Lewis C. Lipson

Impaired left ventricular diastolic filling in patients with coronary artery disease: assessment with radionuclide angiography.

To assess left ventricular (LV) diastolic filling at rest in patients with coronary artery disease (CAD), we analyzed high-resolution time-activity curves (10-20 msec/frame) obtained from gated radionuclide angiograms in 231 patients. Peak LV filling rate (PFR), expressed in end-diastolic volumes per second (EDV/sec), was subnormal in CAD patients (1.8 +/- 0.6 [+/- SD] vs normal mean of 3.3 +/- 0.6, p les than 0.001) and time to PFR (TPFR), measured from end-systole to PFR, was prolonged (171 +/- 41 msec vs normal mean of 136 +/- 23 msec, p less than 0.001). These indexes were also abnormal in the 141 patients with normal resting LV ejection fraction (PFR = 2.1 +/- 0.5 EDV/sec; TPFR = 175 +/- 36 msec) and in 123 patients without Q waves on the ECG (PFR = 2.1 +/- 0.5 EDV/sec; TPFR = 168 +/- 38 msec). Abnormal LV filling at rest (PFR less than 2.5 EDV/sec or TPFR greater than 180 msec) was found in 91% of all patients with CAD, 86% of patients with normal resting LV ejection fractions, 85% of patients without Q waves, and 82% of patients with normal resting LV ejection fraction, no resting regional wall motion abnormalities and no Q waves. Thus, LV diastolic filling, evaluated noninvasively by radionuclide angiography, is abnormal in a high percentage of patients with CAD at rest independent of LV systolic function or previous myocardial infarction.

Effects of verapamil on left ventricular systolic function and diastolic filling in patients with hypertrophic cardiomyopathy.

Verapamil improves exercise capacity in patients with hypertrophic cardiomyopathy (HCM), but its mechanisms of action are unknown. We examined the effects of oral verapamil (320–480 mg/day) on resting left ventricular (LV) systolic and diastolic function in patients with HCM. High‐temporal‐resolution time‐activity curves from gated technetium‐99m radionuclide angiograms were analyzed before and after verapamil therapy in 40 patients, of whom 16 were also studied during propranolol therapy (80–960 mg/day). All but one patient had normal or supranormal systolic function, but 70% had evidence of diastolic dysfunction, defined as peak LV filling rate (PFR) < 2.5 end‐diastolic volumes (EDV)/sec or time to PFR > 180 msec. Verapamil did not change LV ejection fraction, peak ejection rate or ejection time, but did increase PFR (control 3.3 ± 1.0 EDV/sec, verapamil 4.1 ± 1.1 EDV/sec; p < 0.001) and reduce time to PFR (control 187 ± 56 msec, verapamil 159 ± 34 msec; p < 0.001). Only 30% of patients had evidence of diastolic dysfunction during verapamil. In contrast, propranolol did not change LV ejection fraction, PFR or time to PFR, but did prolong ejection time and reduce peak ejection rate. Thus, LV diastolic filling is abnormal in a high percentage of patients with HCM, and verapamil normalizes or improves these abnormalities without altering systolic function. This mechanism may contribute to the clinical improvement of many HCM patients during verapamil therapy.

Improved Myocardial Function during Exercise after Successful Percutaneous Transluminal Coronary Angioplasty

Fifty-nine consecutive patients with coronary-artery disease undergoing percutaneous transluminal coronary angioplasty were evaluated with radionuclide ventriculography at rest and during exercise before angioplasty (when possible) and afterward when it was successful. Thirty-eight patients (64 per cent) had an angiographically successful procedure. Three (5 per cent) had coronary occlusion as a complication. Arterial stenosis was reduced from 74 +/- 2 per cent to 31 +/- 3 per cent (mean +/- S.E.M.). The mean ejection fraction was 55 +/- 2 per cent at rest and 51 +/- 3 per cent during exercise before the procedure. After successful angioplasty, the ejection fraction was unchanged at rest but increased to 62 +/- 2 per cent (P less than 0.001) during exercise. Regional dysfunction was present during exercise in 94 per cent of the patients before the procedure and in only 8 per cent after successful angioplasty. Of the 38 patients in whom the procedure was successful, 19 had sustained improvement for over six months, and eight for three to six months. Eleven patients had recurrence of symptoms; the second angioplasty was initially successful in nine. In 24 patients remaining asymptomatic for six months (19 after the first procedure and five after the second), the left ventricular ejection fraction during exercise remained stable or improved.

Improved left ventricular diastolic filling in patients with coronary artery disease after percutaneous transluminal coronary angioplasty.

