Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes.

We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a ß-blocker-based strategy (ß-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10-8). rs11124945 G allele carriers had lower odds for NOD when exposed to the ß-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10-5), whereas A/A homozygotes exposed to the ß-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10-4). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.

Arterial stiffness assessment in coronary microvascular dysfunction and heart failure with preserved ejection fraction: An initial report from the WISE-CVD continuation study.

Background: Heart failure with preserved ejection fraction (HFpEF) is the most common cardiac complication in patients with coronary microvascular dysfunction (CMD), yet its underlying pathways remain unclear. Aortic pulse-wave velocity (aPWV) is an indicator of large artery stiffness and a predictor for cardiovascular disease. However, aPWV in CMD and HFpEF is not well characterized and may provide understanding of disease progression. Methods: Among participants without obstructive coronary artery disease, we evaluated 51 women with suspected CMD and 20 women and men with evidence of HFpEF. All participants underwent aPWV measurement (SphygmoCor, Atcor Medical) with higher aPWV indicating greater vascular stiffness. Cardiac magnetic resonance imaging (CMRI) assessed left ventricular (LV) ejection fraction, CMD via myocardial perfusion reserve index (MPRI), and ventricular remodeling via LV mass-volume ratio. . Statistical analysis was performed using Wilcoxon rank sum tests, Pearson correlations and linear regression analysis. Results: Compared to the suspected CMD group, the HFpEF participants were older (65 ± 12 vs 56 ± 11 yrs., p = 0.002) had higher BMI (31.0 ± 4.3 vs 27.8 ± 6.7 kg/m2, p = 0.013), higher aPWV (10.5 ± 2.0 vs 8.0 ± 1.6 m/s, p = 0.05) and lower MPRI (1.5 ± 0.3 vs1.8 ± 0.3, p = 0.02), but not remodeling. In a model adjusted for cardiovascular risk factors, the HFpEF group had a lower LVEF (estimate -4.78, p = 0.0437) than the suspected CMD group. Conclusions: HFpEF participants exhibit greater arterial stiffness and lower myocardial perfusion reserve, with lower LVEF albeit not remodeling, compared to suspected CMD participants. These findings suggest arterial stiffness may contribute to progression from CMD to HFpEF. Prospective work is needed and ongoing.

Association of KCNJ1 variation with change in fasting glucose and new onset diabetes during HCTZ treatment.

Thiazide-induced potassium loss may contribute to new onset diabetes (NOD). KCNJ1 encodes a potassium channel and one study observed that a KCNJ1 single-nucleotide polymorphism (SNP) was associated with changes in fasting glucose (FG) during hydrochlorothiazide (HCTZ) treatment. We used linear regression to test association of KCNJ1 SNPs and haplotypes with FG changes during HCTZ treatment in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We used logistic regression to test association of KCNJ1 variation with NOD in HCTZ-treated patients from the International Verapamil SR Trandolapril Study (INVEST). Multivariate regression analyses were performed by race/ethnicity with false discovery rate (FDR) correction. In PEAR blacks, a KCNJ1 SNP was associated with increased FG during HCTZ treatment (beta=8.47, P(FDR)=0.009). KCNJ1 SNPs and haplotypes were associated with NOD risk in all INVEST race/ethnic groups (strongest association: odds ratio 2.14 (1.31-3.53), P(FDR)=0.03). Our findings support that KCNJ1 variation is associated with HCTZ-induced dysglycemia and NOD.

Cold Pressor Testing and Sympathetic Nervous System Contribution to Ischemia with No Obstructive Coronary Artery Disease: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project.

Study Objective: Cold Pressor Testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects. Design: Prospective cohort. Setting: Academic hospital. Participants: 107 women with suspected INOCA and 21-age-matched reference women. Interventions: CPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRIRPP). Invasive coronary function testing in a subset of INOCA women (n=42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%. Main Outcome Measure: MPRIRPP. Results: Compared to reference women, the INOCA group demonstrated higher resting RPP (p=0.005) and CPT MPRIRPP (1.09±0.36 vs 0.83±0.18, p=0.002). Furthermore, INOCA women with impaired ΔCBF (n=23) had higher CPT MPRIRPP (p=0.044) compared to reference women despite lower left ventricular ejection fraction (64±7 % vs 69±2 %, p=0.005) and mass-to-volume ratio (0.79±0.15 vs 0.62±0.09, p<0.0001). These differences in CPT MPRIRPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRIRPP among INOCA women did not differ based on defined acetylcholine responses. Conclusions: Myocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. CPT induced a higher MPRIRPP also in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Further investigation in a larger cohort is needed.

