Extent and severity of coronary disease and mortality in patients with end-stage renal failure evaluated for renal transplantation.

The purpose of this study is to explore the relationship between coronary artery disease (CAD), transplantation status and subsequent mortality in end-stage renal disease (ESRD) patients undergoing evaluation for renal transplantation. Two hundred fifty-three ESRD patients at high risk for CAD underwent coronary angiography as part of a renal transplant evaluation. The cohort was divided into three groups: Group 1 (n = 127) had no vessels with >or=50% stenosis, Group 2 (n = 56) had one vessel with >or=50% stenosis and Group 3 (n = 70) had two or more vessels with >or=50% stenosis. Long-term survival was determined; median follow-up was 3.3 years. The baseline characteristics were similar except for older age and higher proportion of diabetes mellitus, dyslipidemia and peripheral vascular disease in Groups 2 and 3 patients as compared to Group 1. Survival was worse in Group 3 compared to Group 1 (p < 0.0001). Each of the three subgroups had better survival with renal transplantation than those who did not undergo transplantation (p < 0.0001). Although the degree of CAD is related to subsequent mortality, transplantation is associated with better survival regardless of the extent and severity of CAD. Thus, the presence of CAD should not exclude ESRD patients from consideration for this therapy.

Effect of exercise conditioning on plasma high density lipoproteins and other lipoproteins.

Epidemiologic studies have demonstrated an inverse correlation between HDL-cholesterol and the incidence of coronary artery disease. Although physically active individuals tend to have higher HDL levels than their sedentary peers, they also have lower body weights. It has yet to be shown that physical activity by itself can raise HDL when other variables such as body weight are maintained constant. We examined the effect of a 6-week exercise conditioning program on 10 young normal subjects who were maintained on a constant composition, iso-weight diet. A training effect was documented by an increase in maximum oxygen consumption from 44 to 49 ml/min/kg and by a fall in heart rate at submaximal exercise from 120 to 109 beats/min. Total plasma cholesterol levels decreased significantly from 156 to 140 mg/dl. However, there was no significant change in plasma triglyceride, VLDL, LDL or HDL-cholesterol levels, although all these values decreased. Thus, under the conditions of this study in which diet and weight were controlled, exercise conditioning did not elevate HDL-cholesterol levels. HDL levels have been shown to be inversely related to body weight. These data are consistent with the concept that exercise conditioning may affect HDL via alterations in body weight.

"Malignant" hypertrophic cardiomyopathy: identification of a subgroup of families with unusually frequent premature death.

Eight families were identified in which premature cardiac death due to hypertrophic cardiomyopathy occurred with unusual frequency. A total of 69 first degree relatives in the eight families were studied; 41 relatives had evidence of hypertrophic cardiomyopathy and 31 (75 per cent) died of their heart disease. Eighteen of these 31 patients were less than 25 years of age at the time of death. Death was sudden and unexpected in 23 of the 31 patients; in 15 of these 23 patients sudden death was the initial manifestation of cardiac disease. The remaining eight patients (seven were from two families) died after a chronic cardiac illness characterized by congestive heart failure, atrial fibrillation or thromboembolic events. Hence, premature cardiac death occurs frequently in certain families with hypertrophic cardiomyopathy. Such deaths are usually sudden, often occur in previously asymptomatic subjects and are common in children and young adults. These findings suggest that some families may manifest an unusually virulent expression of hypertrophic cardiomyopathy. Although this study cannot establish the precise prevalence with which "malignant" hypertrophic cardiomyopathy occurs, such families appear to be uncommon.

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 aspirin's 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.

Hemodynamic function of the Hancock standard orifice aortic valve bioprosthesis.

Reports that the hemodynamic performance of the standard orifice aortic bioprosthesis in less than optimal have prompted recommendations that mechanical prosthesis or anulus-enlarging procedures be used in adult patients with a small aortic root. The hemodynamic function of the Hancock bioprosthesis was evaluated in 77 patients who underwent cardiac catheterization of rest and with isoproterenol infusion (15 patients) an average of 6 months after operation. The average peak systolic gradient (basal conditions) was 7 mm Hg (range 0 to 37 mm Hg); 35 patients had no resting gradient. Fifteen patients received 21 mm diameter valves and had an average systolic valve gradient of 10 mm Hg (range 0 to 30 mm Hg); the average effective valve orifice area was 1.27 +/- 0.17 cm2 for 21 mm, 1.46 +/- 0.11 cm2 for 23 mm, 1.72 +/- k0.20 cm2 for 25 mm, and 1.97 +/- 0.06 for 27 mm bioprostheses. Isoproterenol infusion, elevating cardiac output 66%, increased the peak systolic gradient from an average of 11 mm Hg (range 0 to 37 mm Hg) to 44 mm Hg (range 10 to 85 mm Hg). It is concluded that small-diameter (21 and 23 mm) Hancock bioprostheses can be used with acceptable clinical and hemodynamic function in patients with a small body surface area.

