Metabolic consequences of treating hypertension.

Reduction of morbidity and mortality has been the aim of drug treatment for hypertension since its beginning in the 1950s. Its efficacy has been tested in many trials. An outstanding result of these trials has been their clear success in preventing stroke and stroke-related deaths and in decreasing the incidence of congestive heart failure (CHF) and renal disease. A similar success has not been achieved in reducing coronary heart disease endpoints. Diuretics and beta-blockers played a central role in these studies; however, their adverse effects on lipid metabolism have been cited as a possible explanation for the failure of antihypertensive therapy to affect coronary heart disease (CHD). Recently, the extent and significance of these lipid changes has been put into perspective, and new insights into the role of carbohydrate metabolism and insulin resistance in hypertension have emerged. The same drugs which adversely affect lipid metabolism also adversely affect carbohydrate metabolism, and more is becoming known about these mechanisms and their role in hypertension and its sequelae. Other classes of antihypertensive drugs such as the calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and alpha 1-antagonists do not share these adverse effects. It has become increasingly clear that effective antihypertensive therapy includes both the lowering of blood pressure and containment of the abnormalities that accompany the hypertensive state.

Effects of encainide on the function of implanted pacemakers.

The effect of encainide on chronic pacing thresholds was evaluated in 10 patients, age 64-89, who were exposed to weekly increased encainide dosing (25 mg TID, 50 mg TID, 75 mg TID). Median pacing threshold (mujoules) increased modestly at each period compared to placebo and returned rapidly to baseline after discontinuation. (table; see text) No patient experienced a pacing-related clinical event. One patient had a large threshold increase (566%), but no failure to capture on 24-hour ECG, and one patient whose threshold increased minimally had clinically insignificant capture failure, the longest event being 3 beats. No other failure to capture was noted. Thus, encainide, like a number of other antiarrhythmic drugs, appears to affect pacing thresholds. At the highest dose of 225 mg/day (75 mg TID, which exceeds the generally recommended dose of 50 mg TID), but not at lower doses, some patients may experience loss of capture that does not appear related to the change in threshold energy required. Increases in the duration of the paced QRS induced by encainide did not predict increases in threshold. Therefore, when higher doses of encainide are required in patients with pacemakers, clinical observation and ambulatory electrocardiographic monitoring should be carried out.

Diltiazem as monotherapy for systemic hypertension: a multicenter, randomized, placebo-controlled trial.

A multicenter, randomized, placebo-controlled, parallel group study of diltiazem in essential hypertension was carried out in 77 patients (40 diltiazem, 37 placebo) with stable supine diastolic blood pressure (BP) between 95 and 110 mm Hg. Patients were withdrawn from previous antihypertensive therapy for at least 4 weeks, titrated to the optimal dose, and followed for a total of 12 weeks during therapy. A diltiazem dose of 360 mg/day was required in 85% of the patients. Average BP in all positions was significantly (p less than 0.0001) reduced by diltiazem compared with placebo. With diltiazem, average supine BP fell from 156/100 mm Hg at baseline to 141/87 at end titration and 145/90 mm Hg at week 12, whereas average standing BP fell from 152/101 mm Hg to 136/90 and 143/91 mm Hg, respectively, at those times. There was no significant change in heart rate at week 12. Diltiazem tended to be more effective in older patients, but caused no increase in orthostatic BP drop. There were no statistically significant changes in BP in the placebo group. Two patients receiving placebo and 1 patient receiving diltiazem discontinued therapy as a result of adverse effects, and overall, side effects were only slightly more common with diltiazem treatment. Thus, diltiazem was effective and well tolerated single therapy for mild to moderate systemic hypertension and appears to compare favorably to most agents being used.

Effects of diltiazem on serum lipids, exercise performance and blood pressure: randomized, double-blind, placebo-controlled evaluation for systemic hypertension.

Treatment of hypertension with diuretics, beta blockers and alpha blockers may be associated with adverse effects on exercise performance, serum lipids and blood chemistries, as well as with orthostatic effects and fluid retention. A randomized, double-blind, placebo-controlled trial of a sustained-release preparation of diltiazem as sole therapy for moderate essential hypertension was conducted. Diltiazem was administered 2 times a day (360 mg/day) to 16 patients and placebo to 14 patients in a 12-week study. Average supine blood pressure with diltiazem therapy fell from 161/100 to 144/87 mm Hg without fluid retention or orthostatic effects. In an open-label study, patients from the placebo and diltiazem groups continued with diltiazem therapy. At an average of over 8 months, supine blood pressure on diltiazem was 147/88 mm Hg, and after withdrawal to single-blind placebo, average supine blood pressure increased to 173/104 mm Hg. All changes were significant compared with baseline and placebo (p less than 0.01). On diltiazem therapy, maximal treadmill exercise was increased by an average of 55 seconds (p less than 0.01), whereas heart rate, blood pressure and double product (heart rate X blood pressure) were reduced at submaximal exercise, and heart rate and double product were reduced at maximal exercise. No changes in serum glucose, potassium or uric acid were found. No adverse effects on serum lipids occurred. Diltiazem treatment was associated with an increase in high-density lipoprotein cholesterol (52 to 60 mg/dl, p less than 0.006) and a decrease in total cholesterol:high-density lipoprotein cholesterol ratio (4.7 to 4.2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical hemodynamic profile of trimazosin in hypertension.

