Heart Failure in Women

Gender differences and similarities

Lynette W. Lissin, MD FACC

Palo 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
500
450
400
350
300
250
Death/100,000
200
150
100
50
0
CVD Stroke Breast CA
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

30

25.3
25 24.2
Death during Hospitalization (%)

21.8 21.5
Men Women
20 19.1
18.4

16.6

15 14.4
13.4

11.1
10.7
9.5
10
8.2
7.4
6.1
5.7

5 4.1
2.9

0
< 50 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

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).

Vaccarino NEJM 1999;341:217

One year mortality rates post MI

Schmidt,BMJ. 2012 Jan 25;344

 Women and CAD
Compared to men…..
Less classical symptoms
More related to diabetes, inactivity, obesity,
depression
2/3 women who die suddenly had no previous
heart attack
2x more likely to die soon after heart attack
Worse outcome after bypass surgery
 Incidence of CHD according to
menopausal status
4
3.5
Annual incidence per 1000

3
2.5
2 Pre-menopausal
Post-menopausal
1.5
1
0.5
0
40-44 45-49 50-54
Gender differences in symptoms

90
% chance of angiographic CAD

80
70
60
50 Women
40 Men
30
20
10
0
Typical angina
 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

80
70
60
50
% of population

40 Women
Men
30
20
10
0
35-44 45-54 55-64 65-74 75+
Age
Adapted from AHA 1999
 Hypertension
A Risk Factor for Cardiovascular Disease
Coronary Peripheral artery Cardiac
disease Stroke disease failure
50
45.4

Biennial 40 Normotensive
age- Hypertensive
adjusted 30
rate per 22.7 21.3
1000 20
subjects 12.4 13.9
9.5 9.9
10 6.2 7.3 6.3
3.3 5.0 3.5
2.4 2.0 2.1
0
Men Women Men Women Men Women Men Women
Risk ratio: 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0

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

V012005
 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, 8-14 mmHg
Ca, low fat
Sodium restriction < 2.4 g Na/day 2-8 mmHg

Physical activity At least 30 4-9 mmHg

minutes/day
Moderate alcohol No more than 1-2 2-4 mmHg
consumption drinks/day
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
 sympatholytics
Angiotensinogen + renin digoxin

Angiotensin I ACE inhibitors

converting enzyme

Angiotensin II bradykinin breakdown

AT II receptor
antagonists
receptor

Aldosterone
vasoconstriction aldosterone antagonists
cell hypertrophy
receptor
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