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Biomedical subjects

Jay N Cohn

Publications and source records attributed to Jay N Cohn.

At least 55 records · Page 3Linked to original sources
PubMed2004

New therapeutic strategies for heart failure: left ventricular remodeling as a target.

Structural remodeling of the left ventricle involves myocyte growth and matrix changes that result in chamber enlargement, contractile dysfunction and dyssynchrony. Clinical and experimental data document that these structural changes correlate with progressive worsening of the syndrome of heart failure, that the changes are preventable and reversible, and that a favorable clinical therapeutic response is associated with regression of remodeling. The growing evidence that structural remodeling represents the disease of heart failure has now fueled mechanical as well as pharmacologic approaches to inhibiting the remodeling.

Heart Failure↗
PubMed2004

The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT.

AIMS: Plasma levels of individual neurohormones (NH) have been proposed as reliable indicators for risk stratification of patients with heart failure (HF). Mainly because of small sample size, the predictive value of different NH has never been compared, while taking into account demographic, clinical and echocardiographic markers of risk in HF. METHODS AND RESULTS: Plasma brain natriuretic peptide (BNP), norepinephrine (NE), renin activity (PRA), aldosterone (aldo) and endothelin were measured in 4300 patients before randomization in Val-HeFT. Univariate and multivariate Cox proportional hazard analyses were performed to investigate the relationship between NH and two primary study outcomes, mortality and combined mortality and morbidity (M/M). Higher baseline values for all NH were related to mortality and M/M, with univariate hazard ratios ranging from 1.13 [95% CI 0.99-1.30] (aldo) to 2.47 [2.13-2.87] (BNP) for mortality, and from 1.24 [1.11-1.39] (aldo) to 2.56 [2.28-2.89] (BNP) for M/M. In multivariate analyses, BNP had the strongest association with outcome, followed by NE and PRA. Patients with more activation of renin-angiotensin-aldosterone system tended to show greater benefit from valsartan; but the trend was not statistically significant. CONCLUSION: All the NHs evaluated in 4300 patients with stable moderate to severe HF were found to be significant markers of outcome, despite therapy with ACEi, BB and randomization to an angiotensin receptor blocker or placebo. Several of these markers have been implicated as contributors to progression of HF, but BNP, which is thought to be protective, was the most powerful indicator for poor outcome.

Aldosterone↗
PubMed2004

Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT.

AIMS: To investigate the effect of valsartan in the Valsartan-Heart Failure Trial (Val-HeFT) when added to angiotensin-converting enzyme inhibitor (ACEi) alone in patients with heart failure (HF). METHODS: Subjects in Val-HeFT receiving ACEi but not beta-blocker at baseline were analysed; 1532 were assigned to valsartan and 1502 assigned to placebo. Primary outcome events (all-cause mortality, hospitalisation for adjudicated heart failure, sudden death with resuscitation and need for >4 h of parenteral therapy for worsening heart failure) were monitored. RESULTS: Mortality was not affected by valsartan but morbidity endpoints were significantly reduced (36.3% in placebo, 31.0% in valsartan, p=0.002) in patients receiving an ACEi but no beta-blocker. Quality of life (QOL) was significantly improved, ejection fraction (EF) significantly increased, left ventricular (LV) diameter significantly reduced and plasma B-type natriuretic peptide, norepinephrine and aldosterone levels significantly reduced with valsartan compared to placebo. The morbidity benefit was significant in patients on ACEi doses below the median (22% reduction, p=0.003) and not statistically significant in those receiving ACEi doses above the median (14% reduction, p=0.143). CONCLUSION: Valsartan reduces heart failure hospitalisations and slows LV remodelling in patients treated with an ACEi in the absence of beta-blockade, particularly in those on lower doses of ACEi.

Aged↗
PubMed2004

Antihypertensive utility of perindopril in a large, general practice-based clinical trial.

The authors evaluated, in a community-based open-label trial, the effectiveness and safety of perindopril in 13,220 US hypertensive patients and studied how physicians adhere to hypertension treatment guidelines. Patients received perindopril 4 mg q.d. for 6 weeks. Based on physicians perception of blood pressure response, the patient was either maintained on 4 mg or the dose was increased to 8 mg for an additional 6 weeks. From baseline to week 12, the mean sitting blood pressure significantly declined from 156.9/94.5 mm Hg to 139.2/84.0 mm Hg. Further dose titration resulted in a clinically significant reduction in blood pressure in all patients with inadequate response on 4 mg at week 6. Blood pressure control (<140/<90 mm Hg) was achieved at 12 weeks in 48.8% patients. The subpopulation analyses demonstrated that perindopril monotherapy was effective in both men and women, in patients of all ethnicities, and in patients <65 and > or =65 years of age. Perindopril was safe and well tolerated in all hypertensive subgroups including high-risk patients. Physicians were more attuned to controlling diastolic than systolic blood pressure, and their adherence to the treatment guidelines was found to be not optimal.