Coronary atheroma burden predicts flow reserve in women with ischemia and nonobstructive coronary artery disease.

Background: Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD) with reduced coronary flow reserve (CFR), and compensatory coronary remodeling. Angiographic measurements of epicardial coronary anatomy (AMCA) may improve understanding of relations between CFR and atherosclerosis. We investigated AMCA and CFR in women evaluated for CMD. Methods: Women consecutively enrolled in the Women's Ischemia Syndrome Evaluation CVD Continuation (NCT00832702) were included. All underwent clinically indicated coronary function testing measuring CFR. AMCA included coronary angiographic atheroma burden (AB), percent diameter stenosis (PDS), and tapering reference diameter Z score (RDZ), derived for the left main and left anterior descending coronary epicardial segments. Results: The 51 women were aged 55.8 ±â€¯10.8 years, with 19(38%) hypertensive, 10(20.4%) hyperlipidemic, 4(7.8%) diabetic, 13(25.5%) prior smokers, and mean CFR 3.0 ±â€¯0.8. Both average and maximal AB negatively correlated with CFR (r = -0.30 and -0.31, with p = 0.04 for both), as did average and maximal PDS (r = -0.38 and -0.41 with p = 0.009 and p = 0.005) while average RDZ was directly related (r = 0.37, p = 0.01). Multiple linear regression analyses revealed that both average PDS (Units of CFR -0.03 95% CI: -0.06, -0.002, p = 0.023) and maximal PDS (-0.04 95% CI -0.07, -0.01, p = 0.007) were negatively related to CFR. Conclusions: Measures of epicardial coronary atheroma burden, size and tapering are related to CFR, suggesting that atherosclerotic anatomical findings may contribute to or be a consequence of CMD, with further work is needed to investigate these measures as treatment targets.

Association of CYP3A5 polymorphisms with hypertension and antihypertensive response to verapamil.

In the CYP3A5 gene, the A>G (*3) and G>A (*6) polymorphisms result in severely decreased expression of CYP3A5 enzyme relative to a normal functional allele (*1). We sought to determine if the CYP3A5 genetic polymorphisms were associated with level of blood pressure (BP), risk of hypertension (HTN), and the antihypertensive response to verapamil. A total of 676 normotensive and hypertensive participants (mean age 49+/-8.2 years) from the Hypertension Genes study and 722 patients (mean age 66+/-9 years) from the International Verapamil/Trandolapril Study Genetic Substudy (INVEST-GENES) were genotyped for CYP3A5 to test for associations with BP, HTN, and in the latter cohort, antihypertensive response to verapamil. CYP3A5 haplotypes were determined using PHASE 2, with any allele containing either (*3) or (*6) designated as non functional. In the HTN genes population, there were no significant differences based on the number of functional CYP3A5 alleles, in systolic blood pressure (SBP) or diastolic blood pressure (DBP) among the normotensive whites or blacks (all P> or =0.70) or in allele frequency between normotensives and hypertensives. In INVEST-GENES, when controlled for baseline BP, race, age, and gender, untreated BP in carriers versus non carriers of a CYP3A5 functional allele was 158.2+/-13.7 and 154.8+/-13.7 (P=0.061), respectively. CYP3A5 functional allele status was marginally associated with the SBP response to verapamil in blacks (P=0.075) and Hispanics (P=0.056), but not in whites (P=0.40), with the effect being largely driven by higher SBP in the carriers of two functional alleles. There was no association with DBP response and CYP3A5 allele status. CYP3A5 genotype does not contribute importantly to BP or risk of HTN, but may influence response to calcium channel blockers in populations in which carrier status of two functional alleles is common.

Aortic input impedance during nitroprusside infusion. A reconsideration of afterload reduction and beneficial action.

