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J D Horowitz

Publications and source records attributed to J D Horowitz.

At least 19 recordsLinked to original sources
PubMed1998

Effects of a home-based intervention among patients with congestive heart failure discharged from acute hospital care.

BACKGROUND: We examined the effect of a home-based intervention (HBI) on readmission and death among "high-risk" patients with congestive heart failure discharged home from acute hospital care. METHODS: Hospitalized patients with congestive heart failure and impaired systolic function, intolerance to exercise, and a history of 1 or more hospital admissions for acute heart failure were randomized to either usual care (n=48) or HBI at 1 week after discharge (n=49). Home-based intervention comprised a single home visit (by a nurse and pharmacist) to optimize medication management, identify early clinical deterioration, and intensify medical follow-up and caregiver vigilance as appropriate. The primary end point of the study was frequency of unplanned readmissions plus out-of-hospital deaths within 6 months of discharge. Secondary end points included duration of hospital stay and overall mortality. RESULTS: During follow-up, patients in the HBI group had fewer unplanned readmissions (36 vs 63; P=.03) and fewer out-of-hospital deaths (1 vs 5; P=.11): 0.8+/-0.9 vs 1.4+/-1.8 (mean +/- SD) events per patient assigned to HBI and usual care, respectively (P=.03). Patients in the HBI group also had fewer days of hospitalization (261 vs 452; P=.05) and fewer total deaths (6 vs 12; P=.11). Patients assigned to usual care were more likely to experience 3 or more readmissions for acute heart failure (P=.02). Predictors of unplanned readmission were (1) 14 days or more of unplanned readmission during the 6 months before study entry (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.8-16.2), (2) previous admission for acute myocardial ischemia (OR, 3.3; 95% CI, 1.2-9.1), and (3) an albumin plasma concentration of 38 g/L or less (OR, 2.4; 95% CI, 1.2-6.0). Home-based intervention was also associated with a trend toward reduced risk of unplanned readmission (OR, 0.4; 95% CI, 0.2-1.1). CONCLUSION: Among a cohort of high-risk patients with congestive heart failure, HBI was associated with reduced frequency of unplanned readmissions plus out-of-hospital deaths within 6 months of discharge from the hospital.

Acute Disease↗
PubMed1998

Regional differences in the characteristics and treatment of patients participating in an international heart failure trial. The Assessment of Treatment with Lisinopril and Survival (ATLAS) Trial Investigators.

AIMS: This study was designed to determine regional differences in patient characteristics and medication use among patients entered into an international heart failure trial. METHODS AND RESULTS: Data for this analysis were derived from the Assessment of Treatment with Lisinopril and Survival Study (ATLAS), a prospective randomized comparison of high- and low-dose therapy with lisinopril in patients with New York Heart Association class II, III, or IV chronic heart failure, which enrolled 3164 patients in 291 centers in 19 countries on 3 continents. Information was collected at baseline concerning patient demographics, etiology of heart failure, accompanying conditions, prior revascularization procedures, and medication use. The primary findings were a lower incidence of ischemic cardiomyopathy in southern and western Europe, more frequent diabetes in North America, and a greater use of coronary revascularization in the United States and Canada. There was substantial variation in medication use, particularly with regard to digoxin, anticoagulants, and amiodarone. CONCLUSIONS: Although there is considerable overlap in guidelines concerning the treatment of heart failure issued by authorities in Europe and North America, there are significant regional variations in medication use. Some, but not all, of these differences can be explained by differences in patient characteristics.

Aged↗
PubMed1998

Myocardial effect compartment modeling of metoprolol and sotalol: importance of myocardial subsite drug concentration.

