Isolated ventricular myocytes from failing and non-failing human heart; the relation of age and clinical status of patients to isoproterenol response.
Single cardiac myocytes were isolated from the ventricles of failing and non-failing human hearts. The contraction amplitude, time-to-peak shortening and time to 50% and 90% relaxation were measured in cells stimulated at 0.2 Hz at 32 degrees C. The effects of increasing extracellular calcium and isoproterenol were investigated using cumulative concentration/response curves. Maximum contraction amplitude in high calcium or velocities of contraction or relaxation were not impaired in cells from failing hearts. Beta-adrenoceptor function in a single cell was assessed by the maximum contraction amplitude in the presence of isoproterenol relative to that with high calcium in the same cell (isoproterenol/calcium ratio). A decrease in the isoproterenol/calcium ratio correlated positively with an increase in the isoproterenol EC50 (concentration for half-maximal effect) for a cell (P less than 0.02, n = 39). The isoproterenol/calcium ratio in left ventricular myocytes decreased with increasing severity of disease, correlating with failure as defined by New York Heart Association class (P less than 0.001, n = 26 patients), left ventricular ejection fraction (P less than 0.001, n = 24), left ventricular end diastolic pressure (P less than 0.05, n = 21) and amount of diuretics prescribed (P less than 0.001, n = 26). In right ventricular myocytes, only increasing NYHA class correlated with decreasing isoproterenol/calcium ratios. There was a correlation of the isoproterenol/calcium ratio between right and left ventricular cells from patients with ischemic heart disease (P less than 0.05), n = 11). Beta-adrenoceptor subsensitivity occurred in mitral valve disease, ischemic heart disease, congenital abnormalities and congestive cardiomyopathy, but not in the right ventricle of patients with myocarditis. The isoproterenol/calcium ratio correlated negatively with the age of the patient (P less than 0.001, n = 26, left ventricle). Multiple regression indicated that the maximum contraction amplitudes in either high isoproterenol or high calcium declined significantly with age only, but that both age and severity of disease contributed to the decrease in isoproterenol/calcium ratio. Time-to-peak tension in isoproterenol, as well as relaxation times in high calcium also decreased with the age of the patient. Analysis of variance showed that between-patient variation was significantly greater than between-cell for most of the parameters measured. Beta-adrenoceptor desensitisation may be detected in individual myocytes from failing hearts, and this relates more to the severity of disease and the age of the patient rather than the etiology of heart failure. A decline in absolute contractility of muscle cells with age was detected.
Harding
S E
SE
National Heart and Lung Institute, London, UK.
Jones
S M
SM
O'Gara
P
P
del Monte
F
F
Vescovo
G
G
Poole-Wilson
P A
PA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002648:Child; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012518:Sarcomeres / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology
D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol; D002118:Calcium