statins in the treatment of chronic heart failure - cardiovascular

Cardiovascular Research 71 (2006) 443–454www.elsevier.com/locate/cardiores

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Review

Statins in the treatment of chronic heart failure: Biological andclinical considerations

Pim van der Harst a,⁎, Adriaan A. Voors a, Wiek H. van Gilst b, Michael Böhm c,Dirk J. van Veldhuisen a

a Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen,The Netherlands

b Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlandsc Klinik and Poliklinik Innere Medizin III, Universitat des Saarlandes, Homburg, Germany

Received 5 February 2006; received in revised form 6 April 2006; accepted 19 April 2006Available online 27 April 2006

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Abstract

Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statinshave been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary arterydisease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levelsof cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in othercritical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggeststhat cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect ofstatin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora ofpleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictorylines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacologyof statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide anoverview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines ofevidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize theimportance of additional research specifically in CHF models and patients.© 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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Keywords: Chronic heart failure; Statins; Cholesterol; HMG-CoA reductase inhibitors

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The efficacy of 3-hydroxy-3-methylglutaryl co-enzyme-A inhibitors, or statins, in reducing morbidity and mortalityin patients with documented coronary artery disease (CAD)or those at increased risk of CAD has been overwhelminglyand indisputably demonstrated [1–15]. The result is thatstatin therapy is the treatment of choice in the primary andsecondary prevention of cardiovascular disease for almostevery suitable patient. But what if statin treatment has notbeen initiated? Is it still beneficial to begin statin treatment in

⁎ Corresponding author. Tel.: +31 503612355; Tel./fax: +31 503614391.E-mail address: [email protected] (P. van der Harst).

0008-6363/$ - see front matter © 2006 European Society of Cardiology. Publishedoi:10.1016/j.cardiores.2006.04.011

end stage CAD that has resulted in chronic heart failure(CHF)? Or might we do more harm than good? Evidence forstatin treatment in patients with established chronic heartfailure (CHF) has not been well established and remains asubject of debate [16,17]. CHF patients have beensystematically excluded from large clinical statin trials.Although a few smaller, uncontrolled trials do provide someevidence for the use of statins in CHF, there is some reason tothink that statins may have harmful effects in patients withCHF. For example, recent data suggests that high cholesterollevels are beneficial in a state of CHF, even when CADcoexists. In this article, the potentially harmful and beneficial

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http://dx.doi.org/10.1016/j.cardiores.2006.04.011

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effects of statins in CHF patients will be reviewed, both froma pathophysiological and a clinical perspective.

1. Cholesterol in CHF

Hypercholesterolemia is a well-known risk factor for thedevelopment of CAD and long-term morbidity and mortality,at least in middle-aged persons. However, controversialassociations have been found in elderly patients and inpatients with a wide range of chronic and acute diseases [18–24]. It seems that with advancing age or in critically diseasedpatients, the traditional association between elevated cho-lesterol and increased morbidity and mortality no longerapplies. In fact, serum cholesterol levels are inverselycorrelated with in-hospital mortality in patients withinfectious diseases [18,19] as well as acutely ill patients[20], regardless of malnutrition, frailty, inflammation, andcomorbidity. In the Framingham study, dyslipidemia initiallyappeared to be a risk factor for the development of CHF [25].However, subsequent studies have challenged this finding[26–28]. Importantly, in a more detailed analysis of the sameFramingham database, the association between total choles-terol and all-cause mortality was positive at 40 years of age,negligible at 50–70 years, and negative at age 80 years andabove [29]. Since both the incidence and prevalence of CHFis increasing steeply with age, the accepted associationbetween cholesterol and CHF might change [30]. Severalobservational studies have addressed the relationshipbetween serum cholesterol levels and outcome, specificallyin CHF patients. In 1998, Vredevoe et al., were the first toreport that lower total cholesterol was significantly associ-ated with increased mortality in patients with advanced,idiopathic CHF [31]. This observation has been confirmed inother studies, indicating that both in ischemic and non-ischemic CHF, higher cholesterol levels are associated withdecreased mortality [32–37]. Based on Receiver OperatingCharacteristic (ROC) curves analysis, the best cut-off levelfor total cholesterol in predicting mortality in CHF patients isestimated to be around 4.9–5.2 mmol/L (190–200 mg/dL)[32,35]. Mortality increased 25% for each mmol/L decreasein total cholesterol.

