature. Am J Physiol Heart Circ Physiol. 301 (4): H1205–19.

84. Kalm LM, Semba RD. 2005. They Starved So That Others Be Better Fed: Remembering Ancel Keys and the Minnesota Experiment. J. Nutr. 135 (6): 1347–52.

85. Libert S, Guarente L. 2013. Metabolic and neuropsychiatric effects of calorie restriction and sirtuins. Annual review of physiology,75; 669-84.


Prosthetic Heart ValveThrombosis: How to Manage?

REVIEW ARTICLE

Y K ARORA

Keywords z valve replacement z thrombosis z transthoracic echocardiogram z trans-oesophageal echocardiography z cinefluoroscopy

Dr. YK Arora is Sr. Consultant, Cardiology, National Heart Institute, Community Center, East of Kailash, New Delhi

AbstractAlthough surgery was the mainstay of treatment for valvular heart disease, transcatheter valve therapies have grown exponentially over the past decade. Two types of artificial heart valve exist: mechanical heart valves (MHV), which are implanted surgically, and bioprosthetic heart valves (BHV), which can be implanted via a surgical or transcatheter approach. Whereas long-term anticoagulation is required to prevent thromboembolism after MHV replacement, its value in patients receiving BHVs is uncertain. Patients undergoing transcatheter BHV replacement are at risk for thromboembolism in the first few months, and recent data suggest that the risk continues thereafter. BHV thrombosis provides a substrate for subsequent thromboembolism and may identify a reversible cause of prosthesis dysfunction. Hereafter, the author: 1) reviews the data on prosthetic valve thrombosis; 2) discuss the pathophysiological mechanisms that may lead to valve thrombus formation; and 3) provide perspective on the implications of these findings in the era of transcatheter valve replacement.

INTRODUCTIONProsthetic heart valve thrombosis (PHVT) is a rare but serious complication of valve replacement, most often encountered with mechanical prostheses. The significantmorbidity and mortality associated with this condition warrant rapid diagnostic evaluation. However, diagnosis can be challenging, mainly because of variable clinical presentations and the degree of valvular obstruction. Transthoracic and trans-oesophageal echocardiography and cinefluoroscopy (formechanical valves)represent the main diagnostic tools.

Although surgical treatment is usually

preferred in cases of obstructive PHVT, optimal treatment remains controversial. The different therapeutic modalitiesavailable for PHVT (heparin infusion, fibrinolytic therapy & surgery) will belargely influenced by the presence ofvalvular obstruction, by valve location (left or right-sided), and by clinical status. Hence; treatment of an obstructive left-sided PVTwill differ from that of non-obstructive or right sided PHVT. The purpose of this article is to review the pathophysiology, diagnosis and treatment of PHVT and to provide recommendations for management.


PATHOLOGYAlthough PHVT can present acutely with a fresh thrombus, it is most often a sub acute or chronic phenomenon. Thrombi are typically formed of different clot layers, with variabledegrees of organization. Interestingly, recent surgical studies have underlined the high prevalence of fibrous pannusformation (present between 45–75% of cases), that is also associated with a risk of thrombosis. Caused by an excessive cicatricial response, pannus formation is usually observed in proximity to the suture site and can be located on both sides of the prosthesis, with variable degrees of obstruction.1 Finally, obstruction may also be caused by a vegetation in the context of prosthetic valve endocarditis.

RISK FACTORSPHVT is more common in mechanical heart valves than bio-prosthetic heart valves. It occurs more frequently in the tricuspid than mitral position. Aortic position has a much lesser incidence than themitraland tricuspidvalves.Bileafletvalves have a lower incidence than the unileaflet and ball and cagemechanicalprosthesis.2 Suboptimal anticoagulation is the major cause for PHVT in almost all theseries.Atrialfibrillation(AF)isawellrecognized risk factor for PHVT. Severe LV dysfunction is also emerging as a risk factor in many studies.

CLINICAL PRESENTATIONThe clinical presentation of PHVT is highly variable, often depending on the presence or absence of obstruction. Severe obstructive PHVT is typically associated with overt heart failure, whereas non-obstructive PHVT is often anincidentalfindingorcanpresentasanembolic episode. Partial obstruction (for example, obstruction of one leaflet) canmanifest itself with dyspnoea on exertion, pain chest, early fatigue or systemic embolism.WhenPHVTisfirstsuspected,a careful physical examination should be performed, with particular attention being paid to muffling or disappearance ofprosthetic sounds and the appearance of a new regurgitant or obstructive murmur. The initial diagnostic workup includes

a transthoracic echocardiogram (TTE), trans-oesophageal echocardiography (TOE)andcinefluoroscopyofmechanicalvalves.

TRANSTHORACIC ECHOCARDIOGRAPHY (TTE)The examination of a patient with a prosthetic cardiac valve by transthoracic echocardiography (TTE) is an essential part of diagnostic assessment. TTE examination can be limited because the prosthesis produces a certain degree of acoustic shadowing and reverberations which need to be distinguished from vegetation or a thrombus. Doppler echocardiography is the most accurate method for detecting and quantifying the degree of trans-valvular gradient increase and is useful in the follow-up of patients during thrombolysis. PHVT may be suspected if the Doppler-derived gradients are twice as high as empirically found in normal prostheses. For mitral prostheses, a mean gradient >6 mmHg and an effective area<1.3 cm2 is suggestive of PHVT and >8 mmHg is indicative of PHVT. For aortic prostheses, mean gradient above 30 mmHg is abnormal and indicate further investigation for PHVT. Mean gradient >45 mmHg in absence of other causes is considered as the criteria for PHVT.

TRANSESOPHAGEAL ECHOCARDIOGRAPHY (TEE)-TEE can help to assess thrombus size and location by its high-resolution imaging and can aid in treatment decisions, such as thrombolysis, anti-coagulation,

and surgery. TEE along with clinical parameters can usually differentiatethrombus from pannus formation and vegetation. The thrombus size visualized by TEE is important in deciding on the optimal treatment strategy. When thrombolysis is contemplated, then TEE and Doppler echocardiography are the preferred modalities to assess serially the hemodynamic success of fibrinolysis. PRO-TEE study showedthat, a thrombus area < 0.8 cm2 confers a lower risk for embolism or death associated with thrombolysis in left-sided OPVT.3 TEE also plays a role in planning the management by calculating thrombus area and has been incorporated in guidelines. However, TEE being an invasive investigation; it is sometimes practicallydifficulttoperforminaClassIV or critically ill patient who is not on mechanical Ventilation. Real-time three-dimensional (3D) TEE provides a live “en face” surgical view of the valves, which can improve diagnostic accuracy for detecting prosthetic valve pathologies. The detection of NOPVT can be challenging, especially when doppler parameters are within normal limits and clinical findings are subtle. Ozkanand colleagues found that real-time 3D TEE provides a more comprehensive delineation of non-obstructive mitral prosthetic valve ring thrombosis by depicting the morphology of thrombus with “en face” images that could be missed with 2D TEE.4

CINEFLUOROSCOPY (CF)CFisquick,effective,andcomplementary

Figure 1. Fluoroscopy of normal bileaflet prosthesis in Mitral position

The opening angle (0), closing angle (C),The excursion of each leaflet (E1, E2), and the total leaflet excursion (E total)


diagnostic tools to diagnose PHVT in most patients. It can diagnose obstructive as well as non-obstructive valve thrombosis in form of decreased leafletmotion, which can be calculated by opening&closingangleof thedisc.Tovisualize the aortic valve in profile, leftanterior oblique view is used while mitral valve is visualized best in right anterior oblique view. In the opposite oblique view, base ring is positioned to yield an en face view. The normal movements of discs of bileaflet prosthesis is shown in(Figure 1).

MULTIDETECTOR CARDIAC COMPUTED TOMOGRAPHY (MDCT)Multidetector cardiac computed tomography is a promising technique for functional evaluation of bileafletmechanical valves, allowing reliable measurements of opening and closing leaflet angles.5 Although the exact cut-offattenuationvalues for thedistinctionbetween thrombus and pannus have not been established, MDCT may allow the differentiation of two entities, which isdifficult with TEE mainly in the aorticposition.6

TREATMENT OF PHVTThe optimal management of PHVT remains controversial. The differenttherapeutic modalities available for PHVT are largely influenced by thepresence of valvular obstruction, by valve location (left or right-sided), and by clinical status. In this review, we evaluate the management strategies of PHVT according to presence of obstruction and prosthesis location (Figure 2). The guidelines for the management of prosthetic valve thrombosis are given in [Table 1]. However,

z TEE should be done in all suspected prosthetic valve thrombosis cases to assess thrombus size and valve motion.

z Fibrinolytic therapy can be considered in a thrombosed left-sided prosthetic heart valve, which is of recent onset (<14 days) with Class I–II symptoms, and a small thrombus (<0.8 cm2) on TEE. It is also acceptable for right-sided valves. For all these patients

a period of IV heparin is also recommended.

z Emergency surgery is recommended for a thrombosed left-sided prosthetic heart valve with Class III–IV symptoms. Surgery is also recommended with a large thrombus (>0.8 cm2).

