• The polymorphism that position 389 appears to also vary based on race³. 

  • Furthermore, a difference in the coupling to adenylyl cyclase has been observed:⁴

Comparative pathophysiology: diastolic vs. systolic heart failure

• ⁵Congestive heart failure is often thought of in terms of a failure of left ventricular contractile function.  

  • Left ventricular failure may occur for a variety of reasons including but not limited to valvular dysfunction or as the consequences significant loss of left ventricular myocardial muscle mass.

• Myocardial-induced dyspnea or fatigue may occur in the absence of abnormal contractility. 

  • In these cases, the pathophysiological process may be associated with abnormalities in diastole, for instance those that are manifest as inadequate left ventricular filling.

• ⁵Heart failure due to diastolic abnormalities exhibit a frequency of about 14%-41%, depending on the study^6-9, with diastolic dysfunction resulting in failure probably more prevalent in elderly patients⁹.

  1. Generally,left ventricular diastolic function normally declines with age despite there being no specific age-related abnormality in contractility.  

  2. Elderly patients  may however be more likely to experience factors that cause enhanced ventricular stiffness or limit ventricular relaxation.  

  3. These factors include: ischemia, hypertension and/or tachycardia (systolic hypertension is one factor that clearly increases in likelihood with advancing age)

• ¹What happens during diastole?  Physiological issues:

  • The myocardial contraction-relaxation cycle centers around fairly rapid changes in  free calcium concentration.  The stepwise process involves:

    1. Membrane depolarization promoting myocyte Ca²⁺ entry through slow (L-type) Ca²⁺ channels

    2. Rhis initial process causes significant additional sarcoplasmic reticular Ca²⁺ release

    3. Ca²⁺ interaction with troponin leads to subsequent promotion of actin-myosin interactions and muscle contraction..

    4. Relaxation can only occur rapidly if the free calcium is rapidly removed.

    5. Calcium transport for purpose of establishing the basal state occurs through the action of a calcium-ATPase, which handles up to 90% of free calcium by re-storage back into the sarcoplasmic reticulum. 

       1. The remaining 10% is removed through Na⁺/Ca²⁺ exchange mechanisms and other mechanisms.

  • From: 1Weinberger, H., Diagnosis and Treatment of Diastolic Heart Failure, Hospital Practice http://www.hosppract.com/issues/1999/03/weinb.htm

• The relaxation phase of the cardiac cycle: This phase consists of 4 components:

  1. Isovolumic relaxation

  2. Rapid filling

  3. Slow filling (diastasis)

  4. Atrial contraction

     1. From: 1Weinberger, H., Diagnosis and Treatment of Diastolic Heart Failure, Hospital Practice  as adapted from Zile MR: Diastolic dysfunction: Detection, consequences, and treatment. Part I: Definition and determinants of diastolic function. Mod Concepts Cardiovasc Dis 58:67, 1989   1Normally, most of the left ventricular filling occurs during the second phase (rapid filling); however, with impaired filling such as might occur with reduced ventricular compliance, less filling occurs during the second phase in more during the atrial contracting phase.

• ¹Looking at each phase separately, the first phase is defined by the time between aortic valve closing and mitral valve opening.  From the ionic point of view, during this time free calcium is translocated back into the sarcoplasmic reticular storage sites.

  • The next phase is initiated when left ventricular pressure falls below left atrial pressure; the pressure differential drives mitral valve opening with attendant left ventricular filling.  This process continues until pressure equilibration.  

    • Although only about 30 percent of the diastolic time occurs during phase 2, typically up to 80% of left ventricular filling occurs during the stage.

  • Therefore, the next phase is referred to as a slow-filling time; the filling is mainly pulmonary vein flow [this phase is most sensitive to an increased heart rate, i.e. reduced filling]

  • Atrial contraction is the last component and typically contributes about 15%-25% of left ventricular diastolic volume-this amount would nominally be referred to as the "atrial kick".  However, with reduced left ventricular compliance this phase is more important, perhaps contributing up to 40%.

