Metabolic and neurohumoral aspects of acute myocardial ischemia in man

This thesis aims at defining the relevance and applicability of some metabolic aspects of acute myocardial ischemia to delineate occurrence and extent of the latter in man. Studies focus on myocardial lactate metabolism and adenine nucleotide catabolism, correlate changes with other markers of ischemia and attempt to define a temporal relation with regional changes in coronary flow. Next, the acute antiischemic properties of different vasoactive compounds are outlined using these metabolites in a properly defined study model. Studies also attempt to differentiate the usefulness of various vasodilator compounds as antiischemic therapy in relation to the underlying cardiac function. In the second part of this thesis the impact of myocardial ischemia on systemic and cardiac neurohormones, i.e. catecholamines and renin-angiotensin system(s), are discussed. The relation between degree of ischemia and neurohumoral activation will be emphasized, potential subsequent systemic and coronary vasoconstrictor effects mentioned, and the usefulness of neurohumoral modulation, i.e. by converting enzyme inhibition in the treatment of myocardial ischemia indicated

Drug-induced heart failure

AbstractHeart failure is a clinical syndrome that is predominantly caused by cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce heart failure in patients without concurrent cardiovascular disease or may precipitate the occurrence of heart failure in patients with preexisting left ventricular impairment. We reviewed the literature on drug-induced heart failure, using the MEDLINE database and lateral references. Successively, we discuss the potential role in the occurrence of heart failure of cytostatics, immunomodulating drugs, antidepressants, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, antiarrhythmics, beta-adrenoceptor blocking agents, anesthetics and some miscellaneous agents. Drug-induced heart failure may play a role in only a minority of the patients presenting with heart failure. Nevertheless, drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes other priorities do not offer therapeutic alternatives (e.g., anthracycline-induced cardiomyopathy). The awareness of clinicians of potential adverse effects on cardiac performance by several classes of drugs, particularly in patients with preexisting ventricular dysfunction, may contribute to timely diagnosis and prevention of drug-induced heart failure

Hemodynamic tolerability and anti-ischemic efficacy of high dose intravenous diltiazem in patients with normal versus impaired ventricular function

AbstractObjectives. This study was designed to compare the acute systemic and coronary hemodynamic effects of high doses of intravenous diltiazem in patients with normal versus impaired left ventricular function, investigate the safety of this drug and compare its anti-ischemic potential in these two patient groups during pacing-induced stress.Background. Because coronary hemodynamic effects and negative inotropic properties of diltiazem are dose related, high dose intravenous diltiazem may improve anti-ischemic efficacy but may not be tolerated in patients with impaired cardiac function.Methods. High dose intravenous diltiazem, 0.4 mg/kg for 5 min followed by 0.4 mg/kg for 10 min, was administered to 23 normotensive patient's with coronary artery disease, 11 (group A) with normal and 12 (group B) with impaired ventricular function (ejection fraction <45%) during two identical atrial pacing stress tests performed 30 min before (pacing test I) and immediately after diltiazem (pacing test II).Results. Diltiazem was well tolerated despite high peak plasma levels, 869 ± 152 μ/liter (group A) and 926 ± 169 μgliter (group B). It resulted in immediate but similar reductions in systemic resistance from 1,321 ± 136 (control value) to 963 ± 113 dynes·s·cm−5(group A) and from 1,267 ± 106 to 865 ± 58 dynes ·s·cm−5(group B) and in mean arterial pressure from 107 ± 3 to 93 ± 4 mm Hg (group A) and from 103 ± 4 to 86 ± 4 mm Hg (group B), at 5 min after diltiazem (all p < 0.05 vs. control value). Diltiazem improved stroke output from 36 ± 3 (control value) to 46 ± 4 mi/beat per m2in group 6 and from 44 ± 4 (control value) to 49 ± 5 ml/beat per m2in group A, an effect that was significantly greater and more prolonged in group B than in group A. Although neither heart rate nor contractility was affected in either group, left ventricular end-diastolic pressure increased in group A (9 ± 2 mm Hg to 12 ± 1 mm Hg, p < 0.05) but not in group B. Despite similar reductions in coronary resistance and improvements in coronary flow, diltiazem consistently reduced myocardial oxygen extraction, but only in group B. Also, the anti-ischemic effects of diltiazem were more pronounced in group B. During pacing test II, myocardial lactate extraction normalized in group B (7 ± 5% vs. −6 ± 12% [pacing test I]) but not in group A, contractility indexes improved more and the increase in left ventricular filling pressure was reduced to a greater extent in group B. Moreover, the ischemia-induced increase in arterial pressures, observed in both groups during pacing test I, was prevented in group B but recurred in group A during pacing test II.Conclusions. High dose intravenous diltiazem is well tolerated, augments coronary flow and improves left ventricular pump function, particularly in patients with preexisting ventricular dysfunction. As its anti-ischemic effects also appear more pronounced in the latter group, high dose diltiazem may be particularly useful when ventricular function is depressed, for example, during prolonged ischemia at rest