Relative effects of aspirin on platelet aggregation and prostaglandin-mediated coronary vasodilatation in the dog.

Aspirin, as an inhibitor of platelet aggregation, may be of benefit in ischemic heart disease. However, aspirin blocks not only platelet aggregation but also synthesis of prostacyclin, a vasodilator and platelet deaggregator. The relative sensitivity of prostaglandin-mediated coronary vasodilatation and platelet aggregation to inhibition by aspirin remains uncertain. We therefore investigated the relative dose-response relationship of aspirin on arachidonic acid-induced increments in coronary blood flow and on ADP-induced aggregation of platelets. In 11 open-chest dogs, intracoronary arachidonic acid, 0.1-3.0 mg, produced dose-related increases in coronary blood flow that were inhibited progressively by i.v. aspirin over the dose range 0.3-3.0 mg/kg. Aspirin at 3 mg/kg almost completely obliterated the response to 3 mg of arachidonic acid. Similarly, aspirin doses of 0.3-3.0 mg/kg progressively raised the minimal concentration of ADP necessary for platelet aggregation. The threshold concentration of ADP that produced aggregation of platelets from 10 control dogs ranged from 2.3 x 10(-6) M to 1.2 x 10(-5) M. Aspirin at 3 mg/kg completely inhibited aggregation of platelets from 11 of 12 dogs, even with ADP at 2.3 x 10(-4) M concentration, the maximum tested. Aspirin at 0.1 mg/kg failed to inhibit either ADP-induced platelet aggregation or arachidonic acid-induced increments in coronary blood flow. Thus, the two test systems showed similar sensitivity to inhibition by aspirin with respect to threshold dose and maximal effect. These results show that very low doses of aspirin inhibit arachidonic acid-induced coronary vasodilatation and that aspirin at low doses does not appear to selectively inhibit platelet activity relative to coronary vasodilatation.

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 (PTCA). No patient had ECG evidence of previous myocardial infarction. Despite normal regional and global LV systolic function at rest in all patents, LV diastolic filling was abnormal (peak LV filling rate [PFR] less than 2.5 end-diastolic volumes (EDV)/sec or time to PFR greater than 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 less than 0.001). LV diastolic filling at rest improved: PFR increased from 2.3 +/- 0.6 to 2.8 +/- 0.5 EDV/sec (p less than 0.001) and time to PFR decreased from 181 +/- 22 to 160 +/- 18 msec (p less than 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.

Aortic valve replacement without myocardial revascularization in patients with combined aortic valvular and coronary artery disease.

To test the hypothesis that coronary artery bypass grafting (CABG) is not routinely required in patients undergoing aortic valve replacement (AVR) who have coexistent coronary artery disease (CAD), we compared the results of operation in 55 consecutive symptomatic patients who had CAD and underwent AVR without CABG with results in another 142 patients without CAD who underwent AVR during the same period, and with published results from other centers in which CABG was used in patients with CAD who underwent AVR. Operative mortality was 4% in patients with CAD and 5% in patients without CAD. Late survival was not significantly different between the two groups when analyzed for the entire population (80% survival at 3 years in CAD patients, 82% for non-CAD patients), or for the subgroup of patients with aortic stenosis, aortic regurgitation or aortic stenosis plus regurgitation. Eight patients with CAD (15%) developed recurrent angina after AVR (mean follow-up 43 months); only three patients (6%) required CABG because of medically refractory angina (12-43 months). Operative mortality, operative infarction (9%), recurrent angina and long-term survival in patients with CAD after AVR were similar to those at other centers after AVR plus CABG. These data suggest that preoperative detection of CAD does not necessitate CABG in all patients at the time of AVR.

Long-term hemodynamic assessment of the porcine heterograft in the mitral position. Late development of valvular stenosis.

We undertook a study of patients who had porcine mitral valves in place for more than 5 years and who had no clinical signs or symptoms suggestive of valve dysfunction. Of the first 54 patients who had porcine valves implanted in the mitral position, 18 were available for catheterization; all had a routine hemodynamic study postoperatively (mean 7 months) for comparison. Mean follow-up was 85 months (range 61-111 months). Compared with the early postoperative data, there was a significant increase in mean mitral valve gradient, from 5.9 +/- 0.7 to 8.6 +/- 0.7 mm Hg (p less than 0.01), and a significant decrease in calculated mitral valve area, from 2.2 +/- 0.2 to 1.7 +/- 0.2 cm2 (p less than 0.01). Moreover, seven patients showed a decrease in valve area greater than 1.0 cm2, five with valves in place for more than 80 months and only two of 11 patients with valves in place for 80 months or less (p less than 0.05). We conclude that there is a significant incidence of hemodynamic deterioration of porcine heterografts in the mitral position for greater than 5 years, even in patients who are clinically stable.

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.

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.

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 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.

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 mechanism 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) less than 2.5 end-diastolic volumes (EDV)/sec or time to PFR greater than 80 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 less than 0.001) and reduce time to PFR (control 187 +/- 56 msec, verapamil, 159 +/- 34 msec; p less than 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.