This phenomenon of ‘reverse epidemiology’ in CHF hasnot only been observed for serum cholesterol levels, but alsofor body mass index and blood pressure [38]. Nevertheless,previously mentioned studies were observational and do notprove causality. Low cholesterol could merely be aconsequence of advanced CHF, without a causal role, orhigh cholesterol could be an indicator of a greater metabolicreserve to deal with the disease [39,40]. Although severalstudies corrected for general health indicators, like nutritionalstatus, and cachexia, it remains possible that low cholesterolcarries a poor prognosis because it is a marker of poor healthor a consequence of CHF. Consequently, the association withmortality could be a consequence of inadequate adjustmentfor other confounding factors. Alternatively, lower mortalityamong patients with elevated cholesterol could be a

consequence of a selection bias. Patients surviving elevatedcholesterol could represent a selected subgroup withadvantageous genetic or other characteristics that protectthem from the harmful effects of high cholesterol. Finally,lower cholesterol might just mark an end-stage diseaseepiphenomenon, due to reduced hepatic cholesterol syntheticcapacity. Any of the aforementioned possibilities do notexclude the possibility that cholesterol may, even in a state ofCHF, still be a pro-atherogenetic factor. Further research intothe mechanism to explain the inverse associations remainsobligatory. Since it has not been established whether lowcholesterol is causally involved or is simply a marker,interventions aimed at lowering cholesterol will remaincontroversial. However, such an association betweenincreased mortality and lipid lowering therapy has as yetnot been demonstrated. Although high cholesterol seemsadvantageous in elderly patients, treatment with statins doesnot necessarily cause harm in these patients [8,10]. Theseseemingly contradictory findings might thus be explained bya difference in intrinsicly low cholesterol levels as comparedto pharmacologically induced low cholesterol levels.

2. Potentially harmful effects of statin treatment in CHF

Potentially harmful effects of statins in CHF are not far-fetched. In addition to the observed inverse relationshipbetween cholesterol and survival in CHF, there are otherlines of evidence suggesting adverse effects of statins. Mostnoteworthy are the endotoxin–lipoprotein hypothesis, thecoenzyme Q10 (ubiquinone) hypothesis, and the selenopro-tein hypothesis.

2.1. Endotoxin lipoprotein hypothesis

Rauchhaus et al. were the first to propose that higher levelsof cholesterol are beneficial in CHF on the basis of the abilityof serum lipoproteins to modulate the inflammatory immunefunction [41]. CHF patients have increased serum cytokinelevels, which might be linked to increased endotoxin levels[42]. Circulating cholesterol- and triglyceride rich lipopro-teins are natural nonspecific buffers of endotoxins (Fig. 1).They have the capacity to bind and detoxify bacteriallipopolysaccharides (LPS). LPS are very strong stimulatorsof the release of inflammatory cytokines from circulatingimmune competent cells and LPS are an important stimulusof proinflammatory cardio-depressive cytokine production inCHF. For example, LDL receptor deficient mice, withconsequently very high plasma cholesterol concentrationsare protected against lethal endotoxaemia and severe gram-negative infections [43]. Edematous and severely affectedCHF patients show substantial immune activation in parallelwith raised LPS plasma concentrations, comparable topatients with sepsis and liver cirrhosis [42]. In CHF patients,episodes of endotoxaemia can occur, and lowering oflipoproteins could adversely effect LPS bioactivity modifi-cation [41]. This hypothesis suggests that normal patients

Fig. 1. The hypothetical effects of statins on Chronic Heart Failure through the intermediates of the mevalonate pathway. HMG-CoA: 3-hydroxy-3-methylglutaryl co-enzyme-A; Sec-tRNA: Selenocysteine-tRNA[Ser]sec; Farnesyl-PP: Farnesyl pyrophosphate; t-t GGPP: trans–trans geranylgeranyl diphosphate;ATP: adenosine triphosphate; AT-1 receptor: angiotensin II type 1 receptor; NADPH: nicotinamide adenine dinucleotide phosphate-oxidase; eNOS: endothelialnitric oxide synthase.

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with CAD should be treated differently from patients withischemic CHF.