Beneficial effects of nitroprusside infusion in heart failure are purportedly a result of decreased afterload through "impedance" reduction. To study the effect of nitroprusside on vascular factors that determine the total load opposing left ventricular ejection, the total aortic input impedance spectrum was examined in 12 patients with heart failure (cardiac index <2.0 liters/min per m(2) and left ventricular end diastolic pressure >20 mm Hg). This input impedance spectrum expresses both mean flow (resistance) and pulsatile flow (compliance and wave reflections) components of vascular load. Aortic root blood flow velocity and pressure were recorded continuously with a catheter-tip electromagnetic velocity probe in addition to left ventricular pressure. Small doses of nitroprusside (9-19 mug/min) altered the total aortic input impedance spectrum as significant (P < 0.05) reductions in both mean and pulsatile components were observed within 60-90 s. With these acute changes in vascular load, left ventricular end diastolic pressure declined (44%) and stroke volume increased (20%, both P < 0.05). Larger nitroprusside doses (20-38 mug/min) caused additional alteration in the aortic input impedance spectrum with further reduction in left ventricular end diastolic pressure and increase in stroke volume but no additional changes in the impedance spectrum or stroke volume occurred with 39-77 mug/min. Improved ventricular function persisted when aortic pressure was restored to control values with simultaneous phenylephrine infusion in three patients. These data indicate that nitroprusside acutely alters both the mean and pulsatile components of vascular load to effect improvement in ventricular function in patients with heart failure. The evidence presented suggests that it may be possible to reduce vascular load and improve ventricular function independent of aortic pressure reduction.

Management of patients with acute coronary syndromes in the United States by platelet glycoprotein IIb/IIIa inhibition. Insights from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial.

BACKGROUND: A multinational, randomized, placebo-controlled trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, PURSUIT) demonstrated that the platelet glycoprotein IIb/IIIa receptor antagonist eptifibatide reduced the incidence of death or myocardial infarction among patients with acute ischemic syndromes without ST-segment elevation. Because of expected differences in practice patterns, a prospectively planned analysis of outcomes as a function of regions of the world was performed. The current study provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States. METHODS AND RESULTS: Patients presenting with chest pain within the previous 24 hours and ischemic ECG changes or creatine kinase-MB elevation were eligible for enrollment. Of the 10 948 patients randomized worldwide, 4035 were enrolled within the United States. Patients were allocated to placebo or eptifibatide infusion for up to 72 to 96 hours. Other medical therapies and revascularization strategies were at the discretion of the treating physician. Eptifibatide reduced the rate of the primary end point of death or myocardial infarction by 30 days from 15.4% to 11.9% (P=0.003) among patients in the United States. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 15.2%; P=0.004). Bleeding events were more common in patients receiving eptifibatide but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the United States than elsewhere in the world. CONCLUSIONS: Platelet glycoprotein IIb/IIIa receptor blockade with eptifibatide reduces the incidence of death or myocardial infarction among patients treated for acute ischemic syndromes without ST-segment elevation within the United States.

Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study.

BACKGROUND: Intravascular ultrasound (IVUS) can assess stent geometry more accurately than angiography. Several studies have demonstrated that the degree of stent expansion as measured by IVUS directly correlated to clinical outcome. However, it is unclear if routine ultrasound guidance of stent implantation improves clinical outcome as compared with angiographic guidance alone. METHODS AND RESULTS: The CRUISE (Can Routine Ultrasound Influence Stent Expansion) study, a multicenter study IVUS substudy of the Stent Anti-thrombotic Regimen Study, was designed to assess the impact of IVUS on stent deployment in the high-pressure era. Nine centers were prospectively assigned to stent deployment with the use of ultrasound guidance and 7 centers to angiographic guidance alone with documentary (blinded) IVUS at the conclusion of the procedure. A total of 525 patients were enrolled with completed quantitative coronary angiography, quantitative coronary ultrasound, and clinical events adjudicated at 9 months for 499 patients. The IVUS-guided group had a larger minimal lumen diameter (2.9+/-0.4 versus 2.7+/-0. 5 mm, P<0.001) by quantitative coronary angiography and a larger minimal stent area (7.78+/-1.72 versus 7.06+/-2.13 mm(2), P<0.001) by quantitative coronary ultrasound. Target vessel revascularization, defined as clinically driven repeat interventional or surgical therapy of the index vessel at 9 month-follow-up, occurred significantly less frequently in the IVUS-guided group (8.5% versus 15.3%, P<0.05; relative reduction of 44%). CONCLUSIONS: These data suggest that ultrasound guidance of stent implantation may result in more effective stent expansion compared with angiographic guidance alone.

