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Biomedical subjects

J D Horowitz

Publications and source records attributed to J D Horowitz.

At least 19 recordsLinked to original sources
PubMed2000

Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial.

BACKGROUND: Sudden unexpected death frequently occurs in chronic heart failure. The importance of acute coronary events in triggering sudden death (SD) is unclear. METHODS AND RESULTS: We evaluated at autopsy the prevalence of acute coronary findings (coronary thrombus, ruptured plaque, or myocardial infarction [MI]) and their relation to SD. Autopsy results in 171 patients in the randomized ATLAS trial were reviewed. The prevalence of acute coronary findings was 33%: in 54% of patients with significant coronary artery disease (CAD) who died suddenly, 32% who died of myocardial failure, but in non-CAD patients, they were present in only 5% and 10% respectively. The percentage of patients classified as dying of MI was 28% in the autopsy group versus 4% in the nonautopsied group (P<0.0001). Of the autopsied group with acute MI, 97% (31 of 32 patients) with SD and 40% (6 of 15 patients) with myocardial failure did not have the MI diagnosed during life. When undiagnosed MI was classified as "sudden unexpected" or "myocardial failure" from clinical information only, the distribution of death causes was similar in the autopsy and nonautopsied groups. CONCLUSIONS: Acute coronary findings are frequent and usually not clinically diagnosed in heart failure patients with CAD, particularly in those dying suddenly, suggesting the importance of acute coronary events as a trigger for SD in this setting.

Acute Disease↗
PubMed2000

Is informed consent to clinical trials an "upside selective" process in acute coronary syndromes?

METHODS: Patient understanding of clinical trial details was assessed on 2 occasions (10 +/- 4 and 24 +/- 3 hours after randomization) in 20 patients enrolled for randomized investigation of pharmacotherapy for unstable angina pectoris or non-Q-wave myocardial infarction in the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organized Network (PARAGON B) and Organization to Assess Strategies in Ischemic Syndromes (OASIS-2) trials. RESULTS: Initial total score for understanding of 52.0% (+/-15.7%) of maximal values improved to 67.7% (+/-18.3%) at repeat interview (P <.001). The mean initial score for knowledge of potential benefit was 85.0% (+/-33.3%) with no significant improvement at repeat interview. Scores for knowledge of risk improved from 35.0% (+/-36.6%) to 68.2% (+/-41.2%) at repeat interview (P <.005). Significant determinants of poor initial score were female sex, limited education, and presence of pain during the consent process; young age was the only determinant of improvement on repeat assessment. CONCLUSION: Thus initial understanding of the research protocols for patients with unstable angina pectoris or non-Q-wave acute myocardial infarction was imperfect, with far greater impairment of knowledge of risk than of benefit.

Adult↗
PubMed2000

The positive inotropic effects of milrinone but not of digoxin are attenuated at short cycle lengths.

The effects of inotropically active agents on the left ventricular force-interval relation are a potential determinant of their clinical utility and safety. However, little information is available concerning the effects of noncatecholamine positive inotropic agents on this relation. Therefore this study compared the short-term effects of digoxin and milrinone on resting hemodynamics, frequency potentiation (FP), and mechanical restitution (MR) in patients undergoing nonemergency cardiac catheterization. Both digoxin and milrinone produced similar increases in LV + dP/dt at rest (12.2 +/- 1.3%, p < 0.000001 and 11.4 +/- 3.2%, p < 0.01, respectively). The positive inotropic effects of digoxin were marginally attenuated during FP (by 8.5 +/- 4.2% and 4.6 +/- 2.9% at 10 and 60 s, respectively, both p = NS compared with baseline). Similarly, on MRC analysis, the parameter c (a measure of sensitivity of contractile performance to reductions in cycle length) increased by 3.6 +/- 3.7% (p = NS). Whereas the positive inotropic effects of milrinone were not significantly attenuated during FP, they were abolished and possibly reversed at short cycle lengths on MR curve construction (6.8 +/- 5.9% negative inotropic effect at 60% of resting cycle length; p = NS; p < 0.05 vs. resting cycle length). In conclusion, in patients with well-preserved left ventricular systolic function, the positive inotropic effects of milrinone but not of digoxin are markedly dependent on heart rate. These properties may influence both relative safety and efficacy of both agents.

Cardiotonic Agents↗
PubMed1999

Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits. METHODS AND RESULTS: We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction < or = 30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (P=0.128) but a significant 12% lower risk of death or hospitalization for any reason (P=0.002) and 24% fewer hospitalizations for heart failure (P=0.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions-These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small.

Aged↗
PubMed1999

Effects of a multidisciplinary, home-based intervention on unplanned readmissions and survival among patients with chronic congestive heart failure: a randomised controlled study.

