Heart Failure in WomenGender differences and similarities

Lynette W. Lissin, MD FACCPalo Alto Medical Foundation

April 21, 2012

Goals

• Epidemiology and types of heart failure• Differences in incidence, clinical

characteristics, prognosis in women vs. men• Myopathies specific to women

– Takotsubo, pregnancy, cancer rx• Contemporary treatment of heart failure

– Issues in women

CVD is the leading cause of death in women

CVD CA Stroke

Lung CA

Breast CA

050

100150200250300350400450500

Death/100,000

AHA 2003

Cardiovascular disease in women• Coronary artery disease

– Heart attacks, angina• Congestive heart failure

– Preserved systolic function/Hypertensive– Peri-partum cardiomyopathy– Chemotherapy induced cardiomyopathy– Autoimmune related cardiomyopathy

• Arrhythmia– Atrial fibrillation

• Valvular heart disease– Aortic stenosis– Mitral regurgitation

• Stroke• Pericardial disease

Sex differences: Physiology

• Compared to Men, Women have:– Lower LV mass– Greater contractility– Preserved mass with aging– Lower rate of apoptosis– Small coronary vessels– Lower blood pressure– Faster resting HR– Less catecholamine mediated vasoconstriction

Sex Hormones

• Estrogen– Receptors on cardiac cells– Estrogen affects hepatic gene expression– Improved lipids– Vascular effects: vasodilation– Stimluates immune system

• Affects cytokine/inflammatory pathways

• Testosterone– Increases inflammation/cholesterol

Heart Failure- Sobering Reality• Common diagnosis

– >5 million pts with CHF in US– 2.6 million women– 550,000 new dx per year

• Leading cause of hospitalizations– > 1 million annually– > 85% of CHF admissions > 65 years

• High Mortality Rate– 5-25 % per year– 53,000 deaths yearly

• Costly– $ 39.2 Billion spent on direct/indirect costs

– High rates of readmission• 25% at 30 days; 33% at 90 days; 50% by 6 months

Women vs. Men

• More non-ischemic etiology of HF• More HTN, diabetes• Older age at presentation• Lower QOL, more depression• More frequent LBBB• Similar hospitalization/readmission rates• Lower mortality/transplant rate in DCM• Lower representation in HF trials (17-23%)• Less procedures, including ICDs, CRT

Predictors of Mortality

• Acute presentation• Dyspnea at rest • Age >73 yrs • Systolic BP <125 mm Hg • Heart rate >78 beats/min• Sodium 132 mmol/l • BUN >37 mg/dl 2.53 • Cr >1.5 mg/dl

ADHERE J Am Coll Cardiol, 2006; 47:76-84

Systolic Dysfunction

• Coronary artery disease• Hypertension• Idiopathic• Familial• Infectious• Infiltrative• Toxic• Endocrine• Collagen vascular disease• Tachycardia-induced• Miscellaneous

Plaque Progression

Ross NEJM 1995

Coronary Heart Disease Mortality in Younger Women Higher than in Men

Vaccarino NEJM 1999;341:217

< 50 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

0

5

10

15

20

25

30

2.9

4.1

5.7

8.2

10.7

14.4

18.4

21.8

25.3

6.1

7.4

9.5

11.1

13.4

16.6

19.1

21.5

24.2

Men Women

De

ath

du

rin

g H

os

pit

ali

za

tio

n (

%)

Figure 1. Rates of death during hospitalization for Myocardial Infarction among women and men, according to age. The interaction between sex and age was significant (P<0.001).