The American College of Cardiology/American Heart Association guidelines further state that in NYHA Class I and II patients, it is worthwhile to switch to heparin therapy for few days and to assess the response.7 Although the evidence base is limited, it is a useful option as the risk of adverse events can be minimized by this approach.

RIGHT-SIDED OPVT AND NOPVTPHVT is the most important and

common complication of the mechanical tricuspid valve. Mechanical prosthetic valves are rarely implanted in the right heart, mainly because of their increased thrombogenicity. The incidence of mechanical tricuspid valve thrombosis maybeup to20%during thefirstpost-operative year.9 Although there are no formal prospective studies evaluating differenttreatmentmodalities,intensifiedanticoagulation should be the first-choice of treatment in patients with non-obstructive right-sided PHVT. Patients with obstructive tricuspid valve thrombosis usually present with signs of right heart failure. The treatment of choice in right-sided OPVT is a thrombolytic therapy which has been associated with a high success rate and a low complication rate.10 There is no risk

Guidelines Functional Status Therapeutic Strategy

ACC/AHA

Guidelines 2014

-NYHA Class III, IV

-Mobile or large clot burden (≥0.8 cm2)

-Right sided valves

Emergency surgery

NYHA Class I, II Fibrinolytic therapy

ESC-Guidelines

2012(8)

-Critically ill patients

-Non-obstructive PHVT if complicated

by embolism or persists despite

anticoagulation

-Emergency surgery

-Surgery

-Presence of severe co-morbidities

making a surgery as high risk surgery.

-or unavailability of surgery

-or involvement right-sided valves

Fibrinolytic therapy

The guidelines for the management of prosthetic valve thrombosis

REVIEW ARTICLE

Right-sided PVT

OVT NOPVT

Thrombolysis

Surgery

Thrombolysis Intensified anticoagulation

Surgery

Surgery Thrombolysis

OPVT

Left-sided PVT

Treatment of Prosthetic Valve Thrombosis

Left atrial thrombus

Recent systemic/pulmonary thromboembolism orThrombus diameter ≥10 mm

FailFailYes No

Figure 2. Treatment of prosthetic valve thrombosis


of cerebral embolism and the incidence of thrombo-embolism to the lungs is usually less serious than a cerebrovascular episode. Surgery in form of replacement of the mechanical tricuspid valve with a bioprosthesis can be considered in patients with failed thrombolysis, recurrent thrombosis, evidence of pannus or contraindications to thrombolytic therapy

LEFT-SIDED OPVTThe treatment of OPVT includes surgery (thrombectomyorvalvereplacement)&thrombolytic therapy. Heparin therapy is clearly found to be inferior to both surgery and thrombolysis for obstructive thrombosis cases, and should not be considered as a definitive treatment.Roudaut and coworkers reported their non-randomized, retrospective, and single-center study on prosthetic valve obstruction in 210 patients (263 episodes).11 The study results showed that the two treatment arms had similar mortality rates (surgery 10% versus fibrinolysis 11%), and the authorsfavoredsurgicaltherapyoverfibrinolysisas the embolic and major bleeding complications in the fibrinolytic groupwere higher than in those patients treated surgically (15% to 0.7%, and 4.7% to 0.7%, respectively). In addition, complete hemodynamic success was obtained in only 70% of cases with fibrinolytictherapy (compared to 89% with surgery).

In an International multicenter registry (PRO-TEE study), patients with PHVT underwent thrombolysis, and all of them had undergone TEE before therapy.3 The registry comprised 107 patients, 93 of whom had OPVT, and 14 had NOPVT. The agents used for fibrinolysis were streptokinase (54.7%),urokinase (17%), and t-PA (28.9%). All fibrinolyticagentswereadministeredfora longer period of time, and streptokinase was even used for 120 h. The t-PA dosage was a 10-mg bolus, followed by 90 mg in 2-6 h. Complete hemodynamic success was achieved in 76.3% of the 93 obstructed valves and was similar among different valves and lytic agents. Partialhemodynamic success was infrequently seen (8.6%). This study found a previous

history of the cerebrovascular event and a thrombus size > 0.8 cm2 as one of the major risk factors for systemic embolic complications of thrombolytic therapy.

In the most recent European12 and American guidelines,7 surgery is recommended for patients in NYHA functional classes III and IV unless surgery is high-risk (class IIA). Thrombolysis is given a IIA indication in patients with right-sided valve thrombosis and a class IIB indication in patients with a left-sided but small thrombus. The European Society of Cardiology guidelines13 also emphasized surgery for critically ill patients and restrict thrombolysis to patients with high surgical risk and/or right-sided valve thrombosis. However, the results of more recent studies have reported better outcomes with thrombolytic therapy than did the previous reports, and suggested that thrombolytic therapy would be the treatment of choice in all cases except for patients with contraindications to these agents. Caceres-Loriga and colleagues reported complete success in 85% of cases and partial success in 6% with thrombolytic therapy in their study with 68 patients during a 6-year period.13 Nagy and coworkers reported the results of thrombolytic therapy in 62 OPVT cases;14 complete success was achieved in 73% of these cases, and partial success in 21%, while the mortality (8%) and embolic complication (12%) rates of thrombolytic therapy were similar to those of previous studies and superior to surgery.

In a recent literature survey, 17 studies with clinical out-comes of 756 patients who received thrombolytic agents for treatment of 801 episodes of OPVT were analyzed.15 Of the data that were available in 665 patients, 35% presented in NYHA functional classes I/II and 65% presented in NYHA functional classes III/IV. Complete success was achieved in 81% of patients presenting in NYHA functional classes I/II and 74% of patients presenting in NYHA functional classes III/IV. Streptokinase was used in 12 of the 17 studies. The rate of thromboembolism was 14% and the overall 30 days mortality was 8%. In the largest series of patients with PVT, atrial

fibrillation, obstructive thrombus, largerthrombus, and poor functional capacity, the so-called predictors of poor outcome in thrombolytic treatment of PVT, did not seem to predict the combined endpoint in PVT patients.16 However, similar to the PRO-TEE study, thrombi > 0.9 cm2 were associated with increased major and minor embolic events.

TROIA trial was the largest cohort study of thrombolytics for PHVT published.16 It was a single center study where thrombolytic regimens were constantly re-evaluated for complications and success rates periodically. TROIA usedoverallfiveregimens–rapidSTK,slow STK, rapid full-dose TPA, slow half-dose TPA, and very low-dose slow TPA success of lysis was almost equal in all regimens while complication was least in very low-dose TPA. It was completely TEE-guided thrombolysis and was a nonrandomized study and high thrombus burden cases were likely to be sent for surgery. Repeat doses of thrombolytics were given in event of failure or partial success. The authors found that low-dose TPA (25 mg over 6 h) was found to have the lowest complication rates. Interestingly no mortality occurred in low-dose TPA despite having an adequate sample size of 120 episodes. Predictors of complications by multivariate analysis were any thrombolytic regimen other than low-dose TPA and a history of transient ischemic attack or stroke. Complication rates were least in the low-dose TPA group (10.5%) which is much lower than the previously reported complication rates in major cohort studies with STK. Thefinalsuccessratewascomparableinallfivegroups–thetimeinwhichtherewas good response was different withhigh dose and classical regimen resulting in faster opening of valve and resolution of obstruction. This could be crucial while thrombolysing critically ill patient where an early resolution of obstruction could be lifesaving. In this study, the sick population was not randomized, so critical patients may have been sent for surgery and therefore while applying the results, it is important to remember that in a setting where thrombolysis is the primary mode of treatment, very low


slow infusion may not be prudent for a sick high-risk group.