2.2. Ubiquinone hypothesis

The mode of action of statins through the inhibition ofmevalonate synthesis, decreases the production of ubiqui-none (Coenzyme Q10; Fig. 1). Indeed, in humans, statinshave been shown to cause decreased levels of ubiquinone inseveral studies [44–46]. In the heart, ubiquinone is mostabundant and represents an essential component of themitochondrial respiratory chain. Ubiquinone is involved inthe production of ATP and is therefore related to themetabolic demands of cells (Fig. 1) [47–50]. Anotherfundamental characteristic of ubiquinone is its antioxidant(free radical scavenging) property. By affecting mitochon-drial function through ubiquinone, statins might havedeleterious effects on skeletal or cardiac muscles. Thismechanism is thought to be involved in toxic myopathy, anadverse effect of statins, and might also be relevant in cardiacmuscle. This hypothesis is supported by the finding that in

CHF patients, deficiencies of ubiquinone have been foundfrequently, and are more prominent with increasing NYHAclass [51]. The reported decrease of ubiquinone with statintreatment, in both animal and human experimental studies,might therefore be harmful in CHF [44–46]. A clinical trialin CHF evaluating the efficacy of ubiquinone as anadjunctive treatment in major adverse cardiovascular eventsis currently ongoing [52].

2.3. Selenoprotein hypothesis

Reduction of mevalonate results in the reduction of isopen-tenyl-pyrophosphate (Fig. 1). Selenocysteine-tRNA[Ser]sec

(Sec-tRNA) controls the expression of all selenoproteins[53]. However, Sec-tRNA is only functional after essentialpost-transcriptional modification, one of which is the iso-pentenylation of adenoseine. Isopentenylation of Sec-tRNAis undertaken by tRNA isopentenyl transferase, which usesisopentenyl pyrophosphate (Fig. 1) as a substrate [54].The seloprotein hyopthesis postulates that statins interferewith the mevalonate pathway, which interferes with the

Fig. 2. Three-dimensional bar graph showing hypothetical relation ofdecreased coronary blood flow reserve (vertical axis) in relation toincreasing levels of cholesterol (horizontal axis) and decreasing LeftVentricular Ejection Fraction (LVEF; diagonal axis). Coronary blood flow isreduced in hypercholesterolemia [57,58] and in CHF a relative microvas-cular insufficiency exists [62,63]. Therefore, in patients with increasedcholesterol levels and CHF, coronary flow is jeopardized for two reasons.


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enzyme isopentenylation of Sec-tRNA, and consequentlystatins prevent its maturation to a functional tRNAmolecule [55]. Indeed, a strongly reduced selenoproteinsynthesis has already been demonstrated in cell cultureafter the addition of lovastatin [56]. Considering thatindividuals with statin-induced myopathy have very similarclinical and pathological features to those with syndromesassociated with severe selenoprotein deficiency, the fall inavailable selenoproteins might be particularly harmfull inCHF [55].

3. Potential beneficial effects of statin treatment in CHF

Besides reduction in cholesterol, statins also influenceother isoprenoid intermediates of the cholesterol biosyntheticpathway (Fig. 1). These intermediates are key moieties forposttranslational modification of numerous proteins. Someof these influences are of particular interest in CHF.

3.1. Capillary density and vascular function

Coronary blood flow reserve is strongly and inverselyrelated to serum cholesterol levels [57,58]. Several studieshave indicated that in patients with normal left ventricularfunction, cholesterol lowering drug therapy can improvecoronary blood blow [59,60]. These effects can be observedvery quickly after cholesterol lowering, as has been shownby single LDL apheresis, which improved coronary bloodflow within 24 h [61]. CHF is characterized by a relativemicrovascular insufficiency. The increase in myocytes inboth thickness and length is not adequately matched by aproportional increase in vasculature. In animal studies, it hasbeen found that the eccentric hypertrophy associated withCHF lacks the compensatory angiogenesis, in contrast tophysiological (i.e. exercise or anemia-induced) hypertrophyof the heart [62,63]. Consequently, in patients with increasedcholesterol levels and CHF, coronary flow reserve isjeopardized for two reasons (Fig. 2). A recent study fromJapan showed that cardiac function in CHF patients wasimproved after statin treatment in parallel with decreasinginflammation [64]. It is tempting to speculate that an increasein coronary blood flow was responsible for this effect [65].Furthermore, dysfunction of the endothelium, in bothcoronary and peripheral arteries, and independently ofserum cholesterol has been well documented in patientswith CHF [66,67]. Endothelial dysfunction in CHF patientswas associated with increased mortality risk [68]. Endothe-lial dysfunction in CHF is thought to reflect predominantlydecreased NO bioavailability (Fig. 3) [69]. Indeed, theeffects of statins on eNOS are the basis of the well describedfavourable effects of statins on endothelial dependentvasomotor function [70–73]. In patients with documentedCAD, statins reduced transient myocardial ischemia [74].Their anti-ischemic properties are thought to be a conse-quence of protein kinase Akt activation, subsequentlypromoting collateral growth and increasing capillary density

