William H. Barry

Isolated Single Coronary Artery: Diagnosis, Angiographic Classification, and Clinical Significance

Isolated single coronary artery is a rare congenital anomaly occuring in approximately 0.024% of the population. This entity can be diagnosed during life only by coronary angiography. Ten patients with isolated single coronary artery are reported. Based on angiographic analysis, a new classification is proposed, according to the site of origin and anatomical distribution of the branches. Typical angina did not occur with single coronary artery in the absence of coexisting coronary artery disease or aortic stenosis. No correlation was apparent between the type of anomalous patterns and the symptoms of angina.

Changes in Diastolic Stiffness and Tone of the Left Ventricle During Angina Pectoris

Reported elevations of left ventricular filling pressures during angina suggest increased myocardial stiffness. Both left ventricular beginning- and end-diastolic pressures and volumes were measured in seven patients before, during, and after angina induced by atrial pacing. During nine episodes of angina, mean end-diastolic pressure rose from 12 to 29 mm Hg and ejection fraction fell from 0.47 to 0.37. Logarithms of beginning and end-diastolic pressures were plotted against the corresponding volumes for each angiogram. During angina, there was a marked increase in beginning as well as end-diastolic stiffness of the ventricle. These changes, which were reversible with resolution of angina, may be due to sustained contraction or failure of relaxation of a portion of the left ventricular myocardium during angina pectoris.

Implementing a Geriatric Assessment in Cooperative Group Clinical Cancer Trials: CALGB 360401

PURPOSE Factors captured in a geriatric assessment can predict morbidity and mortality in older adults, but are not routinely measured in cancer clinical trials. This study evaluated the implementation of a geriatric assessment tool in the cooperative group setting. PATIENTS AND METHODS Patients age ≥ 65 with cancer, who enrolled on cooperative group cancer trials, were eligible to enroll on Cancer and Leukemia Group B (CALGB) 360401. They completed a geriatric assessment tool before initiation of protocol therapy, consisting of valid and reliable geriatric assessment measures which are primarily self-administered and require minimal resources and time by healthcare providers. The assessment measures functional status, comorbidity, cognitive function, psychological state, social support, and nutritional status. The protocol specified criteria for incorporation of the tool in future cooperative group trials was based on the time to completion and percent of patients who could complete their portion without assistance. Patient satisfaction with the tool was captured. RESULTS Of the 93 patients who enrolled in this study, five (5%) met criteria for cognitive impairment and three did not complete the cognitive screen, leaving 85 assessable patients (median age, 72 years). The median time to complete the geriatric assessment tool was 22 minutes, 87% of patients (n = 74) completed their portion without assistance, 92% (n = 78) were satisfied with the questionnaire length, 95% (n = 81) reported no difficult questions, and 96% (n = 82) reported no upsetting questions. One hundred percent of health care professionals completed their portion. CONCLUSION This brief, primarily self-administered geriatric assessment tool met the protocol specified criteria for inclusion in future cooperative group clinical trials.

Coronary Vasoconstrictor Effect of Indomethacin in Patients with Coronary-Artery Disease

Prostaglandins may be important regulators of coronary blood flow. To investigate this possibility, we studied the effect of blockade of prostaglandin synthesis by indomethacin in nine patients with coronary-artery disease. Coronary-sinus blood flow (determined with the thermodilution technique) was recorded, together with mean arterial blood pressure and the myocardial arteriovenous oxygen difference from simultaneously obtained arterial and coronary-sinus blood samples, before and 20 minutes after an intravenous dose of indomethacin (0.5 mg per kilogram of body weight). There were significant increases (P less than 0.05) in mean arterial pressure (from 99 +/- 4 to 118 +/- 5 mm Hg [+/- S.E.M.]), coronary vascular resistance (+73 per cent), and myocardial arteriovenous oxygen difference (from 107 +/- 5 to 138 +/- 4 ml per liter) after indomethacin, but coronary blood flow fell significantly, from 181 +/- 29 to 111 +/- 14 ml per minute (P less than 0.05). Thus, despite an increase in myocardial oxygen demand, coronary blood flow fell and coronary vascular resistance increased. This coronary vasoconstrictor effect may have been due to blockade of vasodilatory prostaglandin synthesis or to a direct drug effect. Whatever the mechanism, indomethacin should be used with caution in patients with severe coronary-artery disease.

Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine.

The biochemical basis of the mechanism of vasodilatation by nitroglycerin (NTG) has not been previously investigated in man. However, evidence from in vitro studies suggests that NTG induces activation of guanylate cyclase via a series of enzymatic reactions that are modulated by the availability of sulfhydryl groups. Cysteine appears to be particularly effective in potentiating guanylate cyclase activation by NTG. To determine whether hemodynamic responsiveness to NTG in man might be modulated by sulfhydryl availability, concentration-response curves for effects of intravenously infused NTG on mean arterial pressure (MAP) and mean pulmonary capillary wedge pressure (PCW) were obtained in 10 patients undergoing cardiac catheterization for investigation of chest pain. NTG infusion was repeated 10 min after the intravenous infusion of 100 mg/kg of the cysteine source N-acetylcysteine (NAC). NAC induced no significant hemodynamic effect, but after NAC infusion there was a significant reduction both in the NTG infusion rate associated with a 10% fall from control values in MAP (25.8 +/- 8.3 to 9.3 +/- 2.7 micrograms/min; p less than .01) and in the infusion rate inducing a 30% reduction in PCW (13.6 +/- 4.6 to 4.2 +/- 1.6 micrograms/min; p less than .02). In a control group of five patients who received no NAC, there was no significant change in responsiveness to NTG between infusions. It is concluded that NAC potentiates the vasodilator effects of NTG in man. This suggests that sulfhydryl availability and/or redox state may be determinants of in vivo responsiveness to NTG.

Potentiation of coronary vasoconstriction by beta-adrenergic blockade in patients with coronary artery disease.

Although,β-adrenergic blocking agents reduce myocardial oxygen consumption and symptoms of myocardial ischemia in patients with coronary artery disease (CAD), propranolol has been reported to exacerbate coronary artery spasm in some patients with variant angina. To determine whether increased coronary vasomotor tone can be induced by β-adrenergic blockade, we measured the changes in coronary vascular resistance (CVR) during cold pressor testing (CPT) in 15 patients, nine with severe CAD and six with normal left coronary anatomy, before and after i.v. propranolol (0.1 mg/kg). Coronary blood flow was measured by coronary sinus thermodilution. CVR was calculated as mean arterial pressure divided by coronary sinus blood flow. Heart rate was maintained constant at a paced subanginal rate of 95 ± 5 beats/min.Before propranolol, CPT induced significant increases in coronary vascular resistance in patients with CAD (15.0 ± 2.2%, p < 0.02), but no increase in CVR in the normal patients. After propranolol, the CVR change during CPT was augmented for patients with CAD (29 ± 6%, p < 0.01) and for the normal population (9 ± 5%, NS). The potentiated increase in CVR occurred without significant changes in resting CVR or in the magnitude of the hypertensive response to CPT.We conclude that,β-adrenergic blockade with propranolol can potentiate coronary artery vasoconstriction in some patients with CAD, possibly mediated by unopposed α-adrenergic vasomotor tone. These changes may be important in patients in whom intense adrenergic stimulation may increase coronary artery tone and adversely influence the balance between myocardial oxygen supply and demand.

Mechanisms of transmembrane calcium movement in cultured chick embryo ventricular cells

1. Uptake of calcium was studied in spontaneously contracting monolayers of cultured chick embryo ventricular cells. Ca exchange could be separated into two components: a rapid phase with a rate constant of 3·91/min, accounting for 1·6 nmol/mg protein; and a slower phase with a rate constant of 0·069/min, accounting for 2·7 nmol/mg protein.

Sodium pump inhibition, enhanced calcium influx via sodium-calcium exchange, and positive inotropic response in cultured heart cells.