英語の複数動詞連鎖：分類と機能

博士（文学）神戸大

The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET

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Economic Evaluation of the Randomized Aldactone Evaluation Study (RALES): Treatment of Patients with Severe Heart Failure

Purpose : To use data from the Randomized Aldactone Evaluation Study (RALES) to compare clinical outcomes and costs as part of the assessment of the economic implications of spironolactone treatment of advanced heart failure.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44576/1/10557_2004_Article_405789.pd

Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial

Aims We studied the influence of heart rate (HR), systolic blood pressure (SBP), and beta-blocker dose on outcome in the 2599 out of 3029 patients in Carvedilol Or Metoprolol European Trial (COMET) who were alive and on study drug at 4 months after randomization (time of first visit on maintenance therapy). Methods and results By multivariable analysis, baseline HR, baseline SBP, and their change after 4 months were not independently related to subsequent outcome. In a multivariable analysis including clinical variables, HR above and SBP below the median value achieved at 4 months predicted subsequent increased mortality [relative risk (RR) for HR>68 b.p.m. 1.333; 95% confidence intervals (CI) 1.152-1.542; P120 mmHg 0.78; 95% CI 0.671-0.907; P<0.0013]. Achieving target beta-blocker dose was associated with a better outcome (RR 0.779; 95% CI 0.662-0.916; P<0.0025). The superiority of carvedilol as compared to metoprolol tartrate was maintained in a multivariable model (RR 0.767; 95% CI 0.663-0.887; P=0.0004) and there was no interaction with HR, SBP, or beta-blocker dose. Conclusion Beta-blocker dose, HR, and SBP achieved during beta-blocker therapy have independent prognostic value in heart failure. None of these factors influenced the beneficial effects of carvedilol when compared with metoprolol tartrate at the pre-defined target doses used in COME

The consistency of the treatment effect of an ACE-inhibitor based treatment regimen in patients with vascular disease or high risk of vascular disease: A combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials

AimsAngiotensin-converting enzyme (ACE) inhibitors have been shown to reduce cardiovascular risk in different groups of patients. Whether these effects can be generalized to the broad group of patients with vascular disease is unknown. Therefore, we undertook a combined analysis using individual data from ADVANCE, EUROPA, and PROGRESS to determine the consistency of the treatment effect of perindopril-based regimen in patients with vascular disease or at high risk of vascular disease.Methods and resultsWe studied all-cause mortality and major cardiovascular outcomes during a follow-up of about 4 years in the 29 463 patients randomly assigned a perindopril-based treatment regimen or placebo. The perindopril-based regimens were associated with a significant reduction in all-cause mortality [hazard ratio (HR) 0.89; 95 confidence interval (CI) 0.82-0.96; P = 0.006], cardiovascular mortality (HR 0.85; 95 CI 0.76-0.95; P = 0.004), non-fatal myocardial infarction (HR 0.80; 95 CI 0.71-0.90; P < 0.001), stroke (HR 0.82; 95 CI 0.74-0.92; P = 0.002), and heart failure (HR 0.84; 95 CI 0.72-0.96; P = 0.015). Results were consistent in subgroups with different clinical characteristics, concomitant medication use, and across all strata of baseline blood pressure.ConclusionThis study provides strong evidence for a consistent cardiovascular protection with an ACE-inhibitor treatment regimen (perindopril-indapamide) by improving survival and reducing the risk of major cardiovascular events across a broad spectrum of patients with vascular disease

Individualized angiotensin-converting enzyme (ACE)-inhibitor therapy in stable coronary artery disease based on clinical and pharmacogenetic determinants: The PERindopril GENEtic (PERGENE) risk model

Background-Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model. Methods and Results-Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 t