(Fig. 4A) [75]. This effect of statins on angiogenis is highlydependent on eNOS and is absent in eNOS deficient mice(Fig. 4B) [76]. Recently, the effects of statins on circulatingendothelial progenitor cells in humans have been reported[77,78]. These findings might provide another explanationfor the possible beneficial effects of statins on capillarydensity and vascular function in CHF patients.

3.2. Neurohormonal activation

The principal neurohormonal systems involved in thepathophysiology of CHF are the renin–angiotensin–aldos-teron system and the sympathic system. Therapies aimed atmodifying activation of these systems, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptorblockers (ARB), aldosteron inhibitors and beta-blockershave all been proven to be beneficial in the treatment of CHF.However, statins also modify these neurohormonal systems.In humans, high levels of cholesterol are known to increasethe expression of angiotensin type 1 receptors, andconsequently amplify the biological effects of angiotensinII [79]. In this regard, it is of particular interest that increasedexpression of cardiac angiotensin type 1 receptors is relatedto decreased myocardial microvessel density after experi-mental myocardial infarction [80]. Recently, we havedemonstrated that vasoconstrictor responsiveness to angio-tensin II can be modified by statin treatment in patients withdiseased coronary arteries [81]. Oral treatment with statinsinhibits rac1-GTPase activity and reduces angiotensin IIinduced NADPH oxidase activity, and subsequent oxidativestress, and might therefore be of particular relevance in theventricles of CHF patients [82]. Additionally, statins can

Fig. 4. (A) Adapted with permission from Kureishi et al. [75]. Alkaline phosphatase staining of the adductor muscle from ischemic limbs showing greatercapillary density in statin treated animals (statin=253±23 capillaries/mm2; control=163±9 capillaries/mm2); P<0.01. (B) Adapted with permission fromLandmesser et al. [76]. Effect of statin treatment on capillary density in infarct border zone of wild type (WT) and eNOS−/−mice after myocardial infarction (MI).Average number of endothelial cells per high-powered field in border zone for each experimental group is shown, as determined by platelet and endothelial celladhesion-molecule immunohistochemical staining.

Fig. 3. Simplified schematic overview of the known processes involved in atherosclerosis and the established effects of statin treatment.


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inhibit VEGF-induced ACE upregulation in endothelial cells[83] and enhance the efficacy of angiotensin receptorblockers [84–87].

Besides the renin–angiotensin system, statins can alsomodify the sympathetic system. β-Adrenergic receptorstimulation of cardiac myocytes leads to apoptosis. In rats,statins inhibit β-adrenergic receptor activation of Rac1 andconsequently inhibit the activation of the mitochondrialdeath patways and apoptosis [88]. Statin treatment alsodecreases sympathetic activity and delays the time of onsetof cardiac decompensation in pacing-induced dilatedcardiomyopathy in dogs [52,53].

3.3. Left ventricular hypertrophy (LVH)

Small G proteins are the molecular switches regulatingcardiac hypertophy and fibrosis. Ras, RhoA and Rac1 arekey mediators of the hypertrophic response [89,90]. Byblocking the synthesis of mevalonate, statins inhibitfarnesylation and geranylgeranylation of Ras, RhoA, andRac (Fig. 1) [91]. By inhibiting Rac, statins can inhibitangiotensin II induced [92–95] and noradrenalin [96]induced cardiac radical production and hypertrophy. In ratmodels of cardiac hypertrophy, induced by coarctation of theabdominal aorta, simvastatin treatment reduced the devel-opment of LVH [97,98]. Simvastatin was even more potentin its reduction of LVH than captopril treatment [98]. Also,pravastatin reduced left ventricular mass in patients withhypertension and hyperlipidemia, on top of anti-hyperten-sive treatment [99].

3.4. Atherosclerosis

Statins reduced the progression of coronary atheroscle-rosis in clinical studies [100,101]. Some studies evendemonstrated regression of atherosclerotic plaques withhigh doses of statins (Fig. 3) [102].

3.5. Inflammation

In patients with CHF, elevated systemic levels ofinflammatory parameters have been extensively documentedand associated with progression of CHF and death [103–106]. Several clinical trials have demonstrated the efficacy ofstatin treatment in reducing C-reactive protein [107,108] andother inflammatory markers (Fig. 3) [109,98].

3.6. Matrix metalloproteinase (MMPs)

Recent studies have documented that activated MMPsplay an important role in the development of CHF [110]. Inexperimental studies, production of MMPs was inhibited bystatins [111,112]. Inhibition of MMP attenuated cardiacfibrosis and failure in murine models [113].

The clinical relevance of all of these potentially beneficialeffects remains to be established in clinical studies.

4. Studies on statin therapy in CHF

4.1. Animal experiments

Several animal studies have suggested beneficial effectsof statins in the treatment of CHF. Cerivastatin treatment(starting 1 week after myocardial infarction) significantlyimproved left ventricular systolic and diastolic function inrats with CHF after experimental myocardial infarction[114]. In a murine model of CHF after myocardial infarction,treatment with fluvastatin 6 h after infarction increasedsurvival, without affecting infarct size [115]. Fluvastatin notonly attenuated LV dilatation, but also decreased LV end-diastolic pressure and improved LV ejection performance.However, not all studies favoured statin treatment in CHF. Infemale hamsters with inherited cardiomyopathy, lovastatintreatment significantly reduced median survival time from89 to 30 days [48].

4.2. Retrospective clinical studies

Several post-hoc subgroup analyses from large clinicaltrials have been published on the effects of statins in CHF. Inthe Cholesterol and Recurring Events (CARE) trial pravas-tatin significantly reduced coronary events in patients withdecreased left ventricular ejection fractions (LVEF), al-though the study excluded symptomatic CHF patients andpatients with a LVEF<25% [4]. In the Evaluation ofLosartan in Elderly II (ELITE II) trial, a retrospectiveanalysis suggested that symptomatic CHF patients usingstatins had decreased mortality compared to patients not onstatin therapy [116]. The effects of statins on mortality wereindependent of treatment with either captopril or losartan.The Scandinavian Simvastatin Survival Study (4S) [2]reported a long-term reduction in the development of CHFin patients with a history of myocardial infarction who wererandomized to statin therapy [117]. The PROSPER studyevaluated the benefits of pravastatin treatment in an elderlycohort with a high risk of developing cardiovascular diseaseand stroke [10]. Although PROSPER excluded CHF patientswith NYHA III/IV, the pre-specified outcome parameter‘Heart failure hospitalization’ did not differ betweenpravastatin treated and placebo treated elderly patients(Table 1). A post-hoc analysis of the Heart ProtectionStudy, involving more than 20,000 patients randomized tosimvastatin or placebo treatment, reported a non-significanttrend toward fewer CHF deaths due to any cause (70 (0.7%)vs. 86 (0.8%) patients; RR 0.81 [0.59–1.10]; P=0.2), whichwas supported by a marginally significant reduction in firsthospital admission for worsening CHF or CHF death (354(3.4%) vs. 405 (3.9%); RR 0.86 [0.75–1.00]; P=0.05) [118].An important limitation of the Heart Protection Study datawas that the presence of heart failure at study entry was notroutinely recorded. A subanalysis of the data from theProspective Randomized Amlodipine Survival Evaluation(PRAISE) trial was aimed at evaluating associations of statin

Table 1Large (>1000 patients) placebo controlled statin trials and CHF patients

Trial acronym, date Numberof patients

Intervention Prevention CHF patients Subgroup and secondary analysis

PMSGCRP, 1993 [1] 1062 Pravastatin 20 mg Primary Excluded4S, 1994 [2] 4444 Simvastatin 10–40 mg Secondary ExcludedWOSCOPS, 1995 [3] 6595 Pravastatin 40 mg Primary ExcludedCARE, 1996 [4] 4159 Pravastatin 40 mg Secondary Symptomatic CHF excluded LVEF 26–40% (n=706);

beneficial effect of statin treatmentAFCAPS/TexCAPS,

1998 [5]6605 Lovastatin

20–40 mgPrimary Excluded

LIPID, 1998 [6] 9014 Pravastatin 40 mg Secondary Symptomatic CHF excluded No information on CHFMIRACL, 2001 [7] 3086 Atorvastatin 80 mg Secondary Excluded NYHA IIIb/IV. No difference in new or worsening CHFGREACE, 2002 [11] 1600 Atorvastatin 24 mg Secondary NYHA III and IV excluded Reduction development of CHF

(n=11 vs. n=22). Beneficial effect ofstatin treatment in patients with NYHA II(n=118).

MRC/HPS, 2002 [8] 20,536 Simvastatin 40 mg Secondary Severe heart failure excluded Non-significant trend toward fewer heartfailure deaths due to any cause andmarginally significant reduction in firsthospital admission for worseningheart failure or heart failure death. [118]

LIPS, 2002 [9] 1677 Fluvastatin 80 mg Secondary Excluded LVEF<30% No information on CHFPROSPER,

2002 [10,128]5804 Pravastatin 40 mg Primary/

SecondaryExcluded NYHA III/IV. No difference in CHF hospitalisation.

ALLHAT-LLT,2002 [12]

10,355 Pravastatin 20–40 mg Primary Excluded

ASCOT-LLA,2003 [13]

10,305 Atorvastatin 10 mg Primary Excluded

ALERT, 2003 [14] 2102 Fluvastatin 40 mg andincreased to 80 mgafter 2 years

Renaltransplant

Not reported

CARDS, 2004 [15] 2838 Atorvastatin 10 mg Primary Excluded


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therapy with total mortality among 1153 patients with severeheart failure (ejection fraction <30% and NYHA class IIIBor IV symptoms) of ischemic and nonischemic etiologies[33]. Only 134 patients (12%) used a statin, but inmultivariate analysis this was associated with a 62% lowerrisk of death, which represents a major absolute riskdifference. In the Optimal Trial in Myocardial Infarctionwith the Angiotensin II Antagonist Losartan (OPTIMAAL)[119], the effect of initiating statin treatment in heart failureor left ventricular dysfunction in the acute phase after acutemyocardial infarction was studied post-hoc [120]. Afteradjustment for risk variables before inclusion, statintreatment was associated with a 26.1% decreased mortality.

However, the reported protective associations of statinuse in CHF do not prove causality, and are susceptible toconsiderable confounders and biases. First, probably thesingle largest major confounder in non-statin randomisedtrials can be found in the patient characteristics associatedwith the choice of the physician to prescribe a statin. Statintreatment could therefore have represented a selectedsubgroup. Such characteristics may include ones notregistered, thus unknown in the study databases andunadjused for in multivariate analysis, e.g. socioeconomicstatus, and healthy-heart behaviors. A major potentialconfounder is that patients with a short life expectationwill generally not be treated with statins. In addition, since

cholesterol levels inversely correlate with mortality in CHFpatients, (also in the aforementioned studies in patients notusing statins [33]) the possibility remains that statin therapyin these patients is simply a marker of higher pre-statincholesterol levels (often unavailable in study databases),predicting lower baseline risk. Second, some of these CHFstudies were conducted at a time when beta-blockers andspironolactone were not generally used in severe heartfailure. Third, most of the patients receiving statin treatmentat discharge were on statin treatment before inclusion in thestudy, further complicating this analysis. Finally, althoughstatin therapy seems to reduce new onset heart failure, itcould be related to effects on reduction of recurrentmyocardial infarction and subsequent CHF, rather thandevelopment of CHF without recurrent infarctions.

In conclusion, the effect of statin treatment in establishedCHF has not been definitely addressed by these studies.

4.3. Prospective clinical studies

There are limited data on the effects of statins inestablished CHF. One of the most noteworthy studies hasbeen performed in idiopathic dilated cardiomyopathy. Fifty-one patients were randomly assigned to simvastatin (up to10 mg/day) or placebo [64]. Using M-mode echocardiograpywith 2D monitoring before and after 14 weeks of treatment,


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Node et al. demonstrated improved functional capacity inpatients who received simvastatin compared to placebo. Inthe statin group, 39.1% of patients had an improvedfunctional class and 4.3% deteriorated. In contrast, in theplacebo group, 16% of patients improved and 12%deteriorated (P<0.01 between the groups). The functionalimprovement was associated with improved left ventricularejection fraction in the simvastatin group (from 34% to 41%,P<0.05), but not in the placebo group. Furthermore, plasmaconcentrations of TNF-a, IL-6 and BNP were significantlylower in simvastatin treated patients. Another prospective,double blind study randomised non-ischemic dilated cardio-myopathy patients to cerivastatin 0.4 mg versus placebo[121]. Quality of life and exercise capacity significantlyincreased in the statin group, but not in the placebo group. Inaddition, there was a trend towards increased left ventricularejection fraction and improved endothelial function. A smallstudy involving few CHF patients demonstrated improve-ment of reactive hyperaemia, associated with decreasedplasma concentrations of components of the thrombosis–fibrinolysis system and inflammation [122,123]. Therecently published Treating to New Targets (TNT) studyinvolving 10,001 CAD patients investigated the efficacy of80 mg versus 10 mg atorvastatin. The TNT study excludedpatients with a LVEF<30%. However, a prespecifiedsecondary outcome of the TNT trials was the incidence ofhospitalisation with a primary diagnosis of CHF. A total of164 (3.3%) of the patients on atorvastatin 10 mg vs. 122(2.4%) of the patients on atorvastatin 80 mg werehospitalized with a primary diagnosis of CHF; representinga 26% decreased hospitalization rate for congestive heartfailure in the high dose statin group (HR 0.74 [0.59–0.94];P=0.01) [124]. Thus, in patients with CAD, the TNT trialsuggests that the incidence of new onset CHF can be reducedwith statin therapy.

Despite a considerable amount of circumstantial evi-dence, so far no large randomised controlled clinical trailshave been published on the effects of statins in CHF patients.However, two large clinical trials are currently ongoing[125,126]. The Controlled Rosuvastatin Multinational Trialin Heart Failure (CORONA) will enroll about 4950 patientswith chronic symptomatic systolic CHF with ischemicetiology [125]. CORONA is an endpoint-driven trial that isexpected to last 52 months. The primary outcome is thecomposite endpoint of cardiovascular death or non-fatalmyocardial infarction or non-fatal stroke (time to first event).The GISSI heart failure trial will enrol approximately7000 patients to be randomised to n-3 polyunsaturatedfatty acids or matching placebo and where there is no clearindication for cholesterol-lowering therapy patients will befurther randomized to receive rosuvastatin or matchingplacebo [126]. In contrast to the CORONA trial, the GISSIheart failure trial will enroll patients with both ischemic andnon-ischemic heart failure. The GISSI heart failure trial isalso event driven and has two co-primary endpoints, namelyall-cause mortality and the combined endpoint of all-cause

mortality or cardiovascular hospitalisations. These twostudies are complementary in their inclusion of CHF patientsand will provide a more definite answer to the question ofwhether or not we should start statin treatment in patientswith established CHF.

5. Conclusion

Despite the widespread clinical use of statins forhypercholesterolaemia and prevention of CAD, data arelacking on the effects of statins on clinical outcome in CHF.Theoretical considerations and animal experimental dataindicate both beneficial and harmful effects of statins inCHF. In contrast, the currently available small-scale studiesand post-hoc analyses suggest a neutral or beneficial effect ofstatins, but no harmful effects. Currently, two large placebocontrolled trials are evaluating the efficacy of statin treatmentin CHF [125,126]. Until the results are presented, we arepracticing non-evidence based medicine when prescribingstatins to CHF patients. Currently, we do prescribe statins toCHF patients of non-ischemic etiology when cholesterollevels need to be treated according to the guidelines (basedon non-CHF populations). In CHF patients with coronaryheart disease, most physicians also feel more comfortableprescribing statins than withholding them.

If statins prove to reduce mortality and morbidity inpatients with CHF, future research should be aimed atelucidating the precise mechanism. This is of particularimportance since, in CHF, statins cholesterol loweringefficacy might be of secondary importance [127].

Acknowledgements

P.v.d.H. is supported by Zon-MW 920-03-236 of TheNetherlands Organization for Health Research and Devel-opment. D.J. van Veldhuisen is an Established Investigatorof the Netherlands Heart Foundation (grant D97-017). Welike to thank Maren White for her comments on a previousversion of the manuscript.

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