Left ventricular (LV) diastolic filling is abnormal at rest in many patients with coronary artery disease (CAD), even in the presence of normal resting LV systolic function. To determine the effects of improved myocardial perfusion on impaired LV diastolic filling, we studied 25 patients with one‐vessel CAD by high‐temporal‐resolution radionuclide angiography before and after percutaneous transluminal coronary angioplasty (PICA). No patient had ECG evidence of previous myocardial infarction. Despite normal regional and global LV systolic function at rest in all patients, LV diastolic filling was abnormal (peak LV filling rate [PFR] < 2.5 end-diastolic volumes (EDV)/sec or time to PFR > 180 msec) in 17 of 25 patients. Twenty-three patients had abnormal LV systolic function during exercise. After successful PTCA, LV ejection fraction and heart rate at rest were unchanged, but LV ejection fraction during exercise increased, from 52 8% (± SD) to 63 ± 5% (p < 0.001). LV diastolic filling at rest improved: PFR increased from 2.3 0.6 to 2.8 ± 0.5 EDV/sec (p < 0.001) and time to PFR decreased from 181 ± 22 to 160 ± 18 msec (p < 0.001). Thus, a reduction in exercise‐induced LV systolic dysfunction after PTCA, reflecting a reduction in reversible ischemia, was associated with improved LV diastolic filling at rest. These data suggest that in many CAD patients with normal resting LV systolic function and without previous infarction, abnormalities of resting LV diastolic filling are not fixed, but appear to be reversible manifestations of impaired coronary flow.

Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy: III. Effects of long-term administration.

Abstract To determine the efficacy of long-term therapy with verapamil in patients with hypertrophic cardiomyopathy, 78 patients began treatment with the drug in the hospital. Sixty-two patients (79 percent) were in New York Heart Association functional class III or IV despite treatment with beta receptor blocking drugs. Fifty-four percent of all patients evaluated (42 of 78) and 63 percent of those discharged from the hospital (42 of 68) experienced sustained symptomatic improvement 6 to 30 months (median 14 months) after initiation of verapamil therapy. Of these 42 patients in improved condition, 25 had improvement by at least one New York Heart Association functional class, 14 improved by less than one functional class, two felt better taking verapamil than propranolol, and in one patient verapamil controlled asymptomatic ventricular tachycardia. Of the 53 patients who had the obstructive form of the disorder and were considered operative candidates, 25 (47 percent) experienced sufficient improvement so as to forgo operation. In patients remaining on verapamil therapy, the duration of treadmill exercise performed 5 days after the start of verapamil therapy increased by 3.1 ± 0.6 minutes (53 ± 10 percent, p

Effects of verapamil and propranolol on left ventricular systolic function and diastolic filling in patients with coronary artery disease: radionuclide angiographic studies at rest and during exercise.

To determine the effects of verapamil on left ventricular (LV) systolic function and diastolic filling in patients with coronary artery disease (CAD), we performed gated radionuclide angiography at rest and during exercise in 16 symptomatic patients before and during oral verapamil therapy (480 mg/day). Twelve patients were also studied during oral propranolol (160--320 mg/day). LV ejection fraction at rest was normal in 13 patients, but abnormal diastolic filling at rest, defined as peak filling rate (PFR) less than 2.5 end-diastolic volumes (EDV)/sec or time to PFR greater than 180 msec, was present in 15. During verapamil, resting ejection fraction decreased (control 50 +/- 10% [+/- SD), verapamil 45 +/- 12%, p less than 0.005), but resting diastolic filling improved: PFR increased (control 1.9 +/- 0.6 EDV/sec, verapamil 2.3 +/- 0.9 ECV/sec, p less than 0.005) and time to PFR decreased (control 185 +/- 38 msec, verapamil 161 +/- 27 msec, p less than 0.05). Exercise ejection fraction did not change during verapamil (control 42 +/- 13%, verapamil 43 +/- 12%, NS), but exercise PFR increased (control 3.1 +/- 0.9 EDV/sec, verapamil 3.6 +/- 1.1 EDV/sec, p less than 0.05) and exercise time to PFR decreased (control 108 +/- 30 msec, verapamil 91 +/- 17 msec, p less than 0.05). In contrast, propranolol did not alter ejection fraction, PFR, or time to PFR at rest or during exercise. Thus, LV ejection fraction is decreased by verapamil at rest but is unchanged during exercise. While LV systolic function is not improved by verapamil, LV diastolic filling is enhanced by verapamil, both at rest and during exercise. These mechanisms may account in part for the symptomatic improvement in many patients during verapamil therapy.

Clinical efficacy of verapamil alone and combined with propranolol in treating patients with chronic stable angina pectoris

Abstract To determine the effectiveness of oral verapamil alone and combined with propranolol in patients with chronic angina pectoris, upright bicycle exercise testing was performed in 11 patients in an inpatient single blind crossover study. Compared with placebo, which resulted in an exercise time of 5.1 ± 0.7 minutes (mean ± standard error of the mean), verapamil (480 mg/day) improved exercise time in all patients (mean increment 3.4 ± 0.7 minutes, p

Effects of verapamil on left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy: pressure-volume analysis with a nonimaging scintillation probe.