The effects of sodium pump inhibition produced by exposure to the cardiac glycosides, ouabain or dihydroouabain, or by reduction in extracellular potassium to 1.0 mM, on contractile state and sodium-calcium exchange were studied in primary monolayer cultures of chick embryo ventricular cells. Ouabain, 10−6 M, dihydroouabain, 5 × 10−5M, and extracellular potassium of 1.0 mM all induced similar and prominent positive inotropic effects. These effects were accompanied, in each case, by 40–50% inhibition of the rate of active uptake of 42K and by similar increases in steady state sodium content. Stimulation of the rate of 45Ca uptake on exposure to zero extracellular sodium occurred in response to extracellular potassium (1.0 mM) or to glycoside concentrations that induced a positive inotropic effect and sodium-potassium pump inhibition. Reactivation of the sodium pump after return from 1.0 to 4.0 mM extracellular potassium was rapid and was associated with membrane hyperpolarization and slowing of spontaneous beating rate. With pump reactivation under these circumstances, the time course of disappearance of stimulation of sodium-calcium exchange on exposure to zero extracellular sodium was similar to the time course of loss of the positive inotropic effect. Under physiological conditions (4.0 mM extracellular potassium), exposure to positively inotropic but nontoxic concentrations of ouabain or dihydroouabain caused a small but consistent increase in unidirectional calcium influx, but had no discernible effect on calcium efflux. Since similar inotropic effects were produced for comparable degrees of glycoside or low extracellular potassium-induced sodium pump inhibition and increases in cellular sodium content, sodium pump inhibition rather than a glycoside-specific change in calcium binding appears to underlie the inotropic response. These findings are further consistent with the view that the primary mechanism of the positive inotropic effects of digitalis and low extracellular potassium in this experimental preparation is sodium pump inhibition resulting in increased intracellular sodium. We suggest that increased calcium influx via sodiumcalcium exchange is the principal mechanism whereby increased intracellular sodium results in enhanced calcium availability to the myofibrils, but an additional effect on calcium efflux is not excluded.

Cardiac abnormalities in myotonic dystrophy. Electrophysiologic and histopathologic studies.

Eight young adult male patients with myotonic dystrophy, mean age 26 years, underwent 24-hour Holter electrocardiographic monitoring and intracardiac electrophysiologic study. Right ventricular endomyocardial biopsies were performed at the end of the electrophysiologic study in five of them. The atrial to His[A-H] interval was 155 msec in one case and less than or equal to 55 msec in all patients. Twenty-four hour Holter electrocardiographic monitoring demonstrated more than 4 premature ventricular contractions per minute in two patients and marked cyclical sinus arrhythmia during sleep in two others. Electron microscopic analysis of the endomyocardial biopsy specimens disclosed no prominent sarcoplasmic reticulum abnormalities but prominent I bands compared to previously obtained controls. Myofibrillar degeneration was seen in all cases and was associated with abnormal mitochondria in two. Cardiac abnormalities can be detected very early in the evolution of myotonic dystrophy, even prior to the onset of cardiac symptoms. The reported abnormalities appear closely related to the pathologic process affecting other skeletal muscles.

Contractile reserve and intracellular calcium regulation in mouse myocytes from normal and hypertrophied failing hearts

Mouse myocyte contractility and the changes induced by pressure overload are not fully understood. We studied contractile reserve in isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) during compensatory hypertrophy (4-week AS) and the later stage of early failure (7-week AS) and from control mice. Myocyte contraction and [Ca2+]i transients with fluo-3 were measured simultaneously. At baseline (0.5 Hz, 1.5 mmol/L [Ca2+]o, 25°C), the amplitude of myocyte shortening and peak-systolic [Ca2+]i in 7-week AS were not different from those of controls, whereas contraction, relaxation, and the decline of [Ca2+]i transients were slower. In response to the challenge of high [Ca2+]o, fractional cell shortening was severely depressed with reduced peak-systolic [Ca2+]i in 7-week AS compared with controls. In response to rapid pacing stimulation, cell shortening and peak-systolic [Ca2+]i increased in controls, but this response was depressed in 7-week AS. In contrast, the responses to both challenge with high [Ca2+]o and rapid pacing in 4-week AS were similar to those of controls. Although protein levels of Na+-Ca2+ exchanger were increased in both 4-week and 7-week AS, the ratio of SR Ca2+-ATPase to phospholamban protein levels was depressed in 7-week AS compared with controls but not in 4-week AS. This was associated with an impaired capacity to increase sarcoplasmic reticulum Ca2+ load during high work states in 7-week AS myocytes. In hypertrophied failing mouse myocytes, depressed contractile reserve is related to an impaired augmentation of systolic [Ca2+]i and SR Ca2+ load and simulates findings in human failing myocytes.