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Pathophysiology of Heart Failure Shi Yin Foo MD PhD Cardiovascular Translational Medicine Novartis Institute for Biomedical Research April 6 th 2011. Heart Failure: Epidemiology. In the US alone/yr: 6 million patients 600,000 incident cases 1 million hospitalizations Is deadly

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slide1

Pathophysiology of Heart Failure

Shi Yin Foo MD PhD

Cardiovascular Translational Medicine

Novartis Institute for Biomedical Research

April 6th 2011

slide2

Heart Failure: Epidemiology

  • In the US alone/yr: 6 million patients
  • 600,000 incident cases
  • 1 million hospitalizations
  • Is deadly
    • In-hospital mortality 4-5%
    • Short-term mortality (30day) 9-11%
    • Long-term mortality (1year) 24-28%
    • (5 year) 45-59%
  • Repeat hospitalizations are a significant burden
    • 14% at 30 days
    • 40% at 6 months
  • CHF costs are ~$55 billion annually, with hospitalizations >60%, medications ~5%

Both an opportunity and imperative for improvement

2 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

heart failure many causes to a final common outcome
Heart Failure: many causes to a final common outcome

Hypertensive heart disease

Right heart failure

Atherosclerosis

Cardiomyopathies

Rheumatic heart diease

Congential, inflammatory, and other causes

Heart failure : when the output of the heart is insufficient for the needs of the body

Organ hypoperfusion (most evidently renal)

Hepatic and pedal edema

Decreased exercise capacity

Pulmonary congestion

3 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

heart failure phenotypes and physiology
Heart Failure: Phenotypes and physiology

Atherosclerosis

Hypertension

Pressure overload

→ myocardial hypertrophy

Coronary occlusion

→ myocardial infarct

Systolic dysfunction

i.e. Heart Failure with impaired Ejection Fraction

“Diastolic dysfunction”

i.e. Heart Failure with Preserved Ejection Fraction

4 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

systolic dysfunction is better understood
Systolic dysfunction is better understood

HCVD – hypertensive cardiovascular disease

CHD – coronary heart disease

Etiology of Heart Failure (McKee 1971)

Heart failure as a result of hypertensive heart disease is ~60% of all heart failure

Nevertheless, systolic dysfunction is better understood and better treated

HFPEF is less tractable because it requires cellular-level approaches but has become increasingly important to understand and treat

5 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide6

The Heart as a Pump

-a focus on the left ventricle

  • Preload
  • Myocardial stretch determines contractility (Frank-Starling mechanism)
  • Afterload
  • Determines the energetics and efficiency of myocardial contractility
  • Affected by
    • total body volume
    • venous capacitance/return
    • pulmonary resistance
  • Affected by
    • systemic vascular resistance (blood pressure as surrogate)
    • discrete constrictions
    • intrathoracic pressure

Cardiac output = stroke volume x heart rate (Litres/min)

CO = SV x HR

6 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide7

The Heart as a Pump

PV loops as graphical representation of cardiac function

Pressure-Volume loops are useful to study/predict the effect of drugs on cardiac function, but physiologic changes are seldom only in one parameter

DDAH.org

Cardiac output = stroke volume x heart rate (Litres/min)

CO = SV x HR

Does not take into account myocardial energetics – inferred from systolic contractility, but no capture of diastolic energy use

7 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide8

The Heart as a Pump

Pathophysiological changes e.g., after myocardial infarction

Coronary occlusion

↑↑ myocardial workload and strain

Myocardial cell death

Blood pressure maintenance via vasoconstriction

(↑↑ afterload)

↓↓ Cardiac contractility

Fluid retention

(↑↑ preload)

↓↓ Renal perfusion

Secretion of neurohormones to maintain organ perfusion

8 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide9

What does Acute Decompensated Heart Failure look like?

- an example from the clinic

A 75-year-old man states that for the past two months, he has had gradually progressive fatigue; occasional cough; dyspnea (shortness of breath) during exertion; orthopnea (shortness of breath while lying down); ankle edema; and a 10-lb (22-kg) weight gain. He denies chest discomfort, fever, or chills. He has hypertension treated with diltiazem, quit smoking 20 years ago, and rarely drinks alcohol.

Physical examination :- Heart rate 105 bpm, blood pressure 145/85 mm Hg

Respiratory rate 18/min, oxygen saturation 94% on room air.

Distended jugular veins and mild hepatic fullness.

Pulmonary examination shows expiratory wheezing and wet rales.

The heart rate is regular without murmur, the apical impulse is displaced.

2+ ankle edema.

Laboratory values show acute renal failure with creatinine of 2.1mg/dL

Echocardiography shows moderate left ventricular dilation with segmental hypokinesis in the anterior wall, LVEF of 30%, left atrial enlargement, mild mitral and tricuspid valve regurgitation, and pulmonary artery systolic pressure ranging from 45 mm Hg to 50 mm Hg. Angiography in this patient shows a chronically occluded left anterior descending artery.

