Inotropic state (myocardial contractility)

• Factors that influence the inotropic state affect ventricular performance at a given ventricular end-diastolic volume. These factors change the concentration of Ca²⁺ at the myofilaments and include in part:

  • Adrenergic nerve activity:  The amount of norepinephrine released by cardiac adrenergic nerve terminals is the most important acute factor in changing the position of the force-velocity in ventricular function curves.

  • Circulating catecholames:  Catecholamines released from adrenal medulla and other non-cardiac sympathetic ganglia stimulate cardiac adrenoceptors, thus increasing rate and force of contraction.

  • Exogenously administered agents:

    • Drugs that improve ventricular performance:

      • Cardiac glycosides

      • Dopamine (Intropin)/dobutamine (Dobutrex)

      • Caffeine

      • Isoproterenol (Isuprel)

      • Theophylline

      • Calcium

  • Drugs that decrease ventricular performance:

    • Procainamide (Procan SR, Pronestyl-SR)

    • Disopyramide (Norpace)

    • Certain calcium channel blockers

    • Alcohol

    • Barbiturates

    • Local and general anesthetics

• Physiological Depressants:  Depression of the myocardial force-velocity curves with decreased left ventricular function can occur with:

  • Hypoxia

  • Hypercapnia

  • Ischemia

  • Acidosis

• Loss of ventricular muscle mass:

  • When significant portions of the ventricle are hypokinetic or necrotic either due to ischemia or following myocardiac infarction, total ventricular performance may be significantly depressed.

Ventricular afterload

• Afterload is the stress developed in the wall of the ventricle during ejection and depends on aortic pressure and ventricular dimensions.

• Myocardial fiber tension is determined by the product of the intracavity ventricular pressure and radius divided by wall thickness (Laplace's law).

  • Therefore, for the same level of aortic pressure, afterload increases with ventricular dilation.

  • Left ventricular stroke volume is inversely proportional to afterload.

• In the failing heart with limited or no preload reserve (increasing preload in a normal heart increase contractility), afterload determines ventricular performance.

  • When afterload increases (increase in vasoconstriction) in the failing heart, cardiac output may be reduced further even while oxygen demand increases.

• Vasodilators may improve myocardial performance by reducing ventricular afterload.

Exercise

1. With exercise, venous return is significantly increased and results in enhanced ventricular filling and preload.

2. Increases in cardiac adrenergic activity and increases in circulating levels of catecholamines increase heart rate and enhance the myocardial contractility.

   • These factors result in significantly augmented cardiac output.

3.  Arterial pressure does not increase substantially since vasodilatation in exercising muscles offset the increase in cardiac output.

Myocardial Adaptation including Neurohumoral Adjustments

Adaptive mechanism to assist the failure heart

• Frank-Starling relationship: Increasing preload leads to increased cardiac output.

• Myocardial hypertrophy which tends to reduce ventricular wall tension towards normal.

• Redistribution of cardiac output from skin, kidneys, and skeletal muscle to the brain and heart.

• Neurohumoral adjustments which maintain arterial pressure

  • Renin-Angiotensin System (RAS): Activation of the RAS occurs with declining cardiac output.

    •  Increasing concentrations of circulating angiotensin II and aldosterone results in excess vasoconstriction and salt and water retention respectively.

    •  The clinical condition of patients with chronic heart failure may be improved by administration of aldosterone antagonists and ACE inhibitors.

      • Adrenergic System: Patients with heart failure often have significantly elevated circulating norepinephrine levels.

      • These levels provide critical inotropic support for the failing myocardium.

      •  Administration of beta-adrenoceptor antagonists to  patients with severe failure may worsen their congestive heart failure.

      • Administration of beta-adrenoceptor antagonists to patients with mild to moderate failure may be helpful in management of their congestive heart failure

Congestive Heart Failure: Causes

• Arrhythmias: In patients with heart disease and with a history of congestive failure, an acute arrhythmia is a common precipitating cause of CHF.