Sincethepublicationofthefirstcasereport of low-dose ultraslow TPA,17 this regimen has been evaluated in a larger trial and has shown promising results in the Ultraslow PROMETEE trial. This trial was a prospective observational single-center study, and they analyzed 114 patients with 120 episodes of PHVT who were thrombolysed with low-dose TPA 25 mg which was given over 25 h. Eight sessions were given in case of failure after session with heparin overlap for 6 h between consecutive sessions. Results were notable with remarkable success rates of 90% (85–95%). Mean dose of TPA required was 64 ± 48 mg. Recurrence occurred in six patients(6.3%).Significantpredictorsofthrombolytic failure were higher NYHA class at presentation, AF, and duration of suboptimal anticoagulation, valve area, and thrombus area. On multivariate analysis, only higher NYHA class was the significant predictor. Complicationsoccurred mainly during the initial sessions and there were four nonfatal major complications. Only one patient died due to refractory heart failure. Predictors of complications were higher NYHA class, AF, duration of suboptimal anticoagulation, and higher thrombus area. Major limitation of the study was that NYHA Class IV patients were underrepresented and these patients did not have a good outcome.

Allrecenttrialsofnewerfibrinspecificthrombolytics have shown encouraging results in success rates and fewer embolic events, major hemorrhages, and thus mortality. Success rates vary widely between 60% and 90%. Success rates defined in earlier studies did includepatients with complications also unlike in recent studies. It is clear from studies that low-dose TPA and ultraslow low-dose TPA have minor embolic complications due to slow lysis and lower bleeding complications than STK infusion. However, for NYHA IV patients, immediate surgery or thrombolysis is needed; hence accelerated regimens would be the better choice instead of low-

dose TPA in these type of cases.

THROMBOLYSIS VS SURGERYThere is no RCT comparing thrombolysis to surgery in PHVT. Most of the data are obtained from observational studies. A meta-analysis conducted by Karthikeyan et al. which compared studies comparing surgery to thrombolysis found that surgery resulted in complete success more than thrombolysis, though the differencewasnot statistically significant.18 Mortality was not significantly different betweenthe two groups though numerically it was more in the surgery group. Complications such as systemic embolism, major bleeding, and rethrombosis all occurred significantlylessinthesurgeryarm.Thus,they concluded that surgery is better than thrombolysis.

CONCLUSIONSOne of the most life-threatening complications of mechanical prosthesis is valvular obstruction by pannus, thrombus, or both. Until the 1990s, the treatment of choice for mechanical valve obstruction was surgery but over the last decade, thrombolysis has been used increasingly and has become an alternative to surgery as the first-line therapy in patientswithPVT. Tissue plasminogen activator at a low dose and with prolonged infusion time has recently contributed to the success of thrombolytic therapy, with decreased complication rates.19 Further decrease of tPA with prolongation of the regimen may be associated with lower complication rates. Low-dose and ultra-slow infusion of tPA may be a preferred alternative treatment regimen for PVT in the future, However, the response time is longer and TEE guidance is mandatory during the treatment. Hence, treatment approach can be to individualize the depending on NYHA class, thrombus burden, and availability of surgery.

NYHA Class I-II who have low thrombus burden should receive thrombolysis with low-dose, slow infusion while those with high thrombus burden should be planned for surgery as

the risk of surgery is likely to be lower (5–10%) versus risk of complication of thrombolysis (15–20%). In patients presenting with NYHA Class III, decision is to be individualized based on thrombus burden. Patients presenting with NYHA Class IV and cardiogenic shock/heart failure to be treated with classical dose thrombolysis as time is of great importance here and surgical mortality is very high.20

REFERENCES1. Barbetseas J, Nagueh SF, Pitsavos C, et al. Differentiating

thrombus from pannus formation in obstructed mechanical prosthetic valves: an evaluation of clinical transthoracic and TEE parameters. J Am Coll Cardiol 1998;32:1410–7.

2. Vongpatanasin W, Hillis LD, Lange RA. Prosthetic heart valves. N Engl J Med 1996;335:407-16.

3. Tong AT, Roudaut R, Ozkan M, Sagie A, Shahid MS, Pon-tes Junior SC, Carreras F, et al. Transesophageal echocar-diography improves risk assessment of thrombolysis of prosthetic valve thrombosis: results of the international PRO-TEE registry. J Am Coll Cardiol. 2004;43(1):77-84.

4. Ozkan M, Gursoy OM, Astarcioglu MA, Gunduz S, Cakal B, Karakoyun S, Kalcik M, et al. Real-time three-dimensional transesophageal echocardiography in the assessment of mechanical prosthetic mitral valve ring thrombosis. Am J Cardiol. 2013;112(7):977-983.

5. Biteker M, Gunduz S, Ozkan M. Role of MDCT in the evaluation of prosthetic heart valves. AJR Am J Roent-genol. 2009;192(2):W77.

6. Symersky P, Budde RP, de Mol BA, Prokop M. Comparison of multidetector-row computed tomography to echocardiography and fluoroscopy for evaluation of patients with mechanical prosthetic valve obstruction. Am J Car-diol. 2009;104(8):1128-1134.

7. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57(22)-185.

8. Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451-96..

9. Caceres-Loriga FM, Perez-Lopez H, Santos-Gracia J, Morlans-Hernandez K. Prosthetic heart valve thrombosis: pathogenesis, diagnosis and management. Int J Cardiol. 2006;110(1):1-6.

10. Duran NE, Biteker M, Ozkan M. [Treatment alternatives in mechanical valve thrombosis]. Turk Kardiyol Dern Ars. 2008;36(6):420-425.

11. Roudaut R, Lafitte S, Roudaut MF, Reant P, Pillois X, Durrieu-Jais C, Coste P, et al. Management of prosthetic heart valve obstruction: fibrinolysis versus surgery. Early results and long-term follow-up in a single-centre study of 263 cases. Arch Cardiovasc Dis. 2009;102(4):269-277.

12. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron- Esquivias G, Baumgartner H, Borger MA, et al. Guide-lines on the management of valvular heart disease (ver-sion 2012). Eur Heart J. 2012;33(19):2451-2496.

REVIEW ARTICLE


13. Caceres-Loriga FM, Perez-Lopez H, Morlans-Hernandez K, Facundo-Sanchez H, Santos-Gracia J, Valiente-Mustel-ier J, Rodiles-Aldana F, et al. Thrombolysis as first choice therapy in prosthetic heart valve thrombosis. A study of 68 patients.J Thromb Thrombolysis. 2006;21(2):185-190.

14. Nagy A, Denes M, Lengyel M. Predictors of the out-come of thrombolytic therapy in prosthetic mitral valve thrombosis: a study of 62 events. J Heart Valve Dis. 2009;18(3):268-275.

15. Huang G, Schaff HV, Sundt TM, Rahimtoola SH. Treatment of obstructive thrombosed prosthetic heart valve. J Am Coll Cardiol. 2013;62(19):1731-1736.

16. Ozkan M, Gunduz S, Biteker M, Astarcioglu MA, Ce-vik C, Kaynak E, Yildiz M, et al. Comparison of different TEE-guided thrombolytic regimens for prosthetic valve thrombosis: the TROIA trial. JACC Cardiovasc Imaging. 2013;6(2):206-216.

17. Nguyen PK, Wasserman SM, Fann JI, Giacomini J. Successful lysis of an aortic prosthetic valve thrombosis with a dosing regimen for peripheral artery and bypass graft occlusions. J Thorac Cardiovasc Surg 2008;135:691-3.

18. Karthikeyan G, Senguttuvan NB, Joseph J, Devasenapathy N, Bahl VK, Airan B. Urgent surgery compared with

fibrinolytic therapy for the treatment of left-sided prosthetic heart valve thrombosis: A systematic review and meta-analysis of observational studies. Eur Heart J 2013;34:1557-66.

19. Murat Biteker, IbrahimAltun,OzcanBasaran, et al. Treatment of Prosthetic Valve Thrmbosis: Current Evidence and Fututure Directions. J Clin Med Res.2015;7(12):932- 936.

20. Shanmugam Krishnan. Prosthetic Heart Valve Thrombosis: Diagnosis and Newer Thrombolytic Regimes. J. of Practice of Cardiovascular Sciences.2016;Vol 2(1):7-12.


Nutraceuticals: The New Age Therapeutics and Its Effect on Heart Health

REVIEW ARTICLE

SHIKHA SHARMA, REENA RAWAT, AASTHA JESSICAKeywords z nutraceuticals z heart health z cardiovascular disease z polyphenols

Dr. Shikha Sharma, Managing Director; Dr. Reena Rawat, Deputy Manager (Nutrition and Research) & Dr. Aastha Jessica, Assistant Manager (Nutrition and Research), Nutriwel Health India Pvt Ltd, New Delhi

Abstract

Cardiovascular disease (CVD) ranks among the most common health-related and economic issues worldwide. Dietary factors are important contributors to cardiovascular risk, either directly, or through their effects on other cardiovascular risk factors including hypertension, dyslipidemia and diabetes mellitus. Nutraceuticals are biologically active products derived from food sources that possess health benefits, in addition to the fundamental nutritional value found in foods.