We have recently reported the time course of acute myocardial drug uptake and simultaneous pharmacodynamic effects for metoprolol (4 mg; n = 12) and sotalol (20 mg; n = 10) in patients with ischemic heart disease. The acute pharmacodynamic effects of the two drugs included reductions in both spontaneous heart rate and the contractile index peak positive rate of left ventricular pressure rise and prolongation of the electrocardiographic PR interval, all of which exhibited an equilibration delay compared with myocardial drug content. The objective of the current study was to analyze the relationship between myocardial drug content and effect for both metoprolol and sotalol using an effect compartment model, to examine the potential for the two drugs to share a common subsite of action in the myocardium. The time course of myocardial drug content was best described by a one-compartment model for metoprolol and a two-compartment model for sotalol. A linear pharmacodynamic model, relating the amount of drug at the effect-site (Ae) with each of the three effects, was used in the effect compartment modeling. The slope of each of these effects as a function of Ae was considerably flatter for sotalol than for metoprolol, reflecting the relative beta-adrenoceptor antagonistic potencies of the two drugs. The exit rate constant from the effect compartment (K(eo)) did not differ significantly from each other or from the exit rate constant from the "peripheral" compartment (K21) for sotalol. The results suggest that the effect compartment within the myocardium for both drugs may correspond to a "peripheral" compartment, even though a "peripheral" pharmacokinetic compartment for myocardial metoprolol content was not apparent. Thus, the effect compartment for many cardioactive drugs may correspond to a pharmacokinetically "peripheral" compartment, irrespective of localization of effect to a small (e.g. sinoatrial node) or large (e.g. ventricular myocardium) region of the heart.

Adrenergic beta-Antagonists↗
PubMed1998

Short-term myocardial uptake of d- and l-sotalol in humans: relation to hemodynamic and electrophysiologic effects.

The myocardial concentration of many cardioactive drugs has been identified as an important determinant of their short-term effects in previous studies. Although sotalol is frequently administered via short-term intravenous injection, no previous studies had sought to correlate its uptake by the heart with its various effects. We determined the time course of short-term uptake of d,l-sotalol by human myocardium in vivo and investigated the relation between myocardial content of sotalol and the short-term hemodynamic, electrocardiographic, and electrophysiologic effects of the drug. Sixteen patients received a 20-mg intravenous bolus of sotalol at the time of diagnostic cardiac catheterization. Myocardial content of d- and l-sotalol (by using a paired transcoronary sampling technique) and the short-term hemodynamic and electrophysiologic effects of the drug were determined < or = 20 min after injection. Myocardial accumulation of sotalol was not enantioselective, proceeded very rapidly (maximal at 0.74 +/- 0.10 min, representing 2.05 +/- 0.45% of the total injected dose), and was not significantly influenced by left ventricular systolic function or the extent of coronary artery disease. Approximately one third of peak myocardial content was still present 17.5 min after sotalol administration. Maximal effects of the drug (reduction in spontaneous heart rate, p < 0.005; reduction in maximal rate of LV pressure increase (LV+dP/dtmax, p < 0.005); and prolongation of PR intervals, p < 0.02) were delayed by approximately 10 min relative to maximal myocardial sotalol content. The significant prolongation of AH intervals (p < 0.01) and atrioventricular nodal effective refractory periods (p < 0.0002) that was observed was also maximal 10 min after administration of sotalol. Thus a consistent delay between myocardial sotalol content and the short-term effects of the drug was observed. In conclusion, the accumulation of both d- and l-sotalol by the human myocardium is more rapid than that of any other agent studied to date, with considerable hysteresis between myocardial drug uptake and subsequent cardiac effects.

Adrenergic beta-Antagonists↗
PubMed1998

Relationship between myocardial milrinone content and its acute hemodynamic and electrophysiologic effects.

One of the major determinants of the short-term effects of many cardioactive drugs is the concentration of the drug specifically within the myocardium. However, no information regarding the disposition of the phosphodiesterase inhibitor milrinone in the heart is available. We therefore determined the time course of short-term myocardial milrinone uptake from paired transcoronary sampling and simultaneous coronary sinus blood flow after a 1-mg intravenous bolus in patients undergoing diagnostic cardiac catheterization. In accordance with this intention, a sensitive, reproducible method for the determination of milrinone in human whole-blood samples was developed. The reverse-phase high-performance liquid chromatographic method described used a C18 column with UV-absorbance detection at 326 nm, with a limit of detection of 0.6 ng/ml, and was highly reproducible. The short-term hemodynamic and electrophysiologic effects of the drug also were determined. Significant increases in spontaneous heart rate and LV+dP/dtmax (at constant heart rate) were observed, accompanied by reductions in mean arterial pressure, systemic vascular resistance, and PR interval, without significant changes in atrioventricular nodal or ventricular effective refractory periods. Peak content (1.89 +/- 0.30% of injected dose) was rapidly attained, 0.56 +/- 0.06 min after milrinone injection. Time of peak effects was significantly delayed (7-10 min after injection) relative to time of peak myocardial milrinone content. Residual myocardial milrinone content was 69.1 +/- 5.7% of maximum 12.5 min after injection. It is concluded that both myocardial uptake and the onset of positive inotropic effects after intravenous injection of milrinone were very rapid. However, there was significant hysteresis between peak myocardial content and subsequent hemodynamic effects.