• Pathophysiological issues:

  • ¹With diastolic dysfunction, there is both elevated left ventricular filling pressure and elevated pulmonary venous pressure.  To maintain cardiac output under load, higher filling pressures are required to achieve adequate left ventricular filling.  

    •  However, in patients with diastolic dysfunction, increased left ventricular filling pressure did not result in increased left ventricular diastolic volumes¹³.

    • From: 1Weinberger, H., Diagnosis and Treatment of Diastolic Heart Failure, Hospital Practice Note on the left figure, increased pulmonary capillary wedge pressure was taken as an indication of increased left ventricular filling pressure.  In the right figure, there is a decrease in left ventricular end diastolic volume associated with those patients with diastolic dysfunction.  By contrast, control individuals exhibited an increase in left ventricular end diastolic volume accompanying increased workload associated with exercise.

• Diastolic heart failure may develop slowly and occur as a result those long-term consequences of compensatory physiological responses.  

  • Factors that may induce diastolic functional pathologies include increased heart rate, left ventricular hypertrophy, and myocardial ischemia.  Some of these factors may be associated with progressive myocardial "remodeling"

    • Recall that the key to rapid myocardial relaxation is the ability to re-sequester free Ca²⁺ . 

      • Furthermore, this process requires ionic translocation against a significant concentration gradient (10,000: 1) and as such is coupled to ATP hydrolysis.The ratio is 1 ATP hydrolyzed for every two Ca²⁺  translocated by the calcium-ATPase pump.

    • Therefore, factors the decrease ATP availability will impair this translocation process. 

      •  Myocardial hypertrophy and ischemia reduce ATP availability and can be therefore readily identified as contributing  pathologic factors that impair myocardial relaxation.  Additionally, hypertrophic ventricular muscle tissue exhibits reduced compliance (increased stiffness)

•  ¹Factors that impair ventricular contraction include:

  •  Hypertrophy, ischemia, hypertension, collagen deposition and fibrosis, regional asynchrony, increase preloaded and afterload, intrinsic abnormalities in calcium movement, and tachycardia

• Factors that reduce ventricular compliance (increased stiffness) include:

  • Hypertrophy, hypertension, collagen deposition and fibrosis, pericardial constriction or restriction.

• Aging is associated with increased likelihood of left ventricular hypertrophy and/or ischemia.  

  • Aging is also associated with increased collagen deposition which reduces ventricular compliance.  However other important causes those diastolic failure include coronary vascular disease, hypertension, diabetes, obesity, and aortic stenosis.

• "Management of Congestive Heart Failure"

  Attribution: VanderPluym C Management of Congestive Heart Failure https://www.youtube.com/watch?v=wvqCjLGweh8 (5/2016) OPENPediatrics YouTube Channel:  https://www.youtube.com/channel/UCyQ4ieAnEwDQs9iZLwH9H8w

• ¹Pharmacological interventions: Overview:

  • Many different drug categories at least in principle might be thought to improve isolated diastolic dysfunction and therefore improve exercise tolerance and reduce other symptoms as well as increase left ventricular filling rate and reduce heart rate.  Drug categories that have been evaluated include:

    • Calcium channel blockers

    • β-adrenergic receptor antagonists

    • Angiotensin converting enzyme inhibitors

    • Diuretics

    • Nitrates

  • ¹Presently, isolated diastolic heart failure is managed with many of the above agents.  However based on clinical research verapamil (Isoptin, Calan) appears to be the only agent which has been objectively demonstrated to improve the above parameters, e.g. exercise tolerance, peak left ventricular filling rate (enhanced 30%) with a decrease in heart rate (10%) -- p< 0.05

  • The rationale by which calcium channel blockers might improve diastolic heart failure include:

    1. Direct effects on calcium movements

    2. Indirect effects through blood pressure reduction, reducing myocardial ischemia, decreasing (promoting regression of) left ventricular hypertrophy, decreasing heart rate (for verapamil (Isoptin, Calan) and diltiazem (Cardiazem)) thereby improving left ventricular filling.

• 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.