Nutraceuticals are garnering prominence globally and becoming a part of an average consumer's regular diet. The key reasons for this is an increased rate of lifestyle diseases, increase in life expectancy and poor nutrition due to modern lifestyle choices.

The term "nutraceutical" is used to describe any food, or part of a food supplement, that offers a medical or health benefit beyond simple nutrition. Such benefits may also include the prevention or recurrence of certain diseases. Nutraceuticals range from proteins, vitamins, minerals, pure compounds used in capsules, tablets or foods that contain fortified bioactive ingredients. Everything from vitamins, supplements to sports drinks, dairy products, snacks, pre-prepared diet meals could be considered as nutraceuticals. As stated by Hippocrates “Let food be thy medicine” - nutraceuticals are the best example of it.

The phytochemicals present in the nutraceuticals have a wide range of therapeutic effects against a number of diseases like diabetes, heart disease, common cold, arthritis, hypertension, dyslipidemia, inflammatory bowel disease, depression etc. Compounds like phenylpropanoids, isoprenoids, polyphenols, anthocyanins, flavonoids, terpenoids, carotenoids, phytoestrogens and alkaloids, etc. are responsible for the beneficial effects of a diet rich in fruits and vegetables.


INTRODUCTIONCardiovascular disease (CVD) ranks among the most common health-related and economic issues worldwide. Dietary factors are important contributors to cardiovascular risk, either directly, or through their effects on othercardiovascular risk factors including hypertension, dyslipidemia and diabetes mellitus.12 Nutraceuticals are biologically active products derived from food sources that possess health benefits, in additionto the basic nutritional value found in foods. Nutraceutical products may claim to prevent chronic diseases, improve health, delay the aging process, increase life expectancy, or support the structure or function of the body. Several foods and dietary supplements have been shown to protect against the development of CVD.3

They are regulated as dietary supplements and food additives by the FDA under the authority of the Federal Food, Drug, and Cosmetic Act. A dietary supplement is a product taken orally that contains a dietary ingredient such as vitamins, minerals, herbs or other botanicals, amino acids, enzymes, organ tissues, and metabolites intended to supplement the diet whereas functionalfoodsarefortifiedorenrichedduring processing and then marketed as providingsomebenefittoconsumers.4

Nutraceuticals represent a new opportunity in the prevention and treatment of CVD. Majority of the CVD is preventable and controllable. Dietary factors are also important contributors

to cardiovascular risk, either directly, or throughtheireffectsonotherriskfactorsincluding hypertension, dyslipidemia, and diabetes mellitus. Reduction of risk factors in the population, especially blood pressure reduction and lipid-lowering can have important impacts upon mortality from CVD.1,2 It has been researched that a low intake of fruits and vegetables is associated with a high mortality in CardioprotectiveEffectofNutraceuticals.Several classes of nutraceuticals such as sterols and polyphenols have been proposed to have potential benefits inthe treatment of CVD Nutraceuticals in the form of antioxidants, dietary fibers, omega-3 polyunsaturated fattyacids, vitamins, and minerals are also recommended together with physical exercise for prevention and treatment of CVD.1,3

HEALTH BENEFITS OF NUTRACEUTICALSNutraceuticals range from isolated nutrients, herbal products, dietary supplements, and diets to genetically modifiedfoods, and processed products such as cereals, soups, and beverages. A nutraceutical is any non-toxic food extract that provides health benefitsfor both the treatment and prevention of disease as well.

z The phytochemicals

present in the nutraceuticals have a wide range of therapeutic effectsagainst a number of diseases like diabetes, heart disease, common cold, arthritis, hypertension, dyslipidemia, inflammatory boweldisease, depression etc. Compounds like phenylpropanoids, isoprenoids, polyphenols, anthocyanins, flavonoids, terpenoids, carotenoids,phytoestrogens and alkaloids etc are responsible for the beneficial effectsof a diet rich in fruits and vegetables.

z Isoflavonoids or soy products andflaxseed help in lowering the levelsof total and low-density lipoprotein cholesterol (LDL-C) and increase high-density lipoprotein cholesterol (HDL-C) resulting in reduced risk of CVDs. Phytoestrogens are also beneficialinthepreventionofCVDs.For CVD, important risk factors include obesity, hyperlipidemia, hypertension and diabetes which can be countered by phytochemicals.21

The importance of nutraceuticals is expanding globally in terms of services, legal aspects, and marketing strategies for health promotion, reduction of disease, and health care. The current consumer trend is to be preventive rather than react to the health issues, which involve huge costing for healthcare. The consumers are shifting their preference from synthetic ingredients to natural and organic ingredients.

Fatty acids like conjugated linoleic acid (CLA) present in meat and milk, polyphenols found in citrus fruits, vegetable, cocoa, mustard seeds and rape seeds, Saponins present in soybean, chickpea, and Lucerne (alfalfa), prebiotics/ probiotics/synbiotics, phytoestrogens, carotenoids, dietary fiber are all the components of a Nutraceutical. Few prominent examples of Nutraceuticals range from Barley Grass Extract, Soy Isoflavones, Alfalfa, Apple Cider Vinegar and Spirulina which are very beneficial for heart health.

The aim of this review is to present an update on the most recent evidence relating to the use of nutraceuticals in the context of the prevention and treatment of cardiovascular diseases.

Source: Variant Market Research

2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

CAGR 7.2% (2016-2024)

Figure 1. Global nutraceuticals market size and forecast, 2015-2024 (US$ Billion)


GLOBAL DEMAND FOR NUTRACEUTICALS

z The importance of nutraceuticals is expanding globally in terms of services, legal aspects, and marketing strategies for health promotion, reduction of disease, and health care. The current consumer trend is to be preventive rather than react to the health issues, which involve huge costing for healthcare. The consumers are shifting their preference from synthetic ingredients to natural and organic ingredients.

z Nutraceuticalingredientsfindagoodarea of application, right from cereals, grains, nuts, vegetables, fruits, dairy products and confectionery items to beverages like juices, energy drinks, sports drinks, etc. The functional food category is seeing the highest growth in energy drinks, healthy snacks, and breakfast products. Few examples of functional foods are yogurts with probiotics, drinks with herb blends, soy beverages rich in proteins, etc.

z Germany, the Netherlands and Sweden have emerged as the key nutraceutical innovation hubs in Europe, while the United Kingdom and Spain have emerged as the key test markets for new products, with the European consumers demanding energy providing products that promote healthy teeth, strong bones, prevent digestive health issues, boost immune system and lower cholesterol.19

COMPONENTS OF NUTRACEUTICALS1. Fatty Acids: Conjugated linoleic

acid (CLA) present in meat and milk are considered as the functional component which helps in improving the body composition and also reduces the risk of cancers. Omega 3 fattyacidprovidethehealthbenefitsto the heart patients and also helps in an improving mental and visual functions.

2. Polyphenols: Citrus fruits, vegetable, cocoa, mustard seeds and rape seeds are some of the food sources containing polyphenols such as flavonoids,catechins, and anthocyanins which are the functional components of the food. These provide various health benefits like neutralizing the freeradicals, reducing the risk of cancer and cardiovascular diseases.

3. Saponin: It is the food component present in soybean, chickpea, and

Lucerne (alfalfa), helps in lowering the cholesterol levels and is also anti-cancerous in nature.

4. Prebiotics/probiotics/synbiotics: The functional components present in these biological food products are lactobacillus (yogurt) and fructo-oligosaccharides (whole grains, onions, and a combination of pre and probiotics) which contributes in the improvement and maintenance of gastrointestinal tract.

5. Phytoestrogens: These are plant-derived estrogens also known as dietary estrogens. In human beings, phytoestrogens are readily absorbed into the circulatory system, circulate in plasma, and are excreted in the urine. Phytoestrogens (present in soybean,flax seeds, rye,maize, andlentils) have great beneficial effectson the cardiovascular, metabolic, central nervous systems as well as reduction of risk of cancer and postmenopausal symptoms.