Adult↗
PubMed1998

Effects of home-based intervention on unplanned readmissions and out-of-hospital deaths.

OBJECTIVE: To determine the effect of a home-based intervention (HBI) on the frequency of unplanned readmission and out-of-hospital death among patients discharged home from acute hospital care. DESIGN: A randomized controlled trial comparing HBI with usual care (UC). SETTING: A tertiary referral hospital servicing the northwestern region of Adelaide, South Australia. PARTICIPANTS: Medical and surgical patients (n = 762) discharged home after hospitalization. INTERVENTION: Home-based intervention (n = 381) consisted of counseling of all patients before discharge followed by a single home visit (by a nurse and pharmacist) to those patients considered to be at high risk of readmission (n = 314) in order to optimize compliance with and knowledge of the treatment regimen, identify early clinical deterioration, and intensify follow-up of such patients where appropriate. MEASUREMENTS: The primary endpoint was the number of unplanned readmissions plus out-of-hospital deaths over a 6-month follow-up period. RESULTS: During the study follow-up, the major endpoint occurred most commonly in the UC group (217 vs 155 episodes: P < .001). Overall, the HBI group demonstrated fewer unplanned readmissions (154 vs 197: P = .022), out-of-hospital deaths (1 vs. 20: P < .001), total deaths (12 vs. 29: P = .006), emergency department attendances (236 vs 314: P < .001), and total days of hospitalization (1452 vs 1766: P < .001). There was a disproportionate reduction in multiple events among HBI patients (P = .035). Hospital-based costs of health care during study follow-up tended to be lower in the HBI group ($A2190 vs $A2680 per patient: P = .102). Mean cost of HBI was $A190 per patient visited, whereas other community-based health care costs were similar for both groups. CONCLUSIONS: Among high-risk patients discharged from acute hospital care, HBI is beneficial in limiting unplanned readmissions and reducing risk of out-of-hospital death. It may be particularly cost-effective if applied selectively to patients with a history of frequent unplanned hospital admission.

Aged↗
PubMed1997

Nitroglycerin tolerance at the platelet level in patients with angina pectoris.

Suppression of platelet aggregation may be an important component of the therapeutic effect of nitroglycerin (NTG). Because of the phenomenon of hemodynamic tolerance to NTG, we tested the hypothesis that the anti-platelet effects of NTG in humans are also subject to tolerance induction. In patients with stable angina who had not received nitrates for at least 24 hours before study, sublingual administration of NTG (300 microg; n = 17) attenuated the reversal of adenosine diphosphate-induced platelet aggregation by NTG applied in vitro. Three minutes after in vivo NTG administration, concentration of NTG producing 50% reversal of aggregation (C50) increased from 7.9 +/- 1.9 x 10(-5) to 5.5 +/- 0.3 x 10(-4) M (p <0.01); this change persisted for at least 60 minutes. There was no concomitant change in C50 values for sodium nitroprusside applied in vitro. Basal activity of platelet guanylate cyclase and its response to sodium nitroprusside were not affected after administration of NTG. Brief intravenous infusion of NTG (10 microg/min for 10 minutes) produced no significant changes in platelet responses to NTG in vitro. However, prolonged infusion of NTG (5 microg/min for 24 hours, patients with unstable angina pectoris, n = 11) caused suppression of in vitro platelet response to NTG. Platelets from patients receiving prophylactic nitrates (n = 19) were less responsive to the antiaggregatory effects of NTG in vitro than those from patients who had not received nitrates in the previous 24 hours (n = 21). Thus, clinical exposure to NTG, even in very low doses, induces tolerance to antiaggregatory effects of NTG. This phenomenon is not associated either with cross tolerance to sodium nitroprusside or with down-regulation of platelet guanylate cyclase.