Ongoing clinical trials of angiotensin-converting enzyme inhibitors for treatment of coronary artery disease in patients with preserved left ventricular function.

At present there is considerable activity in the area of prevention of atherosclerosis-related events using angiotensin-converting enzyme inhibitors. Large trials have demonstrated significant reduction in cardiovascular morbidity and mortality with long-term use of angiotensin-converting enzyme inhibitors in patients with left ventricular dysfunction, heart failure or acute myocardial infarction. Reductions in acute ischemic events (e.g., myocardial infarction, unstable angina and need for early revascularization) were independent of ejection fraction and were greater than would be expected from the small reduction in blood pressure that occurred, suggesting that other patients with coronary artery disease may benefit from angiotensin-converting enzyme inhibitor therapy. This hypothesis is being tested in multiple double-blind, randomized, controlled clinical trials with durations of follow-up of 3 to 5 years that will involve approximately 30,000 patients. The trials vary with respect to patient population (e.g., normotensive vs. hypertensive, normolipidemic vs. hyperlipidemic, with vs. without diabetes mellitus), angiotensin-converting enzyme inhibitor used and outcome measures. When available, the results of these clinical trials could have very important implications for the role of long-term angiotensin-converting enzyme inhibitor therapy for preventing or delaying the development of atherosclerosis-related ischemic events.

Aspirin and newer orally active antiplatelet agents in the treatment of the post-myocardial infarction patient.

The thienopyridine derivatives, ticlopidine and clopidogrel, provide alternatives to aspirin for use in the prevention of recurrent ischemic events in the post-myocardial infarction patient. These drugs act through a different mechanism than aspirin and, as a result, have potentially different profiles of safety and efficacy. The following discusses the clinical data collected supporting the use of these drugs for secondary prevention and the unanswered questions that remain regarding their use in subpopulations of individuals at risk. Based on the available data, it may be concluded that aspirin should remain the drug of choice for the prevention of recurrent ischemic events in the majority of patients who have suffered a recent myocardial infarction.

Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The Zatebradine Study Group.

OBJECTIVES: We examined the antianginal and anti-ischemic effects of oral zatebradine, a direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angina pectoris taking extended-release nifedipine. BACKGROUND: Heart rate reduction is considered an important pharmacologic mechanism for providing anginal pain relief and anti-ischemic action in patients with chronic stable angina, suggesting a benefit for sinus node-inhibiting drugs. METHODS: In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60). All subjects had reproducible treadmill exercise-induced angina at baseline, and after randomization they performed a serial exercise test 3 h after each dose for 4 weeks. RESULTS: Zatebradine reduced rest heart rate both at 4 weeks ([mean +/- SEM] 12.9 +/- 1.23 vs. 2.3 +/- 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 +/- 1.2 vs. 3.4 +/- 1.2 [placebo] beats/min, p < 0.0001). Despite the significant effects on heart rate at rest and exercise, there were no additional benefits of zatebradine from placebo baseline in measurements of total exercise duration, time to 1-mm ST segment depression or time to onset of angina. Subjects taking zatebradine also had more visual disturbances as adverse reactions. CONCLUSIONS: Zatebradine seems to provide no additional antianginal benefit to patients already receiving nifedipine, and it raises questions regarding the benefit of heart rate reduction alone as an antianginal approach to patients with chronic stable angina.

Regional coronary venous flow responses to transient coronary artery occlusion in human beings.