6. Carotenoids: Carotenoids are organic pigments that are produced by plants and algae, as well as several bacteria and fungi. Carotenoids give the characteristic color to carrots, tomatoes, corn, egg yolks, bananas and many other foods. There are many kinds of carotenoids including beta-carotene, lutein, zeaxanthin, and lycopene. Beta-carotenes (oats, corns, carrot) works as antioxidants in the body whereas lutein and zeaxanthin (citrus fruits and vegetables, egg) provide healthy vision to an individual. Lycopene

Foods Nutraceuticals

Simple foods provide calorie and energy Nutraceuticals provide a health benefit

beyond the simple nutrition

Regular food helps to maintain the daily

bodily functions

Nutraceuticals have a medical, therapeutic or

health benefit, including the prevention and

treatment of disease

Absorption of nutrients from simple

food is low

Nutrient absorption from Nutraceuticals is

much higher than the regular food

Simple foods cannot treat any disease

and illness, but may only prevent it

Nutraceuticals are considered a category

that carries specific disease treatment or

prevention claims previously allowed only for

drugs.

Why Nutraceuticals Over Regular Foods?

Figure 2. Nutraceuticals market in India

2010-11

11,483

2017-18 (P)FYs

2019-20 (P)

38,590

54,74060,000

50,000

40,000

30,000

20,000

10,000

In R

s. C

r.

Source: IKON Marketing Consultants

REVIEW ARTICLE


containing foods such as tomatoes, help in preventing the prostate cancer.

7. Dietary fiber: Dietary fiber is theplant-derived food component that cannot be completely broken down by digestive enzymes. It has two main components namely soluble and insoluble fiber. Nutraceuticalproductshighindietaryfiberprovidethebeneficialeffectsforthediseaseslike colon and breast cancer. Dietary

fibercanbeusedinvariousfunctionalfoods like bakery, drinks, beverages and meat products which provides various health benefits includingimprovement of the gastrointestinal system, weight loss and maintaining cardiovascular system.Nutraceuticals supply concentrated

form of a biologically active component from the natural food, to enhance health in doses that exceed those that

Some examples for Foods turned into Nutraceuticals:Name Food Form Nutraceutical

Barley Contains high fiber, vitamins and

minerals, antioxidants, heart health

and diabetes protection are just

some of the barley nutrition benefits.

A regular person may not include

barley in his/her diet.

Barley Grass Extract: It is a concentrated form of antioxidants, like Vitamin C

and E. It is anti-inflammatory, anti-carcinogenic, anti-cholesterol and boosts

immunity.

In the form of a nutraceutical, it is easy to consume. It is also rich in functional

ingredients, such as gamma-aminobutyric acid (GABA), flavonoids,

saponarin, lutonarin, superoxide dismutase (SOD), K, Ca, Se, tryptophan,

chlorophyll, vitamins (A, B1, C, and E), dietary fiber, polysaccharide, alkaloid,

metallothioneins, and polyphenols. These nutrients are known to prevent

CVD.1,13,23

Soy Soy as food can be eaten in the form

of tofu, soybeans, soymilk etc. The

acceptance is low due to its taste.

Soy is converted into Nutraceuticals in order to provide maximum benefit

from it. Isoflavones are found in soybeans, chickpeas, and other legumes.

Isoflavones show tremendous potential to fight against diseases. They have

been shown to help prevent the buildup of arterial plaque, which reduces the

risk of coronary heart disease and stroke. Soy isoflavones have antioxidant

properties which protect the cardiovascular system from the oxidation of

LDL (the bad) cholesterol.22

Alfalfa Seeds Alfalfa sprouts contain a

concentrated amount of particular

vitamins and minerals such as vitamin

K, vitamin C, and Calcium.

Alfalfa is a perennial forage legume species with a high production of leaf

protein. Alfalfa saponins and phytoestrogens offer interesting medicinal

and nutraceutical prospects which are beyond the natural form of alfalfa. It

contains proteins, calcium and vitamin A, vitamin B1, vitamin B6, vitamin C,

vitamin E and vitamin K. The fresh alfalfa juice is found very effective in most

heart disease. Alfalfa is known to have a beneficial effect for heart diseases

as it has the cholesterol-lowering effect. Eating alfalfa seeds decreases total

cholesterol and “bad” LDL cholesterol. This is because of its high content

of saponins. It increases the excretion of compounds used to create new

cholesterol. Regular consumption of this herb can lower blood pressure,

balances hormones and prevents atherosclerosis.14,15

Apple Apple as a fruit contains vitamins,

minerals, and roughage which is

good for health. But do not show any

visible change no matter you follow

the saying “An apple a day keeps the

Doctor away”

Apple Cider Vinegar: It is made by crushing apples and squeezing out the

liquid and fermenting it to get converted into vinegar by acetic acid-forming

bacteria (acetobacter).

Various risk factor of the heart diseases can be improved by its consumption.

This specific vinegar helps to reduce obesity and improve the blood sugar

and insulin levels. It also lowers the cholesterol and triglyceride levels in

the body and hence reduces the risk of heart diseases. Drinking a lot of

apple cider vinegar can damage your teeth, hurt your throat, and upset your

stomach. If consumed in required amount apple cider vinegar will not harm

and instead provide health benefits to the body.

Its benefits are way beyond than eating an apple daily.16,17,18

could be obtained from regular food. A nutraceutical is demonstrated to have a physiological benefit or provideprotection against chronic diseases.

CONCLUSIONHypertension, dyslipidemia, and diabetes are the major risk factors for CVD. Current medical treatments for the management of diabetes and dyslipidemia in some especially high-risk patients are


insufficientandcurrentevidencesuggeststhat the application of nutraceuticals may have the potential to increase the effectiveness of therapy. Many of thenutraceuticals investigated such as Barley Grass,SoyIsoflavones,AlfalfaandAppleCider are known for the prevention and treatment of CVD are well tolerated in patients. However, there is often insufficientdataavailablewithrespecttolong-termsafetyandeffectivenessagainstclinical outcomes such as myocardial infarction and mortality. Further, clinical research should be conducted to identify nutraceuticals with the best clinical and cost-effectiveness in the prevention andtreatment of CVD. 12

Financial Support and SponsorshipNil.

Conflicts of InterestTherearenoconflictsofinterest.

AcknowledgementsThis review article was supported by Taniya Chadha (Assistant Manager-

Service and Research) and Swati Mishra (Senior Nutritionist). We thank our colleagues from Nutriwel Health India Pvt. Ltd. who provided insight and expertise that greatly assisted in writing this review article. We would also thank Dr. O.P.Yadava (Editor in Chief), Cardiology Today (NHI) for providing us with an opportunity to submit an article.

REFERENCES1. h t t p s : / / w w w. h i n d u s t a n t i m e s . c o m / b r u n c h /

nutraceutacles-the-new-age-food-therapy/story-1DWTRojWxWzWCj57OadpWP.html

2. Algae as nutritional and functional food sources: revisiting our understanding. Mark L. Wells,1 Philippe Potin,2 James S. Craigie,3 John A. Raven,4,5 Sabeeha S. Merchant,6 Katherine E. Helliwell,7,8Alison G. Smith,7 Mary Ellen Camire,9 and Susan H. Brawley 1

3. New Concepts in Nutraceuticals as Alternative for Pharmaceuticals. Hamid Nasri, Azar Baradaran,1 Hedayatollah Shirzad,2 and Mahmoud Rafieian-Kopaei2

4. https://en.wikipedia.org/wiki/Nutraceutical5. DEVELOPMENTS IN NUTRACEUTICALS. H. DUREJA, D.

KAUSHIK, V. KUMAR. Department of Pharmaceutical Sciences, M. D. University, Rohtak-124 001

6. Tomato as a Source of Carotenoids and Polyphenols Targeted to Cancer Prevention. Raúl Martí,1 Salvador Roselló,1 and Jaime Cebolla-Cornejo2,*

7. Nutraceuticals. P. Dudeja, R.K. Gupta, in Food Safety in the 21st Century, 2017

8. chrome-extension:/ /oemmndcbldboiebfnladdac

bdfmadadm/https://www2.deloitte.com/content/dam/Deloitte/global/Documents/Life-Sciences-Health-Care/gx-lshc-hc-outlook-2018.pdf

9. Nutraceuticals Market - Segmented By Type (Functional Foods, Cereal, Bakery and Confectionary, Dairy, Snacks, Others), By Geography (North America, South America, Europe, MEA, APAC) - Growth, Trends and Forecasts (2018 - 2023)

10. http://www.nutraceuticalseurope.com/event/why-nutraceuticals/

11. h t t p s : / / w w w . n u t r a c e u t i c a l s n o w . c o m /articles/2017/02/15/introduction-winter-2017-issue/

12. The role of nutraceuticals in the prevention of cardiovascular disease. Bozena Sosnowska,1 Peter Penson,2 and Maciej Banach 1,3.

