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Biomedical subjects

Jay N Cohn

Publications and source records attributed to Jay N Cohn.

At least 19 recordsLinked to original sources
PubMed2006

Influence of blood pressure on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine in the African-American Heart Failure Trial.

OBJECTIVES: This study sought to assess the effect of baseline systolic blood pressure (SBP) and changes in SBP on the effectiveness of treatment with fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in patients with heart failure (HF). BACKGROUND: Low SBP is a risk factor for adverse outcomes in patients with HF. However, FDC I/H lowered SBP in the A-HeFT (African-American Heart Failure Trial) and yet prolonged survival. Whether blood pressure (BP) lowering is critical to the efficacy of FDC I/H and whether a low BP limits its effectiveness is unclear. METHODS: The effects of FDC I/H on SBP and on mortality and hospitalization were compared in patients with a low or high baseline SBP using multivariable Cox regression models. The interaction between the effect of treatment and baseline SBP was examined. RESULTS: Mean +/- SD baseline SBP in all of the patients was 126 +/- 18 mm Hg. Patients with baseline SBP equal to or below the median (126 mm Hg) had features of more severe HF. Baseline SBP equal to or below the median was an independent risk factor for death (hazard ratio [HR] 2.09; 95% confidence interval [CI] 1.02 to 4.29) or first hospitalization for HF (HR 1.66; 95% CI 1.18 to 2.34). The FDC I/H treatment reduced BP in patients with SBP above the median but not in patients with SBP below 126 mm Hg. The FDC I/H treatment was associated with a similar decrease in mortality or hospitalization for HF in patients with SBP below the median and above the median. The effects of FDC I/H on mortality alone were also similar. CONCLUSIONS: In A-HeFT, patients with lower SBP had a greater risk but a similar relative benefit from the use of FDC I/H as those with higher SBP. The FDC I/H treatment did not reduce SBP in patients with low SBP. An asymptomatic low SBP should not be considered a contraindication to use of FDC I/H in patients with HF.

Adult↗
PubMed2006

Body mass index, prognosis and mode of death in chronic heart failure: results from the Valsartan Heart Failure Trial.

AIMS: To assess the relationship between body mass index (BMI), mortality and mode of death in chronic heart failure (CHF) patients; to define the shape of the relationship between BMI and mortality. METHODS AND RESULTS: We performed a post-hoc analysis of 5010 patients from the Valsartan Heart Failure Trial. The end-points of the study were all-cause and cardiovascular mortality. Mortality rate was 27.2% in underweight patients (BMI<22 kg/m2), 21.7% in normal weight patients (BMI 22-24.9 kg/m2), 17.9% in overweight patients (BMI 25-29.9 kg/m2) and 16.5% in obese patients (BMI>30 kg/m2) (p<0.0001). The rates of non-cardiovascular death did not differ among groups. The risk of death due to progressive heart failure was 3.4-fold higher in the underweight than in the obese patients (p<0.0001). Normal weight, overweight and obese patients had lower risk of death as compared with underweight patients (p=0.019, HR 0.76, 95% CI 0.61-0.96; p=0.0005, HR 0.68, 95% CI 0.55-0.84; p=0.003, HR 0.67, 95% CI 0.52-0.88, respectively) independently of symptoms, ventricular function, beta-blocker use, C-reactive protein and brain natriuretic peptide levels. CONCLUSIONS: In CHF patients a higher BMI is associated with a better prognosis independently of other clinical variables. The relationship between mortality and BMI is monotonically decreasing.

Adolescent↗
PubMed2006

Outcomes by gender in the African-American Heart Failure Trial.