Adult↗
PubMed2004

Clinical experience with perindopril in elderly hypertensive patients: a subgroup analysis of a large community trial.

OBJECTIVE: To evaluate the effectiveness and safety of perindopril in a subgroup of 3010 elderly (> or =65 years) hypertensive patients, who participated in a large US general practice-based community trial. METHODS: All patients received open-label perindopril 4 mg once a day for 6 weeks. After 6 weeks the dosage was either maintained (group I) or increased to 8 mg/day (group II) based on the physician's assessment of blood pressure (BP) response. Patients were then followed for another 6 weeks for a total study duration of 12 weeks. RESULTS: Demographic and baseline clinical characteristics revealed a higher proportion of women, longer duration of hypertension and higher baseline systolic BP (SBP) among elderly than young (<65 years, n = 7332) hypertensive patients. A clinically relevant BP reduction of similar magnitude was obtained in elderly and young patients with perindopril monotherapy. At week 12, the mean reduction in BP from baseline was 18.4/8.7 mm Hg in the elderly and 17.5/11.3 mm Hg in the young. Elderly patients with hypertension not responding adequately to the 4 mg/day dosage at week 6 had a BP reduction of 6.3/3.6 mm Hg (group II). Up-titration to an 8 mg/day dosage for another 6 weeks gave an additional 8.9/3.5 mm Hg reduction resulting in a total reduction of 15.2/7.1 mm Hg from baseline. A similar magnitude of increase in response to up-titration of perindopril was seen in young patients. BP control (<140/90 mm Hg) on perindopril monotherapy was achieved in 41.4% of elderly and 51.9% of young patients. In both age groups, up-titration to an 8.0 mg/day dosage in group II patients increased BP control by approximately 5-fold at week 12 (28.2% in the elderly and 36.4% in the young). A similar increased response on BP reduction and BP control (<140/90 mm Hg) with up-titration was seen in elderly subgroups of African American and diabetic patients. The 7th Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommended target goal of <130/80 mm Hg was achieved with perindopril monotherapy in 15.6% of hypertensive diabetic patients. Perindopril reduced BP effectively and safely in very elderly (> or =75 years) hypertensive patients. Perindopril was well tolerated in elderly patients including high-risk groups. The incidence of cough (7-10%), the most common symptom, was similar in all age groups. The low incidence of postural hypotension (< or =0.2%) observed in the elderly and very elderly further supports the good tolerance and safety profile of the drug. Data analysis from this study suggests that community physicians, in general, are less aggressive in controlling BP in the elderly and more inclined to treat or control diastolic BP than SBP. CONCLUSION: Perindopril treatment is effective and well tolerated in elderly patients with hypertension.

Aged↗
PubMed2003

Sustained reduction of aldosterone in response to the angiotensin receptor blocker valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial.

BACKGROUND: Aldosterone has been implicated in the progression of heart failure. The Valsartan Heart Failure Trial (Val-HeFT) provided the first opportunity to examine the long-term effects of an angiotensin receptor blocker on plasma aldosterone levels in patients with NYHA class II through IV heart failure. METHODS AND RESULTS: Plasma aldosterone was measured by radioimmunoassay in core laboratories at baseline and during follow-up in patients assigned to valsartan at a target dose of 160 mg twice daily or placebo. In the placebo group, aldosterone (baseline, 150+/-160 pg/mL, mean+/-SD; n=2025) increased at 4, 12, and 24 months. In the valsartan group, aldosterone (baseline, 137+/-124 pg/mL, mean+/-SD; n=2023) decreased at 4 months and remained suppressed for up to 2 years. At end point (last measurement in each patient), mean aldosterone increased by 17.8+/-3.0 pg/mL (SEM) (11.9%) in the placebo group and decreased by 23.8+/-3.0 pg/mL (SEM) (-17.4%) in the valsartan group (P<0.00001). The effect of valsartan was similar in all subgroups, including those receiving neither ACE inhibitors (ACE-I) nor beta-blockers (BB) at baseline and those receiving concomitant ACE-I or BB. In contrast, outcome effects varied in the 4 subgroups, with a statistically significant reduction in the combined mortality/morbidity end point in those receiving neither neurohormonal inhibitor and an adverse trend in those treated with both drugs. CONCLUSIONS: Valsartan added to background therapy for heart failure produces sustained reduction in plasma aldosterone, consistent with the observed significant reduction in the combined mortality/morbidity end point. A similar reduction in all subgroups based on ACE-I or BB therapy, despite differing clinical outcomes in these subgroups, suggests that aldosterone plasma levels may not be a critical marker of the progression of heart failure.