This report describes the clinical hemodynamic response of hypertensive patients to trimazosin. Data were drawn from six different clinical trials involving a total of 171 study patients. Some of the patients were represented in more than one study. These studies range from single-dose experiences, through long-term administration for periods greater than 1 year, to hour-by-hour observation of effects following single doses. These data demonstrate that (1) trimazosin is an effective antihypertensive agent for controlling both systolic and diastolic pressure, (2) its optimum daily dose in monotherapy in this study was at least 600 mg/day, (3) its effects persist without loss of efficacy for more than 1 year, (4) its effects involve a decrease in peripheral vascular resistance without significant cardiac effects, (5) effects on heart rate are small and are seen only mildly in the presence of diuretics in the standing position (being due to the diuretics), (6) reduction of blood pressure during exercise appears to be less than that at rest, and (7) its side effects appear to be minor and are, for the most part, a reflection of its hemodynamic effects.

The treatment of exercise-inducible chronic stable angina with diltiazem. Effect on treadmill exercise.

Although diltiazem has been shown to alleviate vasospastic angina pectoris, its effect on exercise-inducible chronic stable angina has not been objectively studied. Accordingly, the effect of diltiazem was studied in this condition with a placebo controlled double-blind randomized cross-over protocol at three dose levels (120, 180 and 240 mg/day) during graded treadmill exercise. Three end-points were evaluated: 1) time to onset of angina or fatigue if angina were eliminated; 2) time to 1 mm ST segment depression or fatigue if ST depression were eliminated; and 3) time to termination of exercise (2+ angina or fatigue). All end-points were prolonged at all dose levels. At the highest dose of 240 mg/day, time to onset angina or termination was prolonged from a placebo time of 8.0 +/ 0.9 to 9.8 +/- 0.9 minutes (p = < .001); time to ST depression or termination was prolonged from 7.8 +/- 0.9 to 9.1 +/- 0.8 minutes (p = .007); and time to termination was prolonged from 9.9 +/- 0.9 to 10.8 +/- 0.8 minutes (p = .02).

Analysis of myocardial and total body integral extraction ratios of rubidium-86.

Coronary blood flow (QM) measurement with radiorubidium (Rb) assumes that Rb distributes to the myocardium in proportion to flow. This assumption is correct if the integral myocardial Rb extraction ratio (ERM) equals total body extraction (ERTB). A right-heart-bypass preparation was employed to test the hypothesis that ERM = ERTB and to examine the determinants of Rb extraction. Dogs were anesthetized with pentobarbital, and arterial, coronary venous, and total body venous Rb concentrations were continuously measured for 4 min after injection. We found that ERM (0.56 +/- 0.01) was significantly less than ERTB (0.70 +/- 0.01), P less than 0.01 (n = 29) and concluded that Rb did not distribute in proportion to flow. We do not recommend this method for clinical use. ERM is flow dependent and ERRB is a function of the total cardiac output and the distribution of cardiac output. Before employing Rb in animal experiments, it is recommended that a preliminary study be performed comparing flow measured with Rb to an independent measure of blood flow.

Scintigraphic assessment of left ventricular aneurysms.

Thirty-five patients with coronary artery disease and possible left ventricular aneurysm underwent routine clinical examination, gated cardiac blood pool scintigraphy, and radionuclide cineangiography. Thirty-three of the 35 patients had coronary angiography and contrast left ventriculography. Sixteen patients had segmental left ventricular akinesia or dyskinesia, and 17 demonstrated left ventricular hypokinesis on contrast ventriculograms. Two patients had aneurysm confirmed at autopsy. Routine clinical evaluation was not sufficient to separate patients with aneurysm from those with hypokinesis. Radionuclide cineangiography correctly identified all cases of aneurysm or hypokinesis. The cinescintigraphic technique was preferable to the gated cardiac blood pool technique for qualitatively assessing and classifying abnormal ventricular wall motion. There was good correlation of the left ventricular ejection fraction by contrast ventriculograms and gated scintigrams in patients with either aneurysm or hypokinesis.

Analysis of wall motion abnormalities of the heart and great vessels by computer generated cine-radionuclide-equilibrium study.