BACKGROUND: Hospital admissions among patients with congestive heart failure (CHF) are a major contributor to health-care costs. Previous investigations suggest that the therapeutic efficacy of pharmacotherapy in CHF may be improved by strategies incorporating home visits to identify and address factors precipitating deterioration and resultant readmission. METHODS: Chronic CHF patients discharged home after acute hospital admission were randomly assigned usual care (n=100) or a multidisciplinary, home-based intervention (n=100), consisting of a home visit by a cardiac nurse 7-14 days after discharge. The primary endpoint of the study was frequency of unplanned readmission plus out-of-hospital death within 6 months. FINDINGS: During 6 months' follow-up there were 129 primary endpoint events in the usual-care group and 77 in the intervention group (p=0.02). More intervention-group than usual-care patients remained event-free (38 vs 51; p=0.04). Overall, there were fewer unplanned readmissions (68 vs 118; p=0.03) and associated days in hospital (460 vs 1173; p=0.02) among intervention-group patients. Hospital-based costs were Australian $490,300 for the intervention group and A$922,600 for the usual-care group (p=0.16); the mean cost of the intervention was A$350 per patient, and other community-based costs were similar for both groups. INTERPRETATION: A home-based intervention has the potential to decrease the rate of unplanned readmissions and associated health-care costs, prolong event-free and total survival, and improve quality of life among patients with chronic CHF.

Aged↗
PubMed1999

Native and oxidized low density lipoproteins enhance platelet aggregation in whole blood.

The effects of native and oxidized low density lipoproteins on platelet aggregability remain controversial despite numerous studies. In the current investigation, effects of native, minimally and extensively copper-modified low-density lipoproteins on aggregation responses to ADP and collagen in platelet-rich plasma, washed platelets, and whole blood were studied. Preincubation with native and oxidized low-density lipoproteins (1.5-23.2 malondialdehyde equivalents [MDAeq]/mg low density lipoprotein) did not modify aggregability in platelet-rich plasma or washed platelets but increased aggregation markedly in whole blood (40-58%, p<0.01). In whole blood, the increase in response to ADP was not affected by the degree of low-density lipoprotein oxidation. This comprehensive investigation of low density lipoprotein effects on platelet aggregation therefore has demonstrated that low density lipoproteins indirectly increase platelet aggregability in whole blood, but not in platelet-rich plasma and washed platelets, presumably via an interaction between platelets and other formed elements of blood.

Adult↗
PubMed1999

Nitrate resistance in platelets from patients with stable angina pectoris.

BACKGROUND: Hemodynamic resistance to nitrates has been previously documented in congestive heart failure. In patients with stable angina pectoris (SAP), we have observed a similar phenomenon: decreased platelet response to disaggregating effects of nitroglycerin (NTG) and sodium nitroprusside (SNP). METHODS AND RESULTS: In blood samples from normal subjects (n=32) and patients with SAP (n=56), we studied effects of NO donors (NTG and SNP) on ADP-induced platelet aggregation and on intraplatelet cGMP. NTG and SNP inhibited platelet aggregation in patients to lesser extents than in normal subjects (P<0.01). The cGMP-elevating efficacy of NTG and SNP was diminished in platelets from patients in comparison with those from normals (P<0.001). Inhibition of the anti-aggregatory effects of NTG and SNP by ODQ, a selective inhibitor of NO-stimulated guanylate cyclase, was significantly less pronounced in patients than in normal subjects. Content of O2- was higher in blood samples from patients than in those from normal subjects (P<0. 01). In blood samples from patients with SAP, but not in normal subjects, the O2- scavenger superoxide dismutase (combined with catalase) suppressed platelet aggregation (P<0.01) and increased the extent of anti-aggregatory effect of SNP (P<0.01). CONCLUSIONS: In patients with SAP, platelets are less responsive to the anti-aggregating and cGMP-stimulating effects of NO donors; this may reflect both reduction in guanylate cyclase sensitivity to NO and inactivation of the released NO by O2-. The implied impairment of anti-platelet efficacy of endogenous NO (in the form of EDRF) may contribute to platelet hyperaggregability associated with angina pectoris.

Adenosine Diphosphate↗
PubMed1999

Tolerance induction by transdermal glyceryl trinitrate in rats.

Mechanisms of mild glyceryl trinitrate tolerance in rats (transdermal application; 15 mg/day/2 days) were examined in isolated aortic rings contracted with phenylephrine. Tolerance to glyceryl trinitrate was comparable in both endothelium-intact and -denuded vessels; the maximum relaxation decreased to 70-80% and the EC50 increased 3-4-fold. There was minimal cross-tolerance to acetylcholine (1.7-fold increase in EC50) and none to sodium nitroprusside. The results suggest that mild tolerance to glyceryl trinitrate in rats is mediated by mechanisms which are predominantly endothelium-independent and which produce little activation of the cellular mechanism responsible for cross-tolerance.