Aldosterone↗
PubMed2003

Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study.

BACKGROUND: Weight loss in chronic heart failure is linked to impaired survival. We aimed to assess the frequency of weight loss in patients with this disease, whether the degree of weight loss predicts mortality, and whether weight loss can be prevented by angiotensin-converting-enzyme (ACE) inhibitors. METHODS: We investigated weight changes in 1929 patients from the SOLVD trial who had chronic heart failure, were free of oedema at baseline, and survived for at least 4 months after trial entry. Meanfollow-up was 35 months (SD 13). We analysed the effect of weight loss at cutpoints of 5%, 7.5%, 10%, 15% (a priori), and 6% (post hoc) to identify which one best predicted outcome. To validate results, we analysed data for 619 patients in the V-HeFT II trial. FINDINGS: 817 (42%) patients in the SOLVD trial had weight loss from baseline of 5% or more. At 8 months follow-up, all cutpoints for weight loss were significantly associated with impaired survival after adjustment for age, sex, New York Heart Association class, left ventricular ejection fraction, and treatment allocation. Weight loss of 6% or more at any time during follow-up was the strongest predictor of impaired survival (adjusted hazard ratio 2.10, 95% CI 1.77-2.49; p<0.0001). Patients on the ACE inhibitor enalapril had a lower hazard of 6% or more weight loss than did those not taking the drug (adjusted reduction 19%, p=0.0054). Results from analyses of V-HeFT II data lent support to our findings. INTERPRETATION: Weight loss occurs frequently in patients with chronic heart disease, its reversal is rare, and when present, it is independently linked to impaired survival. Weight loss of more than 6% should be used to define the presence of cachexia in patients with chronic heart failure. In chronic heart failure, treatment with an ACE inhibitor reduces the risk of weight loss.

Aged↗
PubMed2003

Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT).

BACKGROUND: Neurohormones are considered markers of heart failure progression. We examined whether changes in brain natriuretic peptide (BNP) and norepinephrine (NE) over time are associated with corresponding changes in mortality and morbidity in the Valsartan Heart Failure Trial. METHODS AND RESULTS: Plasma BNP and NE were measured before randomization and during follow-up in approximately 4300 patients in the Valsartan Heart Failure Trial. The relation between baseline BNP and NE and all-cause mortality and first morbid event (M&M) was analyzed in subgroups, with values above and below the median, and by quartiles. The change and percent change from baseline to 4 and 12 months in BNP and NE were also analyzed by quartiles for subsequent M&M. Risk ratios for M&M were calculated using a Cox proportional hazard model. Risk ratio of M&M for patients with baseline BNP or NE above the median was significantly higher than that for patients with values below the median. Baseline BNP and NE in quartiles also showed a quartile-dependent increase in M&M. BNP had a stronger association with M&M than NE. Patients with the greatest percent decrease in BNP and NE from baseline to 4 and 12 months had the lowest whereas patients with greatest percent increase in BNP and NE had the highest M&M. CONCLUSIONS: Not only are plasma BNP and NE important predictors of heart failure M&M, but changes in these neurohormones over time are associated with corresponding changes in M&M. These data further reinforce their role as significant surrogate markers in HF and underscore the importance of including their measurement in HF trials.

Biomarkers↗
PubMed2003

Endothelial dysfunction and the metabolic syndrome.

The metabolic syndrome is a highly prevalent multifaceted clinical entity produced through the interaction of genetic, hormonal, and lifestyle factors. A distinctive constellation of abnormalities precedes and predicts the accelerated development of inflammation and coagulation represent emerging risk contributors associated with obesity and insulin resistance, central components of the metabolic syndrome, which act in concert with traditional abnormalities to increase cardiovascular risk. The initiation and progression of atherosclerosis may have its origins in impaired endothelial function that can be detected at the earliest stages of development of the syndrome. The basic elements of the metabolic syndrome and accelerated phase of atherogenesis are often silent partners that present many years before the onset of type 2 diabetes mellitus. The ability to detect and monitor subclinical vascular disease, as a reflection of the multiple factors that contribute to impair arterial wall integrity, holds potential to further refine cardiovascular risk stratification. Noninvasive assessment of vascular health may also aid the clinical decision-making process by guiding therapeutic interventions to optimize vascular protection in the metabolic syndrome.

Arteriosclerosis↗
PubMed2003

Screening for early detection of cardiovascular disease in asymptomatic individuals.