Coronary hemodynamic responses to transient coronary artery occlusion in 21 patients were investigated by using regional coronary venous thermodilution to measure regional coronary venous flows. Transient coronary artery occlusion was produced by coronary artery spasm (13 patients) or balloon inflation during coronary angioplasty (8 patients). The left anterior descending coronary artery was transiently occluded in 12 patients, the right coronary artery in 8 patients and the left circumflex artery in 1 patient. During transient coronary occlusion, regional venous flow decreased in 20 of the 21 patients (79 +/- 31 to 53 +/- 29 ml/min, mean +/- standard deviation [SD]; probability [p] less than 0.05) corresponding to the left ventricular region perfused by the occluded artery. Regional coronary resistance increased in all 21 of these regions (1.42 +/- 0.75 to 2.26 +/- 1.45 mm Hg/ml per min, p less than 0.05). Simultaneously measured blood flow and resistance in the left ventricular region supplied by the nonoccluded arteries did not change significantly (62 +/- 27 to 64 +/- 29 ml/min and 1.85 +/- 0.93 to 1.81 +/- 0.98 mm Hg/ml per min, respectively). Coronary hemodynamic changes were similar during transient coronary occlusion, whether produced by coronary spasm or by balloon inflation. However, the presence of angina, reversible electrocardiographic abnormalities and an increase of the left ventricular filling pressure were more common during coronary spasm (p less than 0.05 for all). Regional coronary hemodynamic changes during transient occlusion of the anterior descending, circumflex or right coronary artery were similar. These data show that coronary occlusion decreases regional left ventricular flow in the region perfused by the affected artery. The method of coronary occlusion or the coronary artery affected during occlusion did not seem to elicit different responses.

Influence of acute aortic insufficiency on the hemodynamic importance of a coronary artery narrowing. II. Various magnitudes of aortic insufficiency.

Coronary hemodynamic effects of controlled acute aortic insufficiency were studied in 40 open chest dogs with and without graded coronary diameter narrowing. An adjustable basket device was used to regulate aortic insufficiency, creating three groups: group 1, mild to moderate aortic insufficiency (regurgitant fraction less than 50%); group 2, moderately severe aortic insufficiency (regurgitant fraction greater than 50%); and group 3, aortic insufficiency with mean aortic pressure restored to control levels. Mean coronary blood flow was similar to control values in group 1, but was higher in groups 2 and 3. The endocardial/epicardial flow ratio was similar with and without aortic insufficiency. With graded coronary narrowing greater than 80%, coronary flow and endocardial/epicardial flow ratio decreased with or without aortic insufficiency. However, endocardial/epicardial flow ratio usually decreased more during aortic insufficiency. Peak reactive hyperemic flow after release of a 10 second coronary occlusion also decreased during aortic insufficiency. The amount of decrease compared with control values was related to the magnitude of aortic insufficiency. This value with no coronary narrowing in group 1 was similar to peak reactive hyperemic flow with a 60% coronary narrowing during the control period. In group 2, peak reactive hyperemic flow was similar to that with an 80% coronary narrowing during the control period. Restoring mean aortic pressure to control values in group 3 did not restore peak reactive hyperemic flow to control values. These data suggest that coronary flow reserve assessed with coronary narrowings or during reactive hyperemia is decreased during aortic insufficiency. The decrease in coronary flow reserve was more pronounced as the magnitude of aortic insufficiency increased.

Effect of nifedipine on coronary hemodynamics in patients with left anterior descending coronary occlusion.

The mechanisms responsible for the beneficial effects of calcium channel antagonists in patients with effort angina were investigated by studying the coronary hemodynamic responses of the anterior left ventricular region before and after administration of nifedipine in 13 patients whose left anterior descending coronary artery was filled by flow from collateral vessels. Nifedipine was given bucally in a dose (10 or 20 mg) that decreased aortic pressure 5 mm Hg or more. Nifedipine increased collateral flow (regional thermodilution) in only three patients (p = NS), but consistently decreased coronary resistance in the left ventricular anterior region (p less than 0.05). Anterior region myocardial oxygen consumption did not change after nifedipine administration. Lactate metabolism was evaluated in eight patients: values were abnormal in four patients before nifedipine; after nifedipine, values remained abnormal in three of these patients and became abnormal in one other. During atrial pacing stress, angina occurred in all patients before nifedipine and at the same or lower heart rate in nine patients after nifedipine. After nifedipine administered at the same rate that induced angina during the control period, collateral flow and myocardial oxygen consumption were usually lower (both p less than 0.05), but anterior region coronary resistance was unchanged compared with control values. Lactate metabolism was not usually improved. Thus, although nifedipine maintained collateral flow while aortic pressure decreased, no consistent beneficial effect on pacing-induced angina was seen.

Regional coronary hemodynamic responses during the cold pressor test: lack of effect of nitroglycerin.