OBJECTIVES: Previous trials testing isosorbide dinitrate/hydralazine (I/H) were performed in all-male study cohorts, and thus the efficacy of I/H in women was unknown; 40% of the A-HeFT (African-American Heart Failure Trial) cohort were women. We therefore compared outcomes by gender and treatment. BACKGROUND: Fixed-dose combined I/H significantly reduced mortality and heart failure hospitalizations and improved quality of life in 1,050 black patients with heart failure treated with background neurohormonal blockade. Previous trials testing I/H were done in all-male study cohorts, and thus the efficacy of I/H in women was unknown. METHODS: Baseline characteristics and medications were compared between men and women by I/H and placebo treatment. Survival, time to first heart failure hospitalization, change in quality of life, and event-free survival were compared by gender and treatment. RESULTS: At baseline, women had lower hemoglobin and creatinine levels; less renal insufficiency; and higher body mass indexes, diabetes prevalence, and systolic blood pressures; but worse quality of life scores. All-cause mortality was lower in women than in men treated with I/H but without significant treatment interaction by gender. The primary composite score, which weighted mortality, first heart failure hospitalization, and change in quality of life at 6 months, was similarly improved by I/H in men and women. First heart failure hospitalization and event-free survival (time to death or first heart failure hospitalization) were similarly improved in both genders. CONCLUSIONS: Fixed-dose I/H improved heart failure outcomes in both men and women in A-HeFT. The I/H significantly improved the primary composite score and event-free survival as well as reduced the risk of first heart failure hospitalizations similarly in both genders. The I/H had a slightly greater mortality benefit in women, but without a significant treatment interaction by gender.

Adult↗
PubMed2006

Aldosterone synthase promoter polymorphism predicts outcome in African Americans with heart failure: results from the A-HeFT Trial.

OBJECTIVES: We sought to evaluate the effect of the aldosterone synthase promoter polymorphism on heart failure outcomes for subjects in the African American Heart Failure Trial (A-HeFT). BACKGROUND: Genetic heterogeneity modulates clinical outcomes in subjects with heart failure (HF); however, little data exist in African American populations. A common polymorphism exists in the promoter region of the aldosterone synthase gene (CYP11B2) at position -344 (T/C). The -344C allele, associated with higher aldosterone synthase activity, has been linked to hypertension; however, its impact on outcomes in HF is unknown. METHODS: A total of 354 subjects from A-HeFT participated in the GRAHF (Genetic Risk Assessment of Heart Failure in African Americans) substudy and were genotyped for the aldosterone synthase polymorphism. Patients were followed prospectively, and event-free survival (freedom from death and HF hospitalization) compared by CYP11B2 genotype. RESULTS: Of the cohort, 218 patients were TT, 114 CT, and 22 patients were CC. Baseline etiology, blood pressure, and functional class were not significantly different among the 3 cohorts. The C allele was associated with significantly poorer HF hospitalization-free survival with the best survival among TT subjects, intermediate for heterozygotes, and the poorest for CC homozygotes (p = 0.018), and a higher rate of death (% death TT/TC/CC = 1.8/3.5/18.2, p = 0.001). The TT genotype, more prevalent in blacks, was associated with greater impact of fixed combination of isosorbide dinitrate and hydralazine on the primary composite end point (p = 0.01). CONCLUSIONS: The aldosterone synthase promoter -344C allele linked to higher aldosterone levels is associated with poorer event-free survival in blacks with HF. The role of aldosterone receptor antagonists in diminishing this apparent genetic risk remains to be explored.

Black or African American↗
PubMed2006

Efficacy and safety in clinical trials in cardiovascular disease.

Mortality and morbid events are insensitive guides to the efficacy and safety of interventions in chronic cardiovascular disease (CVD). To enhance the ability to find new and effective long-term treatments, especially for the early stages of CVD, a revised strategy for clinical trials should emphasize efficacy on disease progression while monitoring symptoms and quality of life as guides to clinical benefit. Mortality, which is uncommon except in acute or advanced disease, provides at best a crude guide to net efficacy and safety. It must be monitored to support demonstrated efficacy on disease progression without adverse safety effects. This revised approach, made possible by our enhanced ability to monitor the progression of disease, should make it possible to study earlier disease and to improve cardiovascular health while reducing health care costs.

Biomarkers↗
PubMed2006

Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart Failure (Val-HeFT) data.

