Gary Gerstenblith

Diminished Inotropic Response of Aged Myocardium to Catecholamines

The effect of advanced age on the response of active tension, maximal rate of tension development (dT/dt), and contraction duration to catecholamines and to calcium was evaluated in isometric trabeculae carneae from young adult (6-month-old), middle-aged (12-month-old), and aged (25-month-old) rats. Control values were not age dependent except for that for contraction duration which was prolonged in the aged group. At a norepinephrine concentration of 8 × 10−5M, dT/dt increased to 163.8 ± 5.3% of control in the young adult group and to 125.9 ± 6.3% of control in the aged group (P < 0.001).Active tension increased to 121.3± 4.0% of control in the young adult muscles but did not increase in the aged muscles (P < 0.01). Contraction duration shortened proportionately in both age groups. Similar results were obtained with isoproterenol. In contrast to the response to catecholamines, there was no age difference in the response of active tension and dT/dt to increasing concentrations of calcium. It is concluded that the intrinsic inotropic response to catecholamines is diminished in the aged myocardium. This finding does not appear to result from differences in tachyphylaxis, tissue uptake of catecholamines, or the ability of the contractile proteins to respond to increasing concentrations of calcium but instead may result from a decreased ability of catecholamines to increase the intracellular calcium available for contraction.

Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers.

Although a silent ischemic electrocardiographic response to treadmill exercise in clinically healthy populations is associated with an increased likelihood of future coronary events (i.e., angina pectoris, myocardial infarction, or cardiac death), such a response has a low predictive value for future events because of the low prevalence of disease in asymptomatic populations. To examine whether detection of reduced regional perfusion by thallium scintigraphy improved the predictive value of exercise-induced ST segment depression, we performed maximal treadmill exercise electrocardiography (ECG) and thallium scintigraphy (201Tl) in 407 asymptomatic volunteers 40-96 years of age (mean = 60) from the Baltimore Longitudinal Study on Aging. The prevalence of exercise-induced silent ischemia, defined by concordant ST segment depression and a thallium perfusion defect, increased more than sevenfold from 2% in the fifth and sixth decades to 15% in the ninth decade. Over a mean follow-up period of 4.6 years, cardiac events developed in 9.8% of subjects and consisted of 20 cases of new angina pectoris, 13 myocardial infarctions, and seven deaths. Events occurred in 7% of individuals with both negative 201Tl and ECG, 8% of those with either test positive, and 48% of those in whom both tests were positive (p less than 0.001). By proportional hazards analysis, age, hypertension, exercise duration, and a concordant positive ECG and 201Tl result were independent predictors of coronary events. Furthermore, those with positive ECG and 201Tl had a 3.6-fold relative risk for subsequent coronary events, independent of conventional risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute beta-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise.

The cardiovascular response to beta-adrenergic stimulation is markedly blunted with advancing age, and this blunting may underlie some of the prominent age-associated changes in the hemodynamic profile during dynamic exercise. To examine this hypothesis, we administered the nonselective beta-adrenergic receptor blocker propranolol (0.15 mg/kg IV) to 25 healthy normotensive men ages 28 to 72 years from the Baltimore Longitudinal Study of Aging (BLSA) immediately before maximal upright cycle ergometry with 99mTc gated cardiac blood pool scintigraphy. Their hemodynamic responses to exercise were compared with those of 70 age-matched healthy unmedicated male BLSA control subjects. The maximal cycle work rate achieved was similar in propranolol-treated men (158 +/- 32 W) and control subjects (148 +/- 32 W) and declined similarly with age in both groups. Hemodynamics at seated rest were not age-related in either group; however, propranolol-treated men had lower heart rates (HR), systolic blood pressure (SBP), ejection fraction, and cardiac index than control subjects but higher end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) by covariance analysis. At maximal effort, several striking age-drug interactions were evident: Propranolol caused a greater reduction in HR and greater increases in EDVI and stroke volume index (SVI) in younger than in older men. Hence, at maximal work rate, HR declined less with age in the propranolol group (0.46 versus 1.09 beats per minute per year, P < .05 by covariance analysis); EDVI and SVI decreased with age (0.27 and 0.48 mL/m2 per year, respectively) after propranolol compared with increases of 0.47 and 0.16 mL/m2 per year in control subjects, respectively, each P < or = .05 by covariance analysis. The left ventricular contractility index, SBP/ESVI, at exhaustion was reduced by propranolol to a greater extent in younger than older men. Thus, acute beta-adrenergic blockade reverses the age-associated ventricular dilation at end diastole and end systole observed during upright cycle exercise and blunts the decline in maximal HR and myocardial contractility. These data suggest that the age-associated declines in maximal HR and left ventricular contractility during vigorous exercise are manifestations of reduced beta-adrenergic responsivity with advancing age which is partially offset by exercise-induced ventricular dilation.