• Tachyarrhythmias decrease filling time and as a result decrease cardiac output. Since increased heart rate increases myocardial oxygen demand, cardiac ischemia may be induced which may lead to reduced contractility.	A-V dissociation results in loss of the atrial contribution to ventricular filling.  Therefore end-diastolic volume is reduced with an attendant reduction in cardiac output.
  Abnormal intraventricular conduction may cause a reduced synchronicity of contraction with a reduction in myocardial performance. Optimal output requires coordinated impulse propagation and contraction	Severe bradycardia in the absence of increased stroke volume can seriously reduce cardiac output and thus precipitate CHF.  Increased stroke volume may not be possible if the patient has significant heart disease.

   

• Myocardial Infarction: A myocardial infarction, reducing left ventricular function, may precipitate CHF in a previously hemodynamically compensated patient.

• Pulmonary Embolism: Physically inactive patients with low cardiac output may develop deep venous thrombi which may produce pulmonary emboli and elevation of pulmonary arterial pressure. Increased pulmonary artery pressure may worsen or cause left ventricular failure.

• Systemic Hypertension: Rapid increases in arterial blood pressure with associated increases in peripheral resistance can increase afterload to an extent sufficient to produce heart failure.

• *Specific CHF Causes

  • Thyrotoxicois

  • Pregnancy

  • Infection

  • Anemia

  • Rheumatic and other forms of Myocarditis

  • Infective Endocarditis

  • Physical, dietary, fluid, environmental and emotional excesses

*Isselbacher et al. (eds): "Harrison's Principles of Internal Medicine"New York, McGraw-Hill Inc, 1994, p. 999.

• ¹Weinberger, H., Diagnosis and Treatment of Diastolic Heart Failure, Hospital Practice

• ²Liggett SB, Wagoner LE, Craft LL, Hornung RW, Hoit BD, McIntosh TC, Walsh RA. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 102:1534-1539, 1998.

• ³Moore JD, Mason DA, Green SA, Hsu J, Liggett SB. Racial differences in the frequencies of cardiac beta1-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Human Mutation 14(3):271, 1999. 

• ⁴Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 274:12670-12674, 1999. 

• ⁵Spencer, K.T. and Lang, R.M. Kirk T. Spencer, MD Roberto M. Lang, MD, Diastolic heart failure, What primary care physicians need to know , vol. 101, no. 1, January 1997, Postgraduate medicine

• ⁶Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure in elderly patients with normal versus abnormal left ventricular systolic function associated with coronary artery disease. Am J Cardiol 1990;66(17):1257-9 

• ⁷Takarada A, Kurogane H, Minamiji K, et al. Congestive heart failure in the elderly-echocardiographic insights. Jpn Circ J 1992;56(6):527-34 

• ⁸.Iriarte M, Murga N, Sagastagoitia D, et al. Congestive heart failure from left ventricular dysfunction in systemic hypertension. Am J Cardiol 1993;71(4):308-312 

• ⁹.Madsen BK, Hansen JF, Stokholm KH, et al. Chronic congestive heart failure: description and survival of 190 consecutive patients with a diagnosis of chronic congestive heart failure based on clinical signs and symptoms. Eur Heart J 1994;15(3):303-10 

• ¹⁰Iwase M, Nagata K, Izawa H, et al. Age-related changes in left and right ventricular filling velocity profiles and their relationship in normal subjects. Am Heart J 1993;126(2):419-26 

• ¹¹Klein AL, Burstow DJ, Tajik AJ, et al. Effects of age on left ventricular dimensions and filling dynamics in 117 normal persons. Mayo Clin Proc 1994;69(3):212-24 

•  ¹²Zile MR: Diastolic dysfunction: Detection, consequences, and treatment. Part I: Definition and determinants of diastolic function. Mod Concepts Cardiovasc Dis 58:67, 1989 

•  ¹³Kitzman DW et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 17:1065, 1991 
   

General References

• Hollenberg, S.M. and Parrillo, J.E., Shock, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 215-222

• Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.222-224.

• Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p.259.