OBJECTIVE: Primary prevention of cardiovascular disease has been aimed at risk factor identification and treatment without efforts to document early cardiovascular disease. The objective of the current study is to screen individuals with vascular and cardiac tests aimed at identifying early abnormalities likely to progress and to measure risk contributors susceptible to therapy. METHODS: A center was established for comprehensive screening of an asymptomatic population with 10 tests designed to detect early vascular and cardiac abnormalities and blood tests to identify potential targets for risk contributor intervention. The first 396 individuals screened in the center have been analyzed. RESULTS: Using a scoring system from 0 (no disease) to 20 (advanced disease), 49% of the population exhibited scores of > or =5 and 39% exhibited scores of > or =6. These scores appear indicative of early disease mandating initiation of or change in medical therapy, which was recommended to the individuals screened and to their primary care physicians. CONCLUSION: The screening tests utilized are effective in uncovering unsuspected early cardiovascular disease in which targeted treatment could be effective in reducing the incidence of cardiovascular events in susceptible individuals. Documentation of the sensitivity and specificity of this approach requires longitudinal study.

Adult↗
PubMed2003

Reduced small artery but not large artery elasticity is an independent risk marker for cardiovascular events.

BACKGROUND: Atherosclerosis begins in the arterial wall, with endothelial dysfunction accompanied by functional and structural changes that influence arterial stiffness. Pulse contour analysis provides an assessment of compliance or elasticity of the large conduit arteries (C(1)) and small microcirculatory arteries (C(2)). In this study, the predictive value of reduced elasticity of these arteries was evaluated by follow-up of subjects who underwent pulse contour analysis at the University of Minnesota. METHODS: Questionnaires were sent to 870 subjects who had radial artery pulse wave analysis performed between 1993 and 1999 using a noninvasive sensor, parameter estimating algorithm and modified Windkessel model of the circulation. Responses from 419 subjects >19 years of age reported on any cardiovascular events including death, myocardial infarction, stroke, transient ischemic attacks, angina, or coronary or peripheral vascular interventional procedures. RESULTS: Of the subjects, 168 (41%) reported one or more cardiovascular events. Events were more common in those with elevated blood pressure, elevated cholesterol, diabetes, and family history of events. Age, reduced C(1), and reduced C(2) were univariate predictors of events. After adjusting for age, a 2-unit decrease in C(2) remained a significant predictor (odds ratio 1.50, P <.001), whereas C(1) was no longer predictive. CONCLUSION: Reduced small artery elasticity, which is a measure of endothelial dysfunction, is significantly associated with cardiovascular events independent of age.

Arteries↗
PubMed2003

Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON).

BACKGROUND: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. METHODS: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II-IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths. FINDINGS: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (-18.8% from baseline) vs. placebo (+6.9%). INTERPRETATION: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure.

Delayed-Action Preparations↗
PubMed2003

Effect of Valsartan on hospitalization: results from Val-HeFT.

BACKGROUND: Although current therapies have improved heart failure (HF) outcome, hospitalizations continue at high rates. The Valsartan Heart Failure Trial (Val-HeFT) showed that valsartan reduced the risk of first worsening HF hospitalization by 27.5% versus placebo (P <.001). This article analyzes all-cause and investigator-assessed HF hospitalization in Val-HeFT overall and in subgroups defined by preexisting HF therapy. METHODS: Val-HeFT was a randomized, double-blind parallel-arm study in which HF patients (New York Heart Association class II-IV) received either valsartan (n = 2511, force-titrated to 160 mg twice daily) or placebo (n = 2499) in addition to prescribed HF therapy. Total and per patient-year investigator-assessed hospitalizations (all-cause or HF) were analyzed according to prescribed therapy at baseline (angiotensin-converting enzyme inhibitors [ACEI] and beta-blockers [BB]). RESULTS: Hospitalization for worsening HF accounted for 35% of all hospitalizations. There were 2856 and 3106 total all-cause hospitalizations in the valsartan and placebo groups, respectively, an 8% reduction (P =.145). Valsartan significantly reduced the overall number of investigator-assessed HF hospitalizations (-22.4%, P =.002) and reduced HF hospitalizations in the combination therapy subgroups (significant for ACEI+/BB- P =.003 and ACEI-/BB- P =.028) except those receiving both ACEI and BB. The benefit of valsartan versus placebo was more pronounced in reducing the number of patients with recurrent HF hospitalization (-20.6%) than single hospitalizations (-8.7%). CONCLUSIONS: Addition of valsartan to prescribed HF therapy demonstrated significant reductions in HF hospitalizations and was particularly beneficial in reducing recurrent HF hospitalization.

Adrenergic beta-Antagonists↗