Diminished inotropic responsiveness to ouabain in aged rat myocardium.

We studied the effect of advanced age on the response to paired pacing and on the relationship between ouabain-induced inotropy and inhibition of (Na + K)-ATPas in hearts from young adult and senescent rats. In isometric trabeculae carneae, control values of developed tension (DT) and maximal rate of tension development (dT/dt) were not age-related. There was no age-related difference in the response to extrasystolic potentiation at prematurity intervals from 400 msec to the mechanical refractory period. The maximal response occurred at a prematurity interval of 200 msec and was above 200% of control. The inotropic response to ouabain occurred over a concentration range from 2 ∼ 10~6 to 6 ∼ 10′s M. DT and dT/dt in muscles from the young adult group exhibited a greater response than those from the senescent group; e.g., at 6 ∼ 10′s M both parameters were approximately four times greater in the former group. There was no age-dependent difference in ouabain-induced enzyme inhibition, which occurred over the same concentration range as did ouabain-induced alterations in mechanical function. These data indicate that paired pacing, but not ouabain, results in similar increases in inotropy and therefore similar increases in myoplasmic calcium concentration in young adult and aged rat myocardium. The age-dependent difference in ouabain responsiveness appears to be related to an age-associated alteration in a step other than enzyme inhibition linking ouabain binding to increased myoplasmic calcium levels. Circ Res 44: 517-523, 1979

Upregulation of the Nitric Oxide–cGMP Pathway in Aged Myocardium: Physiological Response to l-Arginine

Abstract— Cardiovascular aging is associated with decreased endothelial vasoreactivity and prolonged diastolic relaxation. As diminished NO signaling contributes to age-associated endothelial dysfunction, we tested the hypothesis that impaired NO signaling or bioactivity also contributes to slowed ventricular relaxation with age. Accordingly, we measured myocardial NO synthase (NOS) enzyme activity, protein abundance, and cGMP production in old (22 to 25 months) and young adult (4 to 7 months) male Wistar rats. Both NOS3 protein abundance and calcium-dependent NOS activity were elevated in old compared with young adult hearts (7.2±1.1 versus 4.2±0.6 pmol/mg protein, respectively, P =0.03). However, NOS activity and protein abundance were similar in isolated myocytes, indicating that endothelial NOS likely explains the age difference. Cardiac effluent cGMP (enzyme immunoassay) was 4.8-fold higher (1794±373 fmol/min per mg heart tissue) in older versus younger hearts (P =0.003). To assess NO pathway responsiveness, we administered the NOS substrate l-arginine (100 &mgr;m) to isolated perfused rat hearts. Baseline isovolumic relaxation (&tgr;) was prolonged in old (42.9±2.5 ms, n=16) versus young hearts (36.0±1.9 ms, n=11, P =0.03). l-Arginine decreased &tgr; (P <0.001) and left ventricular end-diastolic pressure in both old and young hearts. Supporting an NO/cGMP-mediating mechanism, the NO donor sodium nitroprusside reduced &tgr; (maximal effect, −14±2%, n=5, P <0.001), and this lusitropic effect was attenuated by the soluble guanylyl cyclase inhibitor 1 H-[1,2,4]oxadiazolo-[4,3,-a]quinoxalin-1-one (n=7, P <0.001). Thus, the NO-cGMP pathway is upregulated in the endothelial cells of aged hearts. l-Arginine, the NOS precursor, enhances ventricular relaxation in old and young hearts, indicating that the NOS pathway may be exploited to modulate diastolic function in aged myocardium.