BACKGROUND: The B-type or brain natriuretic peptides (BNP) and the amino-terminal probrain natriuretic peptide (NT-proBNP) are good markers of prognosis and diagnosis in chronic heart failure (HF). It is unclear, however, whether differences in their biological characteristics modify their clinical correlates and prognostic performance in HF. This work aimed to provide a direct comparison of the prognostic value of BNP and NT-proBNP in patients with chronic and stable HF. METHODS: We measured BNP and NT-proBNP at baseline in 3916 patients enrolled in the Valsartan Heart Failure Trial. To identify the variables associated with both peptides, we conducted simple and multivariable linear regression analyses. We used Cox multivariable regression models to evaluate the independent prognostic value for all-cause mortality, mortality and morbidity, and hospitalization for HF. Prognostic performance was assessed by pairwise comparisons of the area under the curve of receiver-operator characteristic curves. RESULTS: NT-proBNP and BNP had similar relationships with age, left ventrical ejection fraction, and internal diameter and creatinine clearance. Either peptide ranked as the first independent predictor of outcome after adjustment for major confounding clinical characteristics. ROC curves were almost superimposable for all-cause mortality (area under the curve (SE): BNP 0.665 (0.011) vs NT-proBNP 0.679 (0.011); P=0.0734), but NT-proBNP was superior to BNP for predicting mortality and morbidity (P=0.032) or hospitalization for HF (P=0.0143). Overall sensitivity and specificity ranged from 0.590 to 0.696. CONCLUSIONS: The natriuretic peptides BNP and NT-proBNP showed subtle differences in their relation to clinical characteristics and prognostic performance in a large population of patients with chronic and stable HF. They were the most powerful independent markers of outcome in HF.

Aged↗
PubMed2006

Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiology.

Aldosterone is an important mediator of the renin-angiotensin-aldosterone system (RAAS) that plays a major role in the pathophysiology of cardiovascular disease as well as regulation of extracellular fluid volume and potassium. In experimental models, aldosterone has been shown to promote endothelial dysfunction; induce vascular inflammation, myocardial ischemia, and necrosis; increase collagen synthesis in cardiac fibroblasts; contribute to plasminogen activator inhibitor-1 regulation; decrease baroreceptor sensitivity and reflex function; block myocardial uptake of norepinephrine; increase oxidative stress; and stimulate cardiomyocyte apoptosis. A review of animal and human studies with aldosterone blockers reveals improvement in, and in some cases complete reversal of, these pathophysiologic effects of aldosterone on the cardiovascular system.

Aldosterone↗
PubMed2006

Measuring endothelial function.

Dysfunction of the endothelium and of the arterial wall is well described in patients with atherosclerosis, diabetes, and other risk factors for vascular disease. In recent years, clinical research has focused on elucidating the role of this dysfunction in influencing vascular disease progression. Alteration in the structure of arteries and disruption of the homeostatic functions of the endothelium act as a substrate for end-organ damage and the occurrence of vascular events. Dysfunction of the vascular endothelial cells is probably the earliest event promoting atherosclerotic lesion formation. Therefore, methods capable of assessing endothelial function at a preclinical stage hold potential to refine cardiovascular risk stratification and serve as a guide to monitor the effects of therapeutic interventions. A number of methodologies are currently employed to assess endothelial function, but the optimal approach is not firmly established. In this article, we critically appraise the use of different methodologies employed to study endothelial function as a surrogate marker of future cardiovascular risk.

Blood Flow Velocity↗
PubMed2006

Monitoring vascular health beyond blood pressure.

It is well recognized that vascular changes, including atherosclerosis, begin early in life as a silent, asymptomatic disease process and are associated with cardiovascular (CV) risk factors. Importantly, CV risk factors persist or track from childhood to adulthood and are predictive of CV disease risk in adults. Evaluation of arterial stiffness and its predictors may help identify asymptomatic individuals at risk, before blood pressure is elevated above an "arbitrary" level that we currently identify as hypertension. Currently, measurements of arterial stiffness are being used in the research setting and also as part of cardiovascular risk prediction clinics. As the various techniques become more widely available, it is conceivable that the measurement of arterial stiffness could become an important part of the routine assessment of patients in daily practice, as a supplement to blood pressure measurement. Measurement of arterial stiffness will not only be helpful in the detection of early vascular disease but also will be a tool in the follow-up monitoring of strategies aimed at preventing hypertension or reducing further progression of vascular disease before blood pressure elevation can be detected.