13. Preventive and Therapeutic Role of Functional Ingredients of Barley Grass for Chronic Diseases in Human Beings. Yawen Zeng,1 Xiaoying Pu,1,2 Jiazhen Yang,1,2 Juan Du,1 XiaomengYang,1 Xia Li,1 Ling Li,3 Yan Zhou,4 and Tao Yang1

14. http://www.drvikram.com/alfa-alfa.php15. https://www.healthline.com/nutrition/alfalfa#section216. https://en.wikipedia.org/wiki/Apple_cider_vinegar17. https://www.healthline.com/nutrition/6-proven-health-

benefits-of-apple-cider-vinegar#section518. https://www.healthline.com/nutrition/6-proven-health-

benefits-of-apple-cider-vinegar#section519. https://en.wikipedia.org/wiki/Spirulina_(dietary_

supplement)20. https://www.nutrex-hawaii.com/blogs/learn/what-

exactly-is-spirulina21. https://www.healthline.com/nutrition/10-proven-

benefits-of-spirulina#section522. https://www.fwhc.org/health/soy.htm23. https://www.medicalnewstoday.com/articles/295268.

php

REVIEW ARTICLE


QT Interval

ECG OF THE MONTH

SR MITTAL

AbstractQT interval extends from the beginning of q wave to end of T wave. QT interval shortens with increasing heart rate. Bazett’s formula is most commonly used for rate correction. Corrected QT interval (QTc) normally ranges between 360 to 480 ms. QT interval can be prolonged due to a gene mutation. Patients with hereditary long QT syndromes have risk of ventricular arrhythmias, syncope and sudden death specially when exposed to triggers like exertion, emotion, swimming or auditory stimuli. Several drugs also prolong QT interval. Risk of Torsades de pointes in patients with drug-induced QT prolongation depends on comorbidities. Hypokalemia, acute coronary syndrome, head injury, intracerebral hemorrhage and high degree or complete atrioventricular block with Stokes-Adams attacks are also associated with prolongation of QT interval. QT interval less than 320 ms is considered as ‘short’. Hereditary short QT syndrome is rare but may be associated with an increased risk of atrial fibrillation, syncope and even sudden death. Hyperkalemia, acidosis, digitalis, anticonvulsants and early repolarization are also associated with short QT interval.

Keywords z arrhythmias z congenital long QT syndromes z congenital short QT syndrome z sudden death z syncope z torsades de pointes

DEFINITION QT interval extends from beginning of QRS complex to the end of T wave.

MEASUREMENT Automated measurement can be used for working purpose if ECG is normal. Auto-mated measurement should be confirmed by manual measurement if end of T wave is not well defined or T wave is notched or biphasic. It should be measured from the lead in which it is longest usually in leads V2 to V4

1. If U wave fuses with the end of T

Dr. SR Mittal is Head, Department of Cardiology at Mittal Hospital and Research Centre, Ajmer, Rajasthan

wave, point of notch between ‘T’ and ‘U’ wave should be taken as end of T wave2 (Figure 1). In tachycardia, end of T wave may fuse with beginning of next P wave. In such a situation, junction of T wave and P wave should be taken as end of T wave3 (Figure 2). If T wave is notched, end of terminal wave should be taken as end of T wave (Figure 3). If the end of T wave does not touch the baseline, a tangent should be drawn from the steep portion of the down slope of T wave. Point where the tangent touches the baseline should


be taken as end of T wave (Figure 4).

CORRECTION FOR HEART RATE QT interval shortens with increasing heart rate. Exact significance of QT inter-val can be judged only after correcting it for heart rate. Several formulae have been proposed4 Bazett’s formula5 is most com-monly used. It is as under :

QTc = (QT interval (in millisecond))/ (√(R-R) interval (in seconds))

R-R is the preceding R-R interval. It is not possible to measure corrected QT interval in irregular rhythm and in patients with wide QRS.

NORMAL VALUE OF QTCIt ranges between 360 ms to 480 ms6

QT PROLONGATION CausesCongenital long QT syndromes- - Jarvell – Lange- Nielsen syndrome Prolonged QT interval is associated

with congenital deaf-mutism, faint-

ing attacks and sudden death. There is no structural heart disease.7

- Romano-Ward syndrome Prolonged QT interval is associated

with fainting attacks and sudden death. However, there is no deaf-mut-ism.8,9

- Anderson Tawli syndrome It is characterized by a triad of peri-

odic paralysis, skeletal abnormalities (eg. short stature and scoliosis) and ventricular arrhythmias.10 Electrocar-diogram shows pronounced QTc pro-longation, prominent U waves, pro-longed terminal T wave down slope

and ventricular ectopics.10 - Timothy syndrome Fetal bradycardia, extreme prolonga-

tion of QT interval are often associat-ed with macroscopic T wave alternans and 2:1 AV block at birth.10 Cognitive and behavioural problems and im-mune dysfunction may be seen. In addition to these syndromes, muta-tion of several other genes have been linked to long QT syndrome. In many cases QTc may not be prolonged in the resting ECG (concealed long QT). QTc may be prolonged only during stress or after ectopic beats (Figure 5).

ECG OF THE MONTH

Figure 1. Electrocardiogram (leads V2 and V3) showing fusion of T and U wave. QT interval is measured from beginning of QRS wave to notch between T and U wave.

Figure 2. Electrocardiogram (leads V3 and V4) showing sinus tachycardia with fusion of T and P wave. QT interval is measured from beginning of QRS to the point of fusion between T and P wave.

Figure 3. Electrocardiogram (leads V4 and V5) showing notched T wave. QT interval is measured from beginning of QRS to end of terminal part of T wave.

Figure 4. Electrocardiogram (leads V3 and V4) showing tangent method to determine point of end of T wave.

Figure 5. Electrocardiogram (leads II and aVR) showing post ectopic pro-longation of QT interval (*). PVC- Premature ventricular contraction.

Figure 6. Electrocardiogram (leads II and V6) showing pro-longed isoelectric ST segment with late onset T wave.


It is always prolonged before fainting spell.

A variety of T wave morphologies have been described to be associated with the most common long QT syndromes.11 QT 1 is associated with smooth, broad based T waves. LQT 2 is associated with notched or bifid T waves (Figure 3). LQT 3 is often associated with a prolonged isoelectric ST segment with a late onset T wave (Figure 6), asymmetrical

or biphasic T waves. However, these electrocardiographic findings have not been found to be specific.10 Correct diagnosis of the type of long QT syndrome is possible only by study of gene mutation. However, these T wave morphologies may increase suspicion about the presence of long QT syndrome. Beat to beat variation in amplitude or polarity of

T wave (T wave alternans) (Figure 7 & 8) also suggests increased risk of torsades-de-pointes. Torsades de pointes (torsion around a point) is a type of ventricular tachycardia with changing QRS polarity. It is very rapid, usually ill sustained and associated with syncope.

- Significance of congenital prolonga-tion of QTc

Patients with congenital long QT syndromes have high risk of arrhythmias, syncope and sudden death. Other mutations in long QT susceptibility genes are mostly without consequence.10 However, triggers like exertion, swimming, emotion, auditory stimuli and post partum period can rarely increase electrical notability of heart resulting in potentially life-threatening arrhythmias. 10,12

Figure 7. Electrocardiogram (leads V2, V3 and V4) showing alternating change in amplitude of T wave (T1 and T2) and QT interval (QT1 and QT2).

Figure 8. Electrocardiogram (leads II, V2 and V5R) from a patient receiving ivabradin, diltiazem and ranolazine. Lead II showing bradycardia, Lead V2 showing alternans in T wave polarity (T1 and T2) and QT interval, Lead V5R showing ventricular ectopic (PVC) and torsades de pointes (Tdp).

Figure 9. Electrocardiogram (leads I, II, III). (a) at admission showing atrial flutter with fast ventricular rate. (b) showing QT prolongation after Amiodarone.

Figure 10. Electrocardiogram (leads V1) (a) showing atrial fibrillation with controlled ventricular rate (b) and (c) patient on Digoxin + Amiodarone + Sparfloxacin. Showing prolongation of QT and torsades de pointes (Tdp (d) Disappearance of ectopics and torsades de pointes, after stopping amiodarone and sparfloxacin.

Figure 11. Electrocardiogram showing QT prolongation in acute myocar-dial ischemia.


ECG OF THE MONTH

Acquired long QTcCauses Drugs- There is a long list of drugs

that can prolong QT. However only some drugs predispose to risk of tor-sades de pointes.

- Antiarrhythmics Class IA- Quinidine, Procaina-

mide, Disopyramide13 QT interval is prolonged. T wave amplitude is decreased. U wave amplitude is in-creased. QRS prolongation is mini-

mal. Class IC- Flecainide13

There is broadening of QRS. QT pro-longation is minimal.