Administration, Sublingual↗
PubMed1997

Indinavir nephropathy.

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Acquired Immunodeficiency Syndrome↗
PubMed1997

Perhexiline improves symptomatic status in elderly patients with severe aortic stenosis.

BACKGROUND: The prognosis of severe symptomatic aortic stenosis is poor without aortic valve replacement, with no previous reports of beneficial effects of any medical treatment on either symptoms or outcome. However, this condition is increasingly a disease of the elderly and cardiothoracic surgery is associated with significant mortality and morbidity in this group. AIMS: We postulated that perhexiline, a novel anti-ischaemic agent with an oxygen-sparing metabolic effect in the myocardium (via inhibition of carnitine palmitoyltransferase-1) and no adverse haemodynamic effects, may improve symptomatic status in elderly patients with severe aortic stenosis. We report here our initial experience with perhexiline treatment in such patients. METHODS: Elderly patients with symptomatic severe aortic stenosis, who were deemed unsuitable for aortic valve replacement, were treated with perhexiline, the drug dosage titrated according to steady state plasma perhexiline concentrations. NYHA functional class was determined prior to and three months following commencement of perhexiline, and changes were analysed using McNemar's test. RESULTS: Fifteen patients, age range 73-87, were followed for up to 30 months (median 18 months). Symptomatic status improved in 13 of the 15 patients over the first three months of perhexiline therapy (p < 0.01), five patients becoming asymptomatic. Twelve month actuarial survival was 80% (95% CI = 57, 100). Perhexiline was well tolerated, with no withdrawals due to toxicity or deteriorating clinical status. CONCLUSION: Therapy with perhexiline was associated with a marked improvement in clinical status in this group of elderly patients with severe aortic stenosis.

Aged↗
PubMed1996

Heterogeneity of glyceryl trinitrate response in isolated bovine coronary arteries.

Factors determining heterogeneity of response to glyceryl trinitrate in coronary microvessels have been extensively documented in recent years, but determinants of heterogeneity between conduit and large resistance vessels are poorly understood. The current study has characterised heterogeneity to glyceryl trinitrate and other vasodilators in bovine isolated proximal (4.5 mm i.d.) and distal (0.5 mm i.d.) segments of left anterior descending artery. Compared with proximal segments, distal segments were less responsive to glyceryl trinitrate and sodium nitroprusside, equi-responsive to S-nitroso-N-acetylpenicillamine, and more responsive to isoprenaline. Heterogeneity to glyceryl trinitrate was unaffected by the presence of the thiols (cysteine or N-acetylcysteine, 100 microM). The results are interpreted as evidence that heterogeneity of vascular responsiveness to glyceryl trinitrate reflects impairment in the small artery of the cellular events which precede activation of the cyclic GMP pathway. An implication is that the impairment is not a consequence of limited thiol availability, and in this respect the cellular mechanism of heterogeneity differs from those proposed for the coronary microvasculature.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Lack of inhibition of glyceryl trinitrate by diphenyleneiodonium in bovine coronary artery.

Recent studies indicate that diphenyleneiodonium is a potent inhibitor of glyceryl trinitrate-induced relaxation in rat aorta precontracted with phenylephrine. We have explored the generality of this action in bovine coronary artery precontracted with the thromboxane A2 mimetic, 9,11-dideoxy-11 alpha, 9 alpha-epoxy-methano-prostaglandin F2 alpha (U46619). Diphenyleneiodonium 0.3 microM was without effect (endothelium absent) or caused mild potentiation (0.3 microM or 10 microM; endothelium present) of the relaxant response to gylceryl trinitrate. Lack of inhibition was not due to U46619, since inhibition was still prominent in rat aorta precontracted with this agent. It is concluded that diphenyleneiodonium distinguishes between cellular mechanisms mediating vasodilator responses to glyceryl trinitrate in rat aorta and bovine coronary artery.

Animals↗
PubMed1996

Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone.