To investigate the effects of verapamil on left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy, we studied 14 patients at catheterization with a nonimaging scintillation probe before and after serial intravenous infusions of low-, medium-, and high-dose verapamil (total dose 0.17 to 0.72 mg/kg). Percent change in radionuclide stroke counts after verapamil correlated well with percent change in thermodilution stroke volume (r = .87), and changes in diastolic and systolic counts were used to assess relative changes in left ventricular volumes after verapamil. Verapamil produced dose-related increases in end-diastolic counts (19 +/- 9% increase; p less than .001), end-systolic counts (91 +/- 54% increase; p less than .001), and stroke counts (7 +/- 10% increase; p less than .02). This was associated with a decrease in ejection fraction (83 +/- 8% control, 73 +/- 10% verapamil; p less than .001) and, in the 10 patients with left ventricular outflow tract gradients, a reduction in gradient (62 +/- 27 mm Hg control, 32 +/- 35 mm Hg verapamil; p less than .01). The end-systolic pressure-volume relation was shifted downward and rightward in all patients, suggesting a negative inotropic effect. In 10 patients, left ventricular pressure-volume loops were constructed with simultaneous micromanometer pressure recordings and the radionuclide time-activity curve. In five patients, verapamil shifted the diastolic pressure-volume curve downward and rightward, demonstrating improved pressure-volume relations despite the negative inotropic effect, and also increased the peak rate of rapid diastolic filling. In the other five patients, the diastolic pressure-volume relation was unaltered by verapamil, and increased end-diastolic volumes occurred at higher end-diastolic pressures; in these patients, the peak rate of left ventricular diastolic filling was not changed by verapamil. The negative inotropic effects of intravenous verapamil are potentially beneficial in patients with hypertrophic cardiomyopathy by decreasing left ventricular contractile function and increasing left ventricular volume. Verapamil also enhances left ventricular diastolic filling and improves diastolic pressure-volume relations in some patients despite its negative inotropic effect.

Prognosis of asymptomatic or mildly symptomatic patients with coronary artery disease

One hundred forty-seven asymptomatic or mildly symptomatic patients with coronary artery disease, who did not have significant left main coronary occlusion and had an ejection fraction greater than 20 percent, were followed up prospectively for 6 to 67 months (average 25). Significant obstruction of one coronary artery was present in 28 percent of patients, of two coronary arteries in 31 percent and of three coronary arteries in 41 percent. Ejection fraction was 55 percent or greater in 69 percent of patients. During the follow-up there were eight deaths (annual mortality rate 3 percent for the entire group, 1.5 percent for patients with single and double vessel disease but 6 percent for those with triple vessel disease). Better definition of high and low risk subgroups of patients with three vessel disease was accomplished with exercise testing. Despite a history of mild symptoms, 25 percent of the patients with triple vessel disease exhibited poor exercise capacity on exercise testing after administration of beta adrenoceptor blocking agents and nitrates was discontinued; of these, 40 percent either died (20 percent) or had progressive symptoms requiring operation (20 percent) (annual mortality rate 9 percent). Of the patients with good exercise capacity, only 22 percent either died (7 percent) or had progressive symptoms (15 percent) (annual mortality rate 4 percent). Thus, prognosis is excellent in patients with no or mild symptoms who have one or two vessel coronary disease. Patients with three vessel disease who have good exercise capacity documented by objective testing have an annual mortality rate of 4 percent. However, because patients with three vessel disease and poor exercise capacity have an extremely grave prognosis, it would appear reasonable to recommend coronary bypass surgery for this subgroup, even in the absence of supporting data derived from a definitive randomized study.

Lack of effect of aspirin on myocardial infarct size in the dog

Pretreatment with platelet-inhibitory doses of aspirin (3 mg/kg body weight) has been shown to augment epicardial collateral flow by more than 50 percent (p less than 0.05) 4 hours after ligation of the left anterior descending coronary artery in dogs. To determine whether this favorable influence of aspirin is sufficient to decrease the amount of infarcted tissue, either intravenous aspirin, 3 mg/kg (n = 17), or saline solution (n = 17) was administered to dogs 10 minutes before occlusion of the left anterior descending coronary artery. Administration of saline solution or aspirin was repeated every 24 hours. By 72 hours, 5 dogs in each treatment group had died. Survivors were killed at 72 hours. The portion of the left ventricle at risk of infarction was delineated by perfusion of the aortic root with Evans blue and simultaneous perfusion of the distal left anterior descending coronary artery with saline solution under equal physiologic pressures. Slices of the stained heart were incubated with triphenyltetrazolium to identify gross infarct (with histologic confirmation). Total mass of left ventricle, myocardium at risk, and infarct size were measured in each dog. A direct relation was found between the mass at risk and the mass infarcted (r = 0.84, p less than 0.001). Aspirin-treated dogs did not differ from control dogs in percent ventricle at risk (mean +/- standard error 37 +/- 2 versus 40 +/- 2), percent infarct weight/left ventricle (29 +/- 3 versus 31 +/- 2) or percent infarct weight/weight of ventricle at risk (78 +/- 4 versus 77 +/- 3). Thus, despite aspirins ability to inhibit platelet aggregation and to increase epicardial collateral flow by more than 50 percent, aspirin treatment failed to reduce infarct size in this dog model.