Class III- Sotalol, Ibutilide

Promotility drugs- Cisapride Different drugs prolong different

parts of QT interval. Amiodarone prolongs J point to peak of T wave. Quinine prolongs T peak to T end in-terval.

- Risk factors for drug induced tor-sades- de- pointes

Torsades-de-pointes is uncommon with drug induced QT prolongation alone. Most patients have at least one identifiable risk factor in addition to QT prlongation.14 These include

- Magnitude of QT prolongation Patients who develop drug in-

duced torsades de pointes usually have QTc > 500 ms15

- Drug responsible for QT prolon-gation

mQuinidine, procainamide, dofe-tilide, ibutilide, have high-risk of torsades de pointes.

m Amiodarone (Figure 9), drone-darone, ranolazine, lithium, ter-fenadine, astemizole, antibiotics, antipsychotics and other non car-diovascular drugs also prolong

Figure 12. Electrocardiogram (leads V5R) showing bradycardia and ventricular ectopic (PVC). Lead V2 showing ventricular ectopics and torsades de pointes (Tdp).

Figure 14. Electrocardiogram from a case of acute anterior infarction (a) leads V1 to V6 recorded at conventional speed of 25mm/ sec. (b) leads V2 to V5 recorded at 50mm/ sec. QT is prolonged due to slurring of the terminal part of T wave (marked arrow). Duration from peak of T wave (Tp) to end of T wave (Te) is prolonged.

Figure 15. Electrocardiogram (leads V2 to V4) from a case of acute coronary Syndrome. QT is prolonged due to slurring of the terminal part of T wave (arrow). Duration from peak of T wave (Tp) to end of T wave (Te) is increased.

Figure 13. Electrocardiogram (leads V3 to V6) from a patient of hypokalemia showing ST segment depression, reduced amplitude of T wave, prominent ‘U’ wave and prolon-gation of ‘Q-U’ interval.


QT but rarely produce torsades de pointes of their own.16

- Dose, route and rate of administra-tion

- Risk of torsades de pointes with so-talol is dose dependent. Haloperi-dol can produce torsades de pointes when given intravenously.

- Metabolism and excretion of drug- Hepatic and/ or renal insufficiency

can increase serum level of drug even when given in recommended dose.

- Concomitant use of other QT pro-longing drugs (Figure 10)

m Additive effect of drugs m Drug to drug interaction altering

metabolism- Electrolyte imbalance Hypokalemia, hypocalcemia, hy-

pomagnesemia- Cardiac status Gross heart failure, active myocardial

ischemia (Figure 11), extreme brady-cardia (Figure 12), frequent ventricu-lar ectopics, abrupt slowing of heart rate, recent conversion from atrial fibrillation.

- Genetic predisposition m Subclinical mutation in long QT

syndrome genes. m Reduced repolarization reserve. m Reduced rate of drug metabolism. Electrolyte imbalance- Hypokalemia- There is ST segment

depression, flattening of ‘T’ wave and prominence of ‘u’ wave. It is the QU internal that is increased (Figure 13).

- Hypomagnesemia- Hypocalcemia - ST segment is pro-

longed. T wave remains normal14

Heart diseaseMyocarditis Acute coronary syndrome- Terminal

part of T wave is slurred. Interval from T

peak T end (Tp-Te) is increased (Figure 14, Figure 15). QT normalizes over time (Figure 16).

HypothyroidismElectrocardiogram shows sinus

bradycardia, low voltage of all wave forms, inverted T waves without significant ST deviated in many or all leads and prominent ‘u’ waves.13

Head injury, intracerebral hemorrhage

There is widening and inversion of T waves in precordial leads with bradycardia.13

Figure 16. Electrocardiogram (leads V1 to V6) (a) At the time of admission (b) on 2nd day showing prolongation of QT interval (c) on fourth day showing normalization of QT inter-val.

Figure 17. Electrocardiogram (lead II) (a) showing complete AV block, (b) showing ven-tricular ectopics (PVCS), (c) showing runs of torsades de pointes (Tdp).

Figure 18. Electrocardiogram (leads V2, V3, V4) showing old anterior myocardial infarc-tion with short QT interval.


ECG OF THE MONTH

High degree or complete atrio-ventricular block

It predisposes to torsades de pointes (Figure 17). Giant inverted T waves are seen mostly after a syncopal attack (Stokes-Adam’s attack). Hypothermia

Short QT interval QTc less than 320ms is considered as short.10 (Figure 18)

Causes (i) Congenital short QT syndromes Patients with specific gene mutation

are susceptible to paroxysmal atrial fibrillation, ventricular tachycardia, syncope or even sudden death.17,18,19 Tall peaked T waves with narrow base are seen in precordial leads specially in leads V2 and V3 with either no or very short ST segment.10 J point to peak of T wave is short (100 ms or less). In general population, short QTc is rare and is not associated with cardiac risk.20,21

(ii) Acquired Electrolyte imbalance Hypercalcemia QT shortening is due to shortening of

ST segment. ST segment virtually dis-appears becoming incorporated into T wave.14

Hyperkalaemia Hypermagnesemia- Acidosis- Drugs Digitalis induced shortening of QTc is

associated with ‘coved’ or downslop-ing ST segment depression with flat-tened T waves.13 Changes are usually seen in leads with tall R waves.

- Anticonvulsants22

- Hyperthermia22

- Early repolarization They may be associated with short QT

interval.23 Early repolarization perse may be associated with increased risk of death.24 However, this increased risk is not related to shortening of QT interval.25

- Carnitine deficiency26 - Epilepsy27

It is not clear if shortening of QT in-terval is related to epilepsy perse or is an effect of anticonvulsants.22

REFERENCES1. Mirvis DM, Goldberger AL. Electrocardiography. In Mann

DL, Zipes DP, Libby P, Bonow RO(eds). Braunwald’s Heart Disease. Saunders, Philadelphia; 2015:114-152.

2. Goldenberg I, Moss AJ, Zareba W. QT interval: How to measures it and what is normal. J Cardiovasc Electro-physiol 2006:17:333-6.

3. Wagner GS, Lim TH. Interpretation of normal electrocar-diogram. In Wagner GS (ed). Marriott’s Practical Electro-cardiography. Wolters Kluwer, Philadelphia; 2008:43-70.

4. Luo S, Michler K, Johnston P, Macfarlane PW. A compari-son of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J Electrocardiol 2004; 37 (suppl):81-90.

5. Bazett HC. An analysis of the time relations of electrocar-diogram. Heart 1920; 7: 353-70.

6. Priori SG, Blomstorm- Lundquist C, Mazzanti A, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and prevention of sudden cardiac death. Eur Heart J 2015; 36:2793- 867.

7. Jervell A, Lange- Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the QT in-terval and sudden death. Am Heart J 1954;59-68.

8. Romano C, Gemme G, Pongiglione R. Rare cardiac ar-rhythmias of the pediatric age II. Syncopal attacks due to paroxysmal ventricular fibrillation(Italian). Clin Pediatr (Bologna)1963;45: 656-83.

9. Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc 1964; 54:103-6.

10. Tester DJ, Ackerman MJ. Genetics of cardiac arrhythmias. In Mann DL, Zipes DP, Libby P, Bonow RO (eds). Braun-wald’s Heart Disease. Saunders, Philadelphia ; 2015 : 617 -623.

11. Zhang I, Timothy KW, Vincent GM, et al. Spectrum of ST- T wave patterns and repolarization parameters in congeni-tal long – QT syndrome. ECG findings identify genotypes. Circulation 2000; 102 : 2849-55.

12. Goldenberg I, Horr S, Moss AJ, et al. Risk of life threaten-ing cardiac events in patients with genotype- confirmed Long QT syndrome and normal range corrected QT inter-vals. J Am Coll Cardiol 2010; 57 : 51-9.

13. Wagner GS, Wang TY. Miscellaneous conditions. In Wag-ner GS (ed). Marriott’s Practical Electrocardiography. Wolters Kluwer, Philadelphia ; 2008 : 209-237.

14. Kallergis EM, Goudis CA, Simantirakis EN, Kochiadakis GE, Vardas PE. Mechanisms, risk factors and manage-ment of acquired long QT syndrome: A comprehen-sive review. Scientific World Journal. 2012; Article ID: 212178, doi: 10.1100/2012/212178. Epub 2012 Apr 19.

15. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes Heart 2003; 89 : 1363-7.

16. Roden DM, Predicting drug induced QT prolongation and torsades de pointes. J Physiol 2016; 594: 2459-68.

17. Gaita F, Giustella C, Bianchi F, et al. Short QT syndrome : a familial cause of sudden death. Circulation 2003; 108: 965-70.