Cardiac wall motion was evaluated in 54 patients by ECG-gated blood pool scintigraphy (GBPS) and computer assisted cine-radionuclide-equilibrium study (CRES). The cine format in CRES enhances the subtle aspects of great vessel and cardiac chamber motion and volume abnormalities. An off-line system using a general purpose computer permitted CRES to be initiated in smaller nuclear medicine facilities without large financial investiments.

Immunopathogenesis of Libman-Sacks endocarditis. Assessment by light and immunofluorescent microscopy in two patients.

The possible contribution of immunological mechanisms in the development of Libman-Sacks endocarditis was studied in 2 patients with systemic lupus erythematosus who underwent aortic valve replacement. Sections of verrucous lesions, stained with haematoxylin and eosin, showed three apparently distinct zones: an outer exudative zone of fibrin, nuclear debris, and haematoxylin-stained bodies; a middle organizing zone of proliferating capillaries and fibroblasts; and an inner zone of neovascularization which showed distinct, thin-walled junctional vessels. The striking finding was the apparently selective deposition of immunoglobulins and complement identified by direct immunofluorescence, within the walls of the small junctional vessels of the zone of neovascularization. We suggest that the observed immune deposits are immune complexes and that circulating immune complexes may play a critical role in the growth and proliferation of the verrucous lesion.

Accuracy of numerical coronary profile. Correlation of risk factors with arteriographically documented severity of atherosclerosis.

We compared a coronary risk profile (developed by the Framingham Study) based on age, sex, cigarette smoking, glucose intolerance, left ventricular hypertrophy, systolic blood pressure and serum cholesterol to angiographically determined severity of coronary-artery disease in 158 consecutive patients undergoing cardiac catheterization. A profile of 1.0 indicated average relative risk. Risk profiles for 105 patients with angiographically documented coronary-artery disease was 1.52 whereas it was 1.08 for the group without coronary disease (P less than 0.01). There was no difference between the patients with coronary disease with (1.44) and those without previous infarct (1.46). The coronary risk profile, however, increased with increasing severity of coronary disease. The high-risk coronary patient can be identified by seven easily measured risk factors, and the extent of coronary-artery disease increases with the number and severity coronary risk factors.

New approach to interpretation of technetium-99m pyrophosphate scintigraphy in detection of acute myocardial infarction: clinical assessment of diagnostic accuracy.

A modified classification for interpreting technetium-99m pyrophosphate scintigrams defines the 2+ diffuse pattern of tracer uptake as equlvocal rather than positive for acute myocardial infarction. Results of scintigraphy using this classification were compared with results of standard diagnostic tests for myocardial infarction in 235 patients admitted to a coronary care unit with acute chest pain. Of 81 patients with acute transmural infarction by standard clinical, electrocardiographic and serum enzyme criteria, 76 had a positive, 5 an equivocal and none a negative scintigram. Of 18 with acute nontransmural infarction by standard criteria, 7 had a positive, 9 an equivocal and 2 a negative scintigram. This it was uncommon for a patient with acute myocardial infarction, transmural or nontransmural, to have a definitely negative technetium-99m pyrophosphate study. Ten patients had equivocal evidence of infarction by standard criteria. Of the remaining 126 patients with no evidence of acute myocardial infarction by standard criteria, 87 had a negative, 35 an equivocal and 4 a definitely positive scintigram. Thus the definitely positive scintigraphic pattern was relatively highly specific for acute myocardial infarction. If the 2+ pattern had been considered positive, the specificity of the technique would have been greatly decreased. Computer processing strengthened observer certainty of the visual impression but changed the scintigraphic evaluation in only eight cases. Thus, use of an equivocal pattern renders technetium-99m pyrophosphate imaging both an extremely sensitive and specific method for detecting acute myocardial infarction.

Evaluation of myocardial uptake of 99mtechnetium pyrophosphate in clinical exercise-induced ventricular ischemia.

Although acute infarction of the myocardium is known to accumulate 99mtechnetium pyrophosphate, it is not entirely clear that ischemia alone without necrosis does not result in abnormal uptake of 99mtechnetium pyrophosphate. The present study investigates whether transient myocardial ischemia is associated with localization of 99mtechnetium pyrophosphate by evaluating images obtained with the scintillation camera at rest and after exercise in 15 patients with unequivocal myocardial ischemia. All patients had angina pectoris, multivessel coronary artery stenoses by selective arteriographic studies, and electrocardiographic ischemic responses on treadmill exercise. Eleven of the 15 patients also underwent radionuclide imaging with 81rubidium at rest and after exercise; the results demonstrated scintigraphic ischemia. The scintiscans with 99mtechnetium pyrophosphate revealed no evidence of increased myocardial radioactivity after exercise compared to rest in 14 of the 15 patients. In contrast, myocardial activity was observed with 99mtechnetium pyrophosphate after treadmill exertion in the remaining patient, in whom a small subendocardial infarction appeared to have occurred with the exercise. It is concluded from these results that transient myocardial ischemia does not cause localization of 99mtechnetium pyrophosphate. These findings support the specificity of abnormal localization of 99mtechnetium pyrophosphate for acute myocardial infarction.