Atherosclerosis↗
PubMed2006

What is the role of angiotensin-receptor blockade in cardiovascular protection?

The role of angiotensin II, the key mediator of the renin-angiotensin-aldosterone system, in the pathophysiology of cardiovascular disease is well known. Pharmacologic interruption of the activity of angiotensin II, either through blockade of the angiotensin receptor or inhibition of angiotensin-converting enzyme, is associated with a reduction in cardiovascular disease morbidity and mortality, as evidenced by accumulated data from large-scale, well-controlled clinical trials in high-risk populations. As the underlying mechanisms of vascular disease and the effects of blockade of the renin-angiotensin-aldosterone system on these processes have been further defined, the therapeutic focus has begun to shift toward prevention of disease progression at earlier stages. Continued research has identified early signs of vascular disease, such as endothelial dysfunction and vascular and cardiac remodeling, which occur long before clinical manifestations of cardiovascular disease become evident. Diagnostic tests are now available to assess otherwise healthy individuals for these signs. A preliminary trial is under way to evaluate the role of angiotensin receptor blockade as preventive treatment of individuals with early signs of vascular or cardiac disease.

Angiotensin II↗
PubMed2006

Incremental prognostic value of changes in B-type natriuretic peptide in heart failure.

PURPOSE: B-type natriuretic peptide is one of the most sensitive and specific biohumoral markers of heart failure. We hypothesized that B-type natriuretic peptide changes during treatment of heart failure may provide independent information on disease progression and outcome in patients enrolled in the Val-HeFT trial. METHODS: Patients were divided into four groups according to concentrations of B-type natriuretic peptide at baseline versus 4 months (n = 3740) or 12 months (n = 3343), with respect to the baseline median (97 pg/mL): low-->low (stable below median, 44%-46%), high-->high (stable above median, 32%-37%), high-->low (above to below median, 12%-14%), and low-->high (below to above median, 6%-9%). Cox multivariate regression analysis was used to assess the risk of death and morbidity, with adjustment for baseline B-type natriuretic peptide concentrations. RESULTS: Patients who improved their B-type natriuretic peptide at 4 months (high-->low) had a similar risk for mortality (hazard ratio = 1.191, 95% confidence interval [CI] 0.870-1.631, P =.2746) compared with the low-->low patients. Conversely, patients who worsened in their B-type natriuretic peptide (low-->high) had a risk for mortality (hazard ratio 2.578, CI, 1.861-3.571, P <.0001) higher than patients in the low-->low group, and indistinguishable from the high-->high group. Worsening of B-type natriuretic peptide (low-->high) was associated with 0.03 cm/m2 increase in left ventricular end-diastolic diameter, whereas it decreased by 0.10 cm/m2 in high-->low and low-->low groups (P <.001). CONCLUSIONS: Changes in B-type natriuretic peptide over time with respect to a threshold value of 97 pg/mL convey an independent and additional prognostic value compared with a single determination of B-type natriuretic peptide in a large population of patients with chronic symptomatic heart failure and might be helpful in the management of these patients.

Aged↗
PubMed2006

Relationships between clinical assessments and patients' perceptions of the effects of heart failure on their quality of life.

BACKGROUND: Hypothetically, most of the effects of heart failure on quality of life might be attributed to symptoms produced by the pathology. Relationships between measures of these concepts need to be quantified to test this conceptual model. METHODS AND RESULTS: Measurements of heart failure pathology and symptoms and quality of life as measured by the Minnesota Living with Heart Failure (MLHF) questionnaire at the 4-month visit in the Valsartan Heart Failure Trial were analyzed. Correlation and regression analyses corrected for estimated reliability of measurements were used to quantify relationships. The percentage of variance in dependent variables