The effects of large coronary vessel dilation on responses to immersion of a hand and forearm in ice water for 1 minute (that is, the cold pressor test) were calculated for 17 patients. Regional coronary blood flow and aortic and left ventricular pressures were continuously measured before and during two cold pressor tests, each performed before and after administration of sublingual (0.4 mg) or low dose intracoronary (0.01 mg) nitroglycerin. During the initial cold pressor test, heart rate and coronary pressures increased in all patients; total and regional coronary resistance usually increased in patients with severe coronary artery disease and usually decreased in patients with a normal coronary angiogram. Sublingual nitroglycerin induced important systemic effects, but intracoronary nitroglycerin did not; both induced dilation of coronary arteries viewed angiographically. Regardless of the route of nitroglycerin administration, coronary hemodynamic responses were directionally similar during the repeat cold pressor test compared with the initial one. These data support the concept that changes in tone of the large coronary arteries are not important in producing the cardiac responses observed during the cold pressor test.

Comparison of diltiazem and nifedipine alone and in combination in patients with coronary artery spasm.

Fifteen patients with coronary artery spasm completed a double-blind placebo-controlled trial comparing diltiazem and nifedipine. Increasingly, higher daily doses (diltiazem, 90 to 360 mg; nifedipine, 30 to 120 mg) were administered to achieve optimal clinical effects. Daily diaries and ambulatory electrocardiographic recordings were used to assess efficacy and side effects. Both drugs significantly decreased angina frequency compared with that in the preceding placebo period (diltiazem 1.4 +/- 0.4 [mean +/- SEM] to 0.4 +/- 0.2 episodes per day; nifedipine 1.4 +/- 0.3 to 0.4 +/- 0.1 episodes per day; both p less than 0.05). Ambulatory electrocardiographic recordings showed fewer ST shifts than were expected during all treatment periods (0.02/h recorded during placebo, none during diltiazem and 0.02/h during nifedipine therapy). Although some patients responded better to one drug than the other, neither drug resulted in a clearly superior clinical response. Diltiazem was discontinued in one patient because of urticaria, but the total number of side effects was higher with nifedipine (12 of 15 patients) than with diltiazem (5 of 15, p less than 0.01). Nine patients remained symptomatic on single drug treatment and entered open label treatment with the combination of diltiazem and nifedipine. Three patients did not tolerate the combination because of important side effects; the other six also had side effects, but these were relatively minor. Four patients received no more benefit from the combination than from a single agent; the condition of two patients improved. Both diltiazem and nifedipine provide effective antianginal therapy for coronary spasm, but diltiazem has fewer side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Contracted plasma and blood volume in chronic heart failure.

OBJECTIVES: The purpose of this study was to determine if long-term pharmacotherapy mediated changes in intravascular plasma and blood volumes in patients with chronic heart failure (CHF). BACKGROUND: Intravascular fluid volume expansion is an acute compensatory adaptation to ventricular dysfunction in patients with CHF. To our knowledge there are no reports on plasma and blood volume measures in clinically stable patients with CHF receiving standard pharmacotherapy. Such information may provide a better understanding of the clinical hallmarks of heart failure. METHODS: Plasma volume (PV) and blood volume (BV) were measured in 12 patients (62.8 +/- 8.2 years old, 175.2 +/- 6.8 cm, 96.2 +/- 18.2 kg, peak oxygen consumption (VO2max) 15.2 +/- 3.3 ml/kg per min) with CHF secondary to coronary artery disease (left ventricular ejection fraction 31.2 +/- 9.7, New York Heart Association functional class 2.5 +/- 0.5) and seven healthy subjects (71.7 +/- 5.3 years old, 177.1 +/- 10.8 cm, 84.4 +/- 11.7 kg, VO2max 26.0 +/- 6.5 ml/kg per min) 3 to 4 h after eating and after supine rest using the Evan's blue dye dilution technique. Venous blood samples were collected before blue dye infusion and analyzed for hematocrit (corrected 4% for trapped plasma and venous to whole body hematocrit ratio) and hemoglobin. RESULTS: Hematocrit was 36.6 +/- 3.5% and 37.4 +/- 1.1%, and hemoglobin was 15.4 +/- 1.9 and 16.2 +/- 1.4 g/dl for patients with CHF and control subjects, respectively. Absolute PV was 3489.3 +/- 655.0 and 3728.7 +/- 813.2 ml, and absolute BV was 5,496.8 +/- 1,025.4 and 5,942.4 +/- 1,182.2 ml in patients with CHF and control subjects, respectively. Relative PV was 34.1 +/- 12.9 versus 44.5 +/- 9.0 ml/kg (p < or = 0.05), and relative BV was 58.5 +/- 12.3 versus 70.8 +/- 12.6 ml/kg (p < or = 0.05) in patients with CHF and control subjects, respectively. CONCLUSIONS: Our data indicate significantly lower intravascular volumes in patients with CHF than in control subjects, indicating a deconditioned state or excessive diuresis, or both. The contracted PV and BV may contribute to exercise intolerance, shortness of breath and chronic fatigue, secondary to reduced cardiac output or regional blood flow, or both.