Acetylcholine↗
PubMed1999

The effects of perhexiline on the rat coronary vasculature.

The predominant site and mechanism(s) of perhexiline-induced coronary vasodilatation were investigated in the rat heart. Perhexiline was more potent in the Langendorff perfused heart than in the left anterior descending coronary artery (EC50; 0.27 microM, confidence limits 0.19-0.39: 2.7 microM, 2.0-3.4, respectively). Selective endothelial inactivation with Triton X-100 in the perfused heart, reduced the response to perhexiline 1 microM (76+8% to 30+3% of control). 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) 3 microM, Nomega-nitro-L-arginine 100 microM, or a combination of the latter with indomethacin 10 microM, had no significant effect on responses to perhexiline in the perfused heart. Unlike bradykinin-induced vasodilatation, responses to perhexiline were not inhibited by tetrabutylammonium 1 mM, or charybdotoxin 20 nM. SKF525A 5 microM inhibited both perhexiline and bradykinin responses, while apamin 1 microM and glibenclamide 3 microM inhibited neither. Perhexiline exerts partially endothelium-dependent coronary vasodilator effects in the rat, predominantly on small coronary arteries, which appear to be independent of nitric oxide (NO), prostacyclin and the endothelium-derived hyperpolarising factor (EDHF) released by bradykinin.

Animals↗
PubMed1999

Effects of guanylyl cyclase and protein kinase G inhibitors on vasodilatation in non-tolerant and tolerant bovine coronary arteries.

The effects in bovine coronary arteries of the soluble guanylyl cyclase inhibitor 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) were examined in order to establish the relative importance of the enzyme (a) in the vasodilator actions of glyceryl trinitrate and S-nitroso-N-acetylpenicillamine and (b) in induction of tolerance to these agents. ODQ strongly inhibited responses to both relaxants with IC50's of the order of 0.5 microM; in contrast, the protein kinase G inhibitor, 8-bromoguanosine-3',5'-monophosphorothioate (Rp-8-Br-cGMPS) had little effect on the responses. Tolerance after pre-incubation with glyceryl trinitrate (10 microM) was unaffected by co-pre-incubation with ODQ (1.0 microM), but similar experiments with S-nitroso-N-acetylpenicillamine were inconclusive because tolerance was associated with depressed contractile activity. It is concluded that in bovine coronary arteries soluble guanylyl cyclase is essential for vasorelaxation to both glyceryl trinitrate and S-nitroso-N-acetylpenicillamine but is unimportant for induction of tolerance to glyceryl trinitrate. Our results add weight to the hypothesis of impaired biotransformation rather than guanylyl cyclase desensitisation as the mechanism of in vitro nitrate tolerance.

Animals↗
PubMed1999

Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure.

BACKGROUND: A single home-based intervention (HBI) applied immediately after hospital discharge in a cohort of "high-risk" patients with congestive heart failure has been shown to decrease numbers of unplanned readmissions plus out-of-hospital deaths during a period of 6 months. The duration of this beneficial effect remains uncertain. METHODS: Hospitalized patients with congestive heart failure who had been randomly assigned to receive either usual care (n=48) or HBI 1 week after discharge (n=49) were subject to an extended follow-up of 18 months. The primary end point of the study was frequency of unplanned readmissions plus out-of-hospital deaths. Secondary end points included total hospital stay, frequency of multiple readmissions, cost of hospital-based care, and total mortality. RESULTS: During 18-month follow-up, HBI patients had fewer unplanned readmissions (64 vs 125; P=.02) and out-of-hospital deaths (2 vs 9; P=.02), representing 1.4+/-1.3 vs 2.7+/-2.8 events per HBI and usual-care patient, respectively (P=.03). The HBI patients also had fewer days of hospitalization (2.5+/-2.7 vs 4.5+/-4.8 per patient; P=.004) and, once readmitted, were less likely to experience 4 or more readmissions (3/31 vs 12/38; P=.03). Hospital-based costs were significantly lower among HBI patients (Aust $5100 vs Aust $10600 per patient; P=.02). Unplanned readmission was positively correlated with 14 days or more of unplanned readmission in the 6 months before study entry (odds ratio [OR], 5.4; P=.006). Positive correlates of death were (1) non-English speaking (OR, 4.9; P=.008), (2) 14 days or more of unplanned readmission in the 6 months before study entry (OR, 4.9; P=.008), and (3) left ventricular ejection fraction of 40% or less (OR, 3.0; P=.03); conversely, assignment to HBI was a negative correlate (OR, 0.3; P=.02). CONCLUSIONS: In this controlled study, among a cohort of high-risk patients with congestive heart failure, beneficial effects of a postdischarge HBI were sustained for at least 18 months, with a significant reduction in unplanned readmissions, total hospital stay, hospital-based costs, and mortality.