One year mortality rates post MI

Schmidt,BMJ. 2012 Jan 25;344

Women and CAD

Compared to men…..Less classical symptomsMore related to diabetes, inactivity, obesity,

depression2/3 women who die suddenly had no previous

heart attack2x more likely to die soon after heart attackWorse outcome after bypass surgery

Incidence of CHD according to menopausal status

40-44 45-49 50-540

0.5

1

1.5

2

2.5

3

3.5

4

Pre-menopausalPost-menopausal

Annu

al in

cide

nce

per 1

000

Gender differences in symptoms

Typical angina0

102030405060708090

WomenMen

% c

hanc

e of

ang

iogr

aphi

c CA

D

Women’s Symptoms

• Prodromal– Unusual fatigue 70%– Sleep disturbance 48%– Shortness of breath 42%– Indigestion 39%– Anxiety 35%

• Acute– Shortness of breath 58%– Weakness 55%– Unusual fatigue 43%– Cold sweat 39%– Dizziness 39%– 43% did NOT have chest pain

Diastolic Dysfunction

• Heart Failure with Preserved Ejection Fraction “HFPEF”– Ventricular Hypertrophy– Constrictive/Restrictive– Diabetic

• Ischemia• Dilated Cardiomyopathy

Incidence of Hypertension

35-44 45-54 55-64 65-74 75+0

10

20

30

40

50

60

70

80

WomenMen

% o

f pop

ulati

on

Age

Adapted from AHA 1999

V012005

22.7

9.5

3.3 2.45.0

2.0 3.5 2.1

45.4

21.3

12.4

6.29.9

7.3

13.9

6.3

0

10

20

30

40

50

Men2.0

Women2.2

Men3.8

Women2.6

Men2.0

Women3.7

Men4.0

Women3.0

Kannel WB. JAMA. 1996; 275:1571-1576.

NormotensiveHypertensive

Coronarydisease Stroke

Peripheral arterydisease

Cardiacfailure

HypertensionA Risk Factor for Cardiovascular Disease

Risk ratio:

Biennial age-

adjusted rate per

1000 subjects

Lifestyle Modifications

Intervention Goal Effect on SBP

Weight reduction BMI 18.5-24.9 5-20 mmHg/10 kg weight loss

DASH diet Fruits, veggies, K, Ca, low fat

8-14 mmHg

Sodium restriction < 2.4 g Na/day 2-8 mmHg

Physical activity At least 30 minutes/day

4-9 mmHg

Moderate alcohol consumption

No more than 1-2 drinks/day

2-4 mmHg

Takotsubo Cardiomyopathy

Takotsubo Cardiomyopathy

• Reported by Japanese in 1990• “Broken heart”, apical ballooning, stress CM• Octopus trap appearance• Up to 90% women, age > 60• 70% with Severe emotional stress• Troponin moderately elevated• Echo resolution within ~ 30 days

Rivera et al. Med Sci Monit, 2011;17(6):RA135-147

Takotsubo Cardiomyopathy

• 1-2% of STEMIs• 2/3 CP, 1/3 STE, TWI, QT prolonged• Conservative mgmt, IABP, ?anticoagulation• Complications 19%: clot, shock, MR arrhythmia• Higher mortality in age > 75 and lower EF on

admission; 1-12%• Prognosis better than ACS• Recurrence is rare 3-15%• ? Long term treatment undefined

Mayo Clinic Criteria: all 4

• CP/dyspnea and STE or TWI• Transient hypokinesia or akinesia of mid-apical

regions and hyperkinesia of basal segments• Normal coronary arteries (< 50%) at onset• Absence of significant head injury, CNS

hemorrhage, pheo, myocarditis or HCM

Bybee et al. Ann Int Med 2004;141:858

Takotsubo Cardiomyopathy

• Elevated serum catecholamines• Higher density of Beta receptors in apex- more

vulnerable to sudden, high levels• High systolic apical wall stress, less elasticity, distal

blood flow “perfusion gradient”• Atypical, or apical sparing 1/3• Reduced estrogen after menopause

– ?indirect action on CNS or direct action on heart• Other conditions

– SAH , thyrotoxicosis, CVA, pheo, dobutamine stress

TCC Mechanism—Stunning??

• CNS– High catecholamines (>> than MI with CHF):

primary or secondary? Direct toxicity?– Density of receptors higher in males-?protective

or less resistant (?Less survival to recovery phase), but more catechol production to stress, more catechol-mediated vasoconstriction, or better repair in females (ie, survive)?