Neuroendocrine activation in heart failure is modified by endurance exercise training.

OBJECTIVES: The purpose of this study was to determine whether endurance exercise training could buffer neuroendocrine activity in chronic heart failure patients. BACKGROUND: Neuroendocrine activation is associated with poor long-term prognosis in heart failure. There is growing consensus that exercise may be beneficial by altering the clinical course of heart failure, but the mechanisms responsible for exercise-induced benefits are unclear. METHODS: Nineteen heart failure patients (ischemic disease; New York Heart Association [NYHA] class II or III) were randomly assigned to either a training group or to a control group. Exercise training consisted of supervised walking three times a week for 16 weeks at 40% to 70% of peak oxygen uptake. Medications were unchanged. Neurohormones were measured at study entry and after 16 weeks. RESULTS: The training group (n = 10; age = 61 +/- 6 years; EF = 30 +/- 6%) and control group (n = 9; age = 62 +/- 7 years; EF = 29 +/- 7%) did not differ in clinical findings at study entry. Resting levels of angiotensin II, aldosterone, vasopressin and atrial natriuretic peptide in the training and control groups did not differ at study entry (5.6 +/- 1.3 pg/ml; 158 +/- 38 pg/ml; 6.1 +/- 2.0 pg/ml; 37 +/- 8 pg/ml training group vs. 4.8 +/- 1.2; 146 +/- 23; 4.9 +/- 1.1; 35 +/- 10 control group). Peak exercise levels of angiotensin II, aldosterone, vasopressin and atrial natriuretic peptide in the exercise and control groups did not differ at study entry. After 16 weeks, rest and peak exercise hormone levels were unchanged in control patients. Peak exercise neurohormone levels were unchanged in the training group, but resting levels were significantly (p < 0.001) reduced (angiotensin -26%; aldosterone -32%; vasopressin -30%; atrial natriuretic peptide -27%). CONCLUSIONS: Our data indicate that 16 weeks of endurance exercise training modified resting neuroendocrine hyperactivity in heart failure patients. Reduction in circulating neurohormones may have a beneficial impact on long-term prognosis.

In vitro effects of argon laser radiation on blood: quantitative and morphologic analysis.

Use of the argon laser to recanalize stenosed arteries may require delivery of the beam through blood. To assess the degree of hemolysis and debris formation, 84 samples of citrated whole blood were exposed to argon laser radiation with varying power (1, 2 and 3 watts) and duration (5, 10, 20 and 40 seconds). Compared with control samples, only blood samples exposed to a power of 3 watts for 40 seconds showed a marked decrease in hematocrit (from 37 +/- 1.3 to 33 +/- 1.4%, p less than 0.01) and a marked increase in both free hemoglobin concentration (from 0.2 +/- 0.2 to 1.3 +/- 0.5 g/100 ml, p less than 0.01) and debris weight (from 0.9 +/- 0.3 to 2.8 +/- 0.5 mg, p less than 0.01). Scanning electron microscopy of debris from samples of whole blood, washed erythrocytes and platelet-rich plasma lased at 3 watts for 40 seconds documented the presence of membrane denaturation of blood elements, resulting in their fusion to form complex mesh-like conglomerates. Similar morphologic changes were observed in whole blood samples exposed to a "hot tip" rather than laser radiation. These data indicate that: 1) argon laser radiation with a power of 3 watts does not produce apparent hemolysis or debris formation for exposure periods up to 20 seconds, and 2) the effects of laser radiation on blood are probably mediated by thermal denaturation of cell membranes, as suggested by the same morphologic changes produced by thermal injury from a "hot tip."