Adult↗
PubMed1999

Baseline clinical characteristics of patients recruited into the assessment of treatment with lisinopril and survival study.

BACKGROUND: The beneficial effect of ACE inhibitors on mortality has been established in a series of trials. However, in clinical practice, ACE inhibitors are commonly administered in doses much lower than those shown to be effective in the landmark trials. AIMS: This report describes the baseline characteristics of the patients recruited into the ATLAS study by age and gender sub-groups. METHODS: The ATLAS study compared the effects of 'low' dose (2.5-5.0 mg/day) to 'high' dose (32.5-35.0 mg/day) lisinopril in a double-blind study of 3164 patients with moderate to severe heart failure and left ventricular ejection fraction < 30% during a mean follow-up period of 46 months. The primary end-point was all cause mortality and the principal secondary end-point a composite of all-cause hospitalisation or all-cause mortality. RESULTS: Among patients with heart failure selected for the presence of left ventricular systolic function there were few differences among age groups or between genders. Older patients were not so heavy, were more likely to have ischaemic heart disease, hypertension and atrial fibrillation contributing to their heart failure and had a higher blood urea. Women were not so heavy as men. Age and gender had no major influence on mean ejection fraction or baseline treatment in the ATLAS study. CONCLUSIONS: Weight and renal function may alter the plasma concentration of any given dose of an ACE inhibitor. Potential interactions between dose of lisinopril, weight and renal function will be explored after the study is completed.

Adult↗
PubMed1999

Early treatment with verapamil or diltiazem in patients with acute myocardial infarction: safety and possible beneficial effects.

While dihydropyridine calcium antagonists may be harmful in the immediate peri-infarction period, the effect of verapamil or diltiazem in these circumstances in uncertain. We utilized the GUSTO-1 formula to calculate the predicted 30-day mortality risk in a cohort of 352 patients with acute myocardial infarction presenting < 6 hours after onset of symptoms, with ECG changes consistent with eligibility for thrombolysis. All patients were treated with an intravenous bolus dose of verapamil followed by oral verapamil (240-360 mg/day) or diltiazem (180-360 mg/day), in the absence of specific contraindications. Predicted 30-day mortality risk was then compared with the actual 30-day mortality rate of the cohort. The actual 30-day mortality of the cohort was 3.7% (95% CI: 2.0,6.3); this was significantly lower than that predicted by the GUSTO-1 formula (7%). A similarly significantly lower mortality (7.5% vs 19.3%) was observed in a "high risk" subset of patients. Of the 13 patients who died, only 4 developed cardiogenic shock. It is concluded that verapamil and diltiazem can be administered safely in a selected patients with evolving acute transmural myocardial infarction. While the current data suggest that this form of treatment may be beneficial, definitive conclusions in this regard should await further randomized studies.

Acute Disease↗
PubMed1998

Inhibition of long-chain fatty acid metabolism does not affect platelet aggregation responses.

A number of anti-anginal agents (perhexiline, amiodarone, trimetazidine) have been shown to inhibit myocardial carnitine palmitoyltransferase-1, which controls access of long-chain fatty acids to mitochondrial sites of beta-oxidation. In view of clinical data suggesting that perhexiline improves symptomatic status in unstable angina pectoris, and the known role of mitochondrial beta-oxidation in platelet metabolism, we compared the platelet carnitine palmitoyltransferase-1 inhibitory and putative anti-aggregatory effects of perhexiline, amiodarone and trimetazidine with those of specific carnitine palmitoyltransferase-1 inhibitors: etomoxir and hydroxyphenylglyoxylate in both normal subjects and patients with stable angina. All of the compounds examined inhibited platelet carnitine palmitoyltransferase-1 activity; rank order of potency etomoxir > malonyl-CoA > hydroxyphenylglyoxylate > amiodarone > or = perhexiline > trimetazidine. However, only perhexiline, amiodarone and trimetazidine inhibited platelet aggregation. We conclude that (a) the carnitine palmitoyltransferase-1 inhibitors perhexiline, amiodarone and trimetazidine exert significant anti-aggregatory effects which may be therapeutically relevant and, (b) these effects are independent of carnitine palmitoyltransferase-1 inhibition.

Adult↗