Probucol: a new cholesterol-lowering drug effective in patients with type II hyperlipoproteinemia.

Type II hyperlipoproteinemia or hyperbetalipoproteinemia (B-HLP), a condition with considerable atherogenic potential, is one of the most difficult lipid disorders requiring treatment. Since this abnormality responds minimally to dietary therapy alone, supplemental drug therapy is usually essential. Although the available bile-sequestering resins are effective in B-HLP, these substances are unpalatable and constipating. Since lifelong drug therapy is necessary as an adjunct to diet in the treatment of B-HLP, the ideal drug should be both effective and well tolerated. Probucol, a new cholesterol-lowering drug in tablet form without serious adverse effects, was evaluated in a 12-wk double-blind crossover trial in 11 patients with B-HLP whose serum cholesterol levels were in excess of 275 mg/dl. Probucol, in a dosage of 500 mg twice daily, produced a 10% or greater reduction in serum cholesterol levels in all 11 patients. Serum cholesterol was lowered (p less than 0.01) from 353 to 291 mg/dl in the entire group receiving probucol. There was no significant change (p greater than 0.1) in serum cholesterol (352 mg/dl) during placebo administration. These were no untoward drug effects during the study, and all patients maintained excellent complicance to the schedule of medication. These results indicate that probucol possesses considerable cholesterol-lowering activity and may be a promising new nontoxic therapeutic agent in type II hyperlipoproteinemia.

Determination of improved myocardial perfusion after aortocoronary bypass surgery by exercise rubidium-81 scintigraphy.

Practical and noninvasive means are needed for evaluating efficacy of coronary bypass surgery (CBS) in improving blood flow (CBF) to ischemic myocardium in coronary patients. Revascularization was assessed in 15 patients by pre- and post-CBS rest and exercise rubidium-81 myocardial images with a scintillation camera equipped with pinhole collimator and high-energy shield. Ischemic areas were detected by decreased 81Rb activity after exercise compared to rest. Before CBS all patients had exercise angina (EA), positive treadmill ECG (TECG), and abnormal exercise 81Rb scans. After CBS all 15 patients had increased physical activity before angina or completion of treadmill exercise with increased heart rate-blood pressure product (HRBP) (+ 63 +/- 3.2 X 10(2) bpm - mm Hg) in 14 of 15 patients indicating increased CBF; four had positive TECG, and five had EA. The increased HRBP in 14 patients was associated with improved post-CBS exercise 81Rb scans: six had normal patterns while nine were improved with less ischemic patterns. Further, lack of angina and increased exercise tolerance correlated closely with increased 81Rb myocardial perfusion. Thus pre- and postoperative rest and exercise 81Rb scintigraphy gives an accurate, noninvasive, objective approach for evaluation of CBF following CBS and demonstrates the usefulness of this revascularization procedure in coronary patients.

Afterload reduction therapy with nitroprusside in severe aortic regurgitation: improved cardiac performance and reduced regurgitant volume.

To assess the hemodynamic effects of afterload reduction in severe aortic regurgitation, nitroprusside was infused at cardiac catheterization in 12 patients with aortic regurgitation. Cardiac hemodynamics, angiographic variables and regurgitant volumes were quantified during control periods, and nitroprusside was infused to reduce systemic systolic pressure to 110 to 125 mm Hg. The following were reduced by the drug: systolic arterial pressure (from 154 +/- 6.4 to 115 +/- 2.3 mm Hg, P less than 0.001); left ventricular end-diastolic pressure (from 23 +/- 2.2 to 11 +/- 1.0 mm Hg, P less than 0.001); systemic vascular resistance (from 1,782 +/- 133 to 1,148 +/- 94 dynes sec cm-5, P less than 0.001); left ventricular end-diastolic volume (from 242 +/- 25 to 196 +/- 19 ml, P less than 0.001); aortic regurgitant fraction (from 0.53 +/- 0.05 to 0.44 +/- 0.06, P less than 0.01); and aortic regurgitant minute volume (from 5.5 +/- 0.10 to 4.3 +/- 0.09 liters/min, P less than 0.01). Effective cardiac index increased (from 2.49 +/- 0.19 to 3.10 +/- 0.24 liters/min per m2, P less than 0.01), and left ventricular ejection fraction rose (from 0.55 +/- 0.03 to 0.61 +/- 0.03, P less than 0.005). These data indicate that afterload reduction with nitroprusside in severe aortic regurgitation improves cardiac performance, greatly decreases left ventricular preload and reduces aortic regurgitant volume. Thus, nitroprusside therapy has special value in severe aortic regurgitation that is of particular benefit in critical clinical conditions.