The mechanism of the anti-anginal effect of perhexiline is unclear but appears to involve a shift in cardiac metabolism from utilization of fatty acid to that of carbohydrate. We tested the hypothesis that perhexiline inhibits the enzyme carnitine palmitoyltransferase-1 (CPT-1), which controls access of long chain fatty acids to the mitochondrial site of beta-oxidation. Perhexiline produced a concentration-dependent inhibition of CPT-1 in rat cardiac and hepatic mitochondria in vitro, with half-maximal inhibition (IC50) at 77 and 148 mumol/L, respectively. Amiodarone, another drug with anti-anginal properties, also inhibited cardiac CPT-1 (IC50 = 228 mumol/L). The rank order of potency for inhibition was malonyl-CoA > 4-hydroxyphenylglyoxylate (HPG) = perhexiline > amiodarone = monohydroxy-perhexiline. Kinetic analysis revealed competitive inhibition of cardiac and hepatic CPT-1 by perhexiline with respect to palmitoyl-CoA but non-competitive inhibition with respect to carnitine. Curvilinear Dixon plots generated "apparent inhibitory constant (Ki)" values for perhexiline, which indicated a greater sensitivity of the cardiac than the hepatic enzyme to inhibition by perhexiline. Perhexiline inhibition of CPT-1, unlike that of malonyl-CoA and HPG, was unaffected by pretreatment with the protease nagarse. These data establish for the first time that two agents with proven anti-anginal effects inhibit cardiac CPT-1. This action is likely to contribute to the anti-ischaemic effects of both perhexiline and amiodarone.

Amiodarone↗
PubMed1996

Suppressed anti-aggregating and cGMP-elevating effects of sodium nitroprusside in platelets from patients with stable angina pectoris.

Platelet hyperactivity plays an important role in the pathogenesis of cardio-vascular diseases. In patients with stable angina pectoris, we have recently demonstrated that nitroglycerin suppressed the increased platelet aggregability. The anti-aggregating effect of NTG and other nitrovasodilators is mediated by platelet guanylate cyclase, which generates cyclic GMP (cGMP) in response to nitric oxide (NO) liberated from the nitrovasodilator molecule. In the current study we utilised a more "direct" NO donor, sodium nitroprusside (SNP), to examine reversal of ADP-induced platelet aggregation in comparison with intraplatelet cGMP elevation in platelets from normal subjects (n = 22) and patients with stable angina pectoris (n = 23). Concentrations of SNP associated with 50% reversal of aggregation were 2.7 +/- 0.4 x 10(-7) mol/L with normal subjects and 4.5 +/- 0.5 x 10(-6) mol/L with patients (P < 0.01). SNP produced a concentration-dependent elevation of intraplatelet cGMP content: with 10(-4) mol/L SNP this was 17-fold for normals and 5-fold for patients (P < 0.01). An increase in cAMP content was seen only with 10(-4) mol/L SNP, and was 157 +/- 11% of baseline in platelets from normal subjects and 138 +/- 14% in patients. There was a strong interrelationship between cGMP-stimulating and anti-aggregating effects of SNP. The decrease in cGMP responsiveness to SNP was not related to a dysfunction of platelet guanylate cyclase; neither basal nor SNP-stimulated activity of the enzyme varied significantly between normal subjects and patients. Lipophilic derivatives of cGMP (db-cGMP) and cAMP (db-cAMP) caused reversal of aggregation; there was a nonsignificant trend towards decreased responsiveness of platelets from patients to both db-cGMP and db-cAMP. The observed decrease in responsiveness of platelets from angina patients to anti-aggregating effects of the exogenous NO donor, SNP, can therefore be attributed to suppressed cGMP accumulation. These results imply reduced platelet sensitivity to endogenous NO (endothelium-derived relaxing factor): this might contribute to platelet hyperaggregability observed in angina pectoris.

Adult↗
PubMed1996

Prediction of outcome after revascularization in patients with poor left ventricular function.