18. Brugada R, Hong K, Cordeiro JM, Dumaine R. Short QT syndrome. CMAJ 2005; 173 : 1349-54.

19. Perez- Riera AR, Paixao Almeida A, Barbosa- Barros R, et al. Congenital short QT syndrome : Landmarks of the newest arrhythmogenic cardiac channelopathy. Cardiol J 2013; 20:464-71.

20. Funada A, Hayashi K, Ino H, et al. Assessment of QT in-terval and prevalence of short QT syndrome in Japan. Clin Cardiol 2008; 31 : 270-4.

21. Reinig MG, Engel TR. The shortage of short QT intervals. Chest 2007; 132 : 246-9.

22. Shah RR. Drug- induced QT interval shortening: potential harbinger of pro arrhythmia and regulatory perspectives. British Journal of Pharmacology 2010; 159 : 58-69.

23. Watanabe H, Makigama T, Koyama T, et al. High preva-lence of early repolarization in short QT syndrome. Heart Rhythm 2010; 7 : 647-52.

24. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010; 7 : 549-58.

25. Tikkanen JT, Anttonen O, Junttila MJ et al. Long term out-come associated with early repolarization on electrocar-diography. N Eng J Med 2009; 361 : 2529-37.

26. Roussel J, Labarthe F, Thireau J, et al. Carnitine defi-ciency induces a short QT syndrome. Heart Rhythm 2015; 13:165-174.

27. Surges R, Taggart P, Sander JW, Walker MC. Too long or too short? New insights into abnormal cardiac repolari-zation in people with chronic epilepsy and its potential role in sudden unexpected death. Epilepsia 2010; 51 : 738-44.


Q1. In children T waves may be normally inverted in leads

(A) I, aVL(B) V5, V6 (C) V1 to V4(D) V7 to V9

Q1. QT interval extends from (A) Beginning of q wave to beginning

of T wave(B) Beginning of q wave to top of T

wave(C) Beginning of q wave to end of T

wave(D) Beginning of q wave to beginning

of ST segment

Q2. QT interval is usually longest in leads

(A) I, aVL(B) II, III, aVF(C) V2 to V4(D) V7 to V9

Q3. Which statement is correct(A) QT interval prolongs with

increasing heart rate(B) QT interval shortens with

increasing heart rate(C) QT interval shortens with

decreasing heart rate(D) QT interval is not affected by heart

rate

Q4. Bazett’s formula is (A) (QT interval in second))/

(√RR interval (in seconds))(B) (QT interval (in millisecond))/

(√RR interval (in milliseconds))(C) (QT interval (in millisecond))/

(√(R-R) interval (in seconds) )(D) (QT interval (in millisecond))/

(√(Heart rate))

Q5. Normal value of corrected QT interval is

(A) 250 to 300 milliseconds (B) 300 to 350 milliseconds (C) 360 to 480 milliseconds (D) 490 to 550 milliseconds

MCQs(C) Auditory stimuli(D) All

Q13. Which drugs predispose to risk of torsades de pointes

(A) Flecainide (B) Quinine (C) Ibutilide (D) Aminodarone

Q14. What magnitude of QTc prolongation predisposes to risk of torsades de pointes

(A) More than 350msec(B) More than 400msec(C) More than 450msec(D) More than 500msec

Q15. Risk of drug induced torsades de pointes is increased by

(A) Extreme tachycardia(B) Extreme bradycardia(C) Hyperkalemia (D) Active myocardial ischemia

Q16. Which factors predispose to risk of drug induced torsades de pointes

(A) Hypokalemia (B) Subclinical mutation in long QT

syndrome genes (C) Concomitant use of QT

prolonging drugs (D) Abrupt increase in heart rate

Q17. Which factors can predispose to risk of drug induced torsades de pointes

(A) Gross heart failure(B) Hepatic failure (C) Renal failure(D) Hypermagnesemia

Q18. Hypokalemia prolongs (A) QRS duration (B) ST segment duration (C) T wave duration (D) Duration of Q-U interval

Q19. ST segment is prolonged by (A) Hypokalemia

Q6. Congenitally prolonged QT interval with fainting attacks without deaf mutism suggests

(A) Jarvell – lange – Nielsen syndrome (B) Romano-Ward syndrome (C) Anderson Tawti syndrome(D) Timothy syndrome

Q7. In patients with hereditary long QT syndrome, QTc interval is

(A) Always prolonged at rest(B) Always prolonged during sleep(C) May be prolonged during stress(D) Is always prolonged before fainting

spell.

Q8. Which T wave abnormalities can be associated with long QT syndrome

(A) Smooth broad based T wave(B) Notched or bifid T wave(C) Biphasic T wave(D) All

Q9. T wave alternans means beat to beat variation in either

(A) T wave amplitude or (B) T wave duration or (C) T wave polarity (D) All

Q10. T wave alternans is associated with

(A) Increased risk of atrial fibrillation (B) Increased risk of atrio-ventricular

nodal re-entrant tachycardia(C) Increased risk of ventricular

tachycardia(D) None

Q11. Torsades-de-pointes is a type of (A) Atrial flutter (B) Atrial fibrillation (C) Atrio-ventricular re-entrant

tachycardia(D) Ventricular tachycardia

Q12. In hereditary long QT syndrome, syncope may be precipitated by

(A) Exertion (B) Swimming

QT Interval


Answers : (1) C, (2)C, (3)B, (4)C, (5)C, (6)B, (7)C,D, (8)D, (9)D, (10)C, (11)D, (12)D, (13)A,B,C (14) D, (15)B,D (16)A,B,C (17) A,B,C (18)D, (19)C, (20)A, (21)C,D, (22) A,B, (23) D, (24) D, (25) B,C,D, (26) D, (27) B,D, (28) A,B, (29) A,B, (30) A,B,C.(B) Hypomagnesemia (C) Hypocalcemia (D) Hypothyroidism

Q20. Interval from T wave peak to T wave end is increased in

(A) Acute coronary syndrome (B) Myocarditis (C) Heart failure (D) Acute pericarditis

Q21. Intracerebral hemorrhage produces

(A) Increase in duration of QRS (B) Increase in duration of ST segment (C) Widening of T waves(D) Inversion of T waves

Q22. Broad and inverted T waves are seen in

(A) Head injury (B) Stokes Adams attacks(C) Hypothyroidism (D) Hypokalemia

Q23. Risk of Torsades-de-pointes in increased in

(A) Hypothyroidism (B) Head injury (C) Hypothermia (D) Complete atrioventricular block

Q24. QT interval is considered short when QTc interval is

(A) Less than 400ms(B) Less than 380ms(C) Less than 350ms(D) Less than 320ms

Q25. In congenital short QT syndrome (A) QRS in narrow (B) ST segment is very short(C) T wave is narrow (D) T wave is tall and peaked

Q26. In general population, short QT interval is

(A) Very frequent (B) Frequent (C) Uncommon (D) Rare

Q27. Patients with congenital short QT syndrome are susceptible to

(A) Atrial flutter (B) Paroxysmal atrial fibrillation (C) Paroxysmal atrial tachycardia (D) Syncope

Q28. Acquired short QT interval is seen in

(A) Hyperkalemia (B) Acidosis (C) Hypocalcemia (D) Alkalosis

Q29. Which drugs can shorten QT in-terval

(A) Digitalis (B) Anticonvulsants (C) Antiarrhythmics (D) Antipsychotics

Q30. Which conditions are associated with short QT interval

(A) Hyperthermia (B) Early repolarization syndrome (C) Epilepsy (D) Raised intracranial pressure

ECG OF THE MONTH PICTORIAL CME


PICTORIAL CME

MONIKA MAHESHWARI

Dr. Monika Maheshwari is Professor, Jawahar Lal Nehru Medical College, Ajmer, Rajasthan

Unusual Dominant Left Circumflex Artery

A 40 year old man presented with atypi-cal chest pain. His physical examination was unremarkable. The ECG showed normal sinus rhythm with ST‐T changes. Selective coronary angiography showed a normal left main and anterior descend-ing coronary artery . However, the left

Figure 1: Left Coronary Angiogram (LAO: 59.6° Cranial : 91.2° view) showing giant and dominant left circumflex coronary artery.

Figure 2. Right Coronary Angiogram (LAO :35.1° Caudal : 2.6° view) showing hypoplastic right coronary artery

circumflex coronary artery was a very dominant and giant vessel (figure-1) to compensate for the right coronary artery which was hypoplastic (figure-2). There was no stenosis of any of the coronary arteries. The patient was discharged on antihypertensive medication