Calcium-dependent enhancement of myocardial diastolic tone and energy utilization dissociates systolic work and oxygen consumption during low sodium perfusion.

The relationships and correlations among functional, metabolic, and ionic consequences of low sodium perfusion were studied in isovolumic, retrograde-aortic perfused working rat hearts by 31P nuclear magnetic resonance, oxygen consumption, and atomic absorption spectrometry. Reduction of perfusate sodium from 144 to 74, 51, 39, and 25 mM in four separate groups of hearts via lithium substitution for 15 minutes decreased cell sodium to mean values of 62, 51, 43, and 36 mumol/g dry weight, respectively (P less than 0.001 vs. control of 107). There was a transient rise and then a fall in developed pressure and a decline in phosphocreatine and adenosine triphosphate, all of which were graded and correlated with perfusate sodium (P less than 0.01 for all parameters vs. perfusate sodium). This was accompanied by a 2- to 7-fold elevation of diastolic pressure while oxygen consumption remained near control levels. All parameters except adenosine triphosphate returned toward baseline values when normal perfusate sodium was reintroduced. Although cell calcium as measured by atomic absorption spectrometry did not differ among the groups, the functional and metabolic changes did not occur if the sodium steps were performed in reduced perfusate calcium (0.08 mM). In hearts in which systolic function was obliterated by verapamil, exposure to zero sodium caused a 4-fold increase in oxygen consumption, an increase in diastolic pressure, and a reduction of high energy phosphates. In the presence of ryanodine, a specific inhibitor of sarcoplasmic reticulum calcium release, the metabolic changes did not occur, and the excess oxygen consumption in zero sodium was substantially reduced. Thus, the effect of lowered perfusate sodium in beating hearts, i.e., to dissociate oxygen consumption and systolic function, and to increase diastolic pressure and its effect in arrested hearts to increase oxygen consumption, are calcium dependent, energy consuming, and modulated by sarcoplasmic reticulum calcium cycling.

Contractile, metabolic and electrophysiologic effects of ethanol in the isolated rat heart

The metabolic, functional and electrical effects of ethanol were studied in the isolated isovolumic rat heart retrogradely perfused at constant flow using phosphorus-31 nuclear magnetic resonance spectroscopy and surface electrogram recordings. Ethanol (0.75 to 6.0 vol%; 128 to 1024 mM) caused a concentration-dependent decline in developed pressure without a change in adenosine triphosphate, phosphocreatine, inorganic phosphate or pH. Ethanol (6%) caused abolition of electrical activity. The functional decline could be rapidly and completely reversed by perfusing with ethanol-free solution and, significantly although not completely, reversed by increasing perfusate calcium to 4 mM. Furthermore, ethanol shifted the perfusate calcium-tetanic pressure relationship in the presence of ryanodine (1 microM) downwards and to the right. The results suggest ethanols acute effects in this model are not mediated by changes in energy metabolism or cellular pH, but rather by sarcolemmal effects and by a decrease in both myofilament calcium sensitivity and maximal force generating ability.

ST-Segment Elevation in an Unresponsive Patient

A distressed woman hailed a car for assistance several blocks from our institution. Upon arrival at the Emergency Department, she was unresponsive. Telemetry demonstrated ventricular fibrillation, and she was defibrillated to sinus rhythm with ECG, as shown in Figure 1. She was taken for emergent cardiac catheterization with a heart rate of 117 bpm and blood pressure of 95/55 mm Hg. Coronary angiography revealed no stenosis or flow abnormalities. During catheterization, ST-segment elevation resolved and …

Sodium modulation of resting force, contractile properties, and metabolism with particular emphasis on its role in the development of calcium overload states.

The crucial role of extracellular calcium in modulating cardiac muscle function has been recognized for over 100 years (1). The manner in which changes in extracellular calcium result in altered cellular calcium and therefore changes in resting and active force development, however, is still being explored. A study of factors influencing cellular calcium is relevant not only because cellular calcium controls cardiac force development but also because calcium overload is now recognized to be an accompaniment and perhaps contributor to the functional and metabolic derangements which occur during certain pathologic states (2).