BACKGROUND: In patients with poor left ventricular function, the determinants of outcome after revascularization are unknown. METHODS: We studied prospectively 57 patients with stable coronary artery disease and poor left ventricular function (left ventricular ejection fraction, 0.28 +/- 0.04) who underwent coronary artery bypass grafting. Clinical variables were assessed as predictors of outcome in all patients, and preoperative stress thallium-201 scintigraphic data were analysed in 37 patients. RESULTS: The operative mortality was 1.7%. At 12 months after operation, 46 of the 49 survivors were angina-free and 35 had fewer heart failure symptoms, but postoperative left ventricular ejection fraction (0.30 +/- 0.09) did not change significantly. Eighteen survivors had left ventricular ejection fraction improved by 0.05 or more (0.30 +/- 0.03 preoperatively, 0.40 +/- 0.05 postoperatively; p = 0.0001). The adjusted odds ratio of large reversible thallium-201 defects in predicting such outcome was 15 (95% confidence interval, 1.6 to 140), whereas other clinical variables had no predictive value. The transplantation-free 5-year survival was 73%. CONCLUSIONS: In patients with poor left ventricular function, surgical revascularization can be performed safely, with good symptomatic relief and long-term survival. One-year survival and improvement in left ventricular function is better in patients with large reversible defects on preoperative stress thallium-201 scintigraphy.

Aged↗
PubMed1996

N-Acetylcysteine potentiates nitroglycerin-induced reversal of platelet aggregation.

N-Acetylcysteine (N-AC) potentiates the systemic and coronary hemodynamic and antianginal effects of nitroglycerin (NGT) in humans; NTG/N-AC reduces the incidence of acute myocardial infarction in patients with unstable angina pectoris. Although previous studies have demonstrated that NTG exerts antiaggregatory effects on platelets, little information is available concerning the possible potentiation by N-AC of NTG antiplatelet effects. In the present study, we examined the in vitro effects of NTG and the combination of NTG with N-AC on reversal of ADP-induced aggregation in platelet-rich plasma (PRP) obtained from normal subjects and patients with stable angina pectoris. We also examined the potential effect of background aspirin therapy on this interaction. NTG, added to platelets 0.5 min after the beginning of aggregation, suppressed the incipient aggregation and provoked the appearance of a disaggregation phase, resulting in a concentration-dependent reversal of platelet aggregation. Platelet responsiveness to NTG was significantly less (p < 0.01) in both groups of patients (receiving and not receiving aspirin) as compared with normal subjects. N-AC (10(-5) M), which did not in itself affect aggregation, induced a threefold potentiation (p < 0.05) of the antiaggregating effect of NTG that was similar in degree for all tested groups of individuals. This potentiation of the antiplatelet effects of NTG by N-AC may contribute to the efficacy of combined NTG/N-AC therapy in patients with acute ischemic syndromes.

Acetylcysteine↗
PubMed1996

Relationship between plasma perhexiline concentration and symptomatic status during short-term perhexiline therapy.

We tested the hypothesis that resolution versus persistence of symptomatic ischaemia and/or development of nausea/dizziness on the third day of loading with perhexiline maleate (PM), is correlated with perhexiline plasma concentrations after the standard loading phase in patients with acute coronary syndromes. Forty consecutive patients with either unstable angina pectoris or non-Q-wave myocardial infarction with persistent angina pectoris, despite maximal pharmacological therapy (other than PM), were studied. All patients received PM 400 mg/day for 3 days and 200 mg/day thereafter. On days 2 and 3 observers blinded to the 72-96 h plasma perhexiline concentration assessed the patient regarding episodes of angina and/or nausea/dizziness. On the third day of loading with PM, 12 patients experienced angina and 11 patients had nausea and/or dizziness. Plasma perhexiline concentrations at 72-96 h varied widely: mean 0.46 +/- 0.26 (range 0.11-1.77) microgram/ml. There was a relationship of borderline statistical significance between resolution of anginal symptoms and plasma perhexiline concentration > 0.15 microgram/ml (p = 0.055). There was a close relationship between emergence of nausea/dizziness with plasma perhexiline concentration > 0.06 microgram/ml (p < 0.01). We conclude that this study (a) suggests that PM exerts incremental antianginal effects over those of other antiischaemic agents in patients with acute coronary syndromes and (b) establishes that the development of nausea and/or dizziness in such patients is strongly predictive of accumulation of perhexiline beyond the therapeutic range of the drug.

Aged↗