Cardiac output = stroke volume x heart rate (Litres/min)

CO = SV x HR

9 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

slide10

Freedom from the Congestion of Acute Heart Failure requires Preload Reduction, i.e. getting rid of body sodium and water

New York Heart Association Class

I – No symptoms or limitation of activity

II – Mild symptoms and slight limitation of ordinary activity

III – Marked limitations; shortness of breath with minimal exertion (20-100m walk)

IV – Severe limitations to activity; shortness of breath at rest, unable to perform activities of daily living without symptoms

Lucas C, et al. Amer Heart J 2000; 140: 840-7.

10 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide11

How clinically relevant are cardiac hemodynamics per se?

Fluid overload is the most proximal and common cause of acute heart failure

NYHA I

NYHA II

NYHA III

NYHA IV

% of HF

Patient s

NYHA

Classification

33%

6%

32%

29%

Compensated

  • 5-Yr Mortality = 50–70%*
  • Five-year mortality rates are comparable to certain types of cancer and other chronic diseases

Episode of acute decompensation

Chronically

Decompen-

sated

Clinical Status

  • 1-Yr Mortality = 10–20%*
  • One-year mortality rates increase dramatically with NYHA class progression

Acutely

Decompensated

Disease Progression

The underlying cause of HF hospitalizations has traditionally been viewed as a problem of fluid overload

11 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide12

The Heart as a Pump

Hemodynamic regulation and the Cardiorenal Axis

↑↑ myocardial workload and strain

↓↓ Cardiac contractility

Blood pressure maintenance via vasoconstriction

(↑↑ afterload)

Hemodynamic?

Neurohormonal?

Fluid retention

(↑↑ preload)

↓↓ Renal perfusion

Secretion of neurohormones to maintain organ perfusion

  • Homeostatic mechanisms activated when cardiac output↓↓ via the CardioRenal Axis
  • Derangements of this axis are arguably the single biggest driver of morbidity and
  • mortality in HF
  • What is the ideal point of regulation of this axis?

12 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide13

The Heart as a Pump

Neurohormones as key regulators of the heart as a pump

  • Neurohormones implicated in heart failure:
    • Renin-Angiotensin-Aldosterone System (RAAS)
    • Catecholamines
    • Endothelin
    • Natriuretic Peptides
    • Others
  • Neurohormones are potent and pleiotropic
    • affect myocardium, vasculature, renal, cerebral beds
    • affect short term hemodynamics and natriuresis (renal sodium loss)
    • regulate longer term fibrosis, remodeling, apoptosis

Modulations of the RAAS is best understood, validated and in clinical use

13 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

slide14

The RAAS system

Heart failure is usually a inappropriately high angiotensin II, aldosterone state

vasoconstriction and fibrosis

fibrosis

Aldosterone

↓perfusion

Salt/water retention, fibrosis

ACE

Renin

Angiotensin II

Angiotensin I

Angiotensinogen

14 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide15

Neurohormonal modulation affects heart failure outcomes

~ no mortality benefit of hemodynamic optimization

  • Neurohormonal activation contributes to
    • increased oxygen consumption
    • accelerated myocardial remodeling/fibrosis
    • lowered threshold for arrhythmias
  • Neurohormonal antagonism leads to
    • decreased mortality
    • decreased hospitalizations
    • improved symptoms and quality of life
  • CONSENSUS:
  • Severe HF
  • 6 mth mortality placebo =44%
  • ESCAPE:
  • Severe HF, hemodynamically optimized
  • No difference in morbidity or mortality

15 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide16

Implications of hemodynamics and neurohormones in HF

Acute symptom relief vs mortality

NYHA I

NYHA II

NYHA III

NYHA IV

% of HF

Patient s

NYHA

Classification

33%

6%

32%

29%

Compensated

  • 5-Yr Mortality = 50–70%*
  • Five-year mortality rates are comparable to certain types of cancer and other chronic diseases

Episode of acute decompensation

Chronically

Decompen-

sated

Clinical Status

  • 1-Yr Mortality = 10–20%*
  • One-year mortality rates increase dramatically with NYHA class progression

Acutely

Decompensated

Disease Progression

DEATH

Muntwyler J, Abetel G, Gruner C, et al. Eur Heart J. 2002; 23:1861-1866.

Ahmed A., Aronow W., Fleg J. American Heart Journal, Volume 151, Issue 2, Pages 444-450.

16 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

slide17

Heart Failure

~ summary and take-homes

  • Physiology of the heart can be likened to a pump
  • Cardiac hemodynamics can be predictable
  • Cardiac hemodynamics do not predict longer term cardiac outcomes
  • Neurohormones, especially the RAAS system, play a critical role in both the acute regulation of hemodynamics and the modulation of longer term morbidity and mortality
  • The lessons learned thus far apply only to systolic Heart Failure

17 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

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