TTC: Mechanisms

• Metabolic– ?glucose or fatty acid metabolism – ?mitochondrial dysfunction

• Vascular– Abnormal vasoreactivity, spasm?, but why regional– Endothelial /microvascular dysfunction

• Endocrine– Striking sex difference, reduced estrogen levels

CMR in TTC

• Typical pattern of LV dysfunction• Edema• Myocardial necrosis with contraction bands• Little LGE (< MI, myocarditis)• +LGE more cardiogenic shock, longer recovery

of EKG, echo

CMR in TTC

Eitel et al. JAMA 2011;306(3):277-286

Stress management

Post-partum Cardiomyopathy

• 1/4000 live US births• 1 month pre or 5 months post-partum• Increased maternal age, multiparity, multiple

gestations, preeclampsia/HTN• 2.9x more likely in AA women• ?viral, immune, stress, prolactin, tocolysis, hereditary• Usual HF therapy, until resolved• 4% need transplant• Future pregnancies NOT recommended

Risk in Pregnancy

Adult Congenital Heart Disease and Pregnancy

• Women with CHD reaching child-bearing age• Contraindications of pulmonary hypertension,

severe LV failure, aortopathy, left sided obstruction

• Risk of HF, arrhythmia, fetal complications• Affected offspring

Heart Failure and Chemotherapy

• Breast cancer most common malignancy• Adriamycin

– Dose dependent cardiotoxicity (>450 mg/m2)– Clinical HF in 2-7% of pts; increases over time

• Herceptin– Reduces recurrence rate up to 50%– CHF in 2-4%; up to 3-27% after combination– Esp in pts with elevated troponin/BNP

• Cyclophosphamide, XRT

Monitoring for LV dysfunction

• Labs• Biopsy• Exercise testing• MUGA• **Echo• MRI

Pulmonary Hypertension

• Primary vs. Secondary– Left heart disease, shunts, PE, drugs

• Work up– Echo, RHC, sleep study, hypercoagulable eval

• Treatment– Vasodilators, Sildenafil, – Endothelin receptor antagonists– Ca Channel blockers

• Transplant– Heart-lung

Shunts: ASD, VSD

Right ventricle

Autoimmune Heart disease

• 80% of AD occurs in women• RA, SLE, Scleroderma, Myositis, Sjogrens,

Antiphospholipid syndrome• Inflammation via Abs and cytokines• RF + associated with mortality• Induced by infections• SLE associated with CAD, thrombosis• RA associated with MI, CHF, CVA

Heart Failure Management

• Identify and treat underlying etiology– Ischemia, valvular disorder, arrhythmia

• Non-pharmacologic therapy– Diet, exercise, follow up

• Drugs– Diuretics, digoxin, vasodilators, disease-modifying, anticoagulants

• Devices– IABP, PM, AICD, LVAD

• Transplant

Aldosteroneantagonists

AT II receptor antagonists

ACE inhibitors

sympatholytics

digoxinAngiotensinogen + renin

Angiotensin I

Angiotensin II

receptor

vasoconstriction

cell hypertrophy

aldosterone

converting enzyme

receptor

bradykinin breakdown

Efficacy of beta blockers

Greater benefit in women vs men

Pharmacologic therapy

• Ace inhibitors– Mortality benefit in symptomatic women

• ARB– Similar effect on women and men

• Digoxin– Increased mortality in women

• Aldosterone antagonists– Reduced mortality in women

ICD

                            

Trial data

• SCD-HEFT– No mortality benefit seen (23% women)

• MADIT-II– Benefit for women (16% enrolled)

• 5 trial metaanalysis– HR 1.01

• Including COMPANION– HR 0.78 (p=ns)

• Sudden death less common

Cardiac Resynchronization Therapy

                                                                                           

CRT

• NYHA Class II, III and IV• LV systolic dysfunction• QRS wide• Improves survival• Lower hospitalizations• Reduces symptoms• More LV volume

– reduction, increase EF Barsheshet et al. Nat Rev Cardiol. 2012;online

Summary

• Heart failure types more common in women– Diastolic HF, Takotsubo CM, pregnancy

• Compared to men, women have differences in cardiovascular:– Physiology– Etiology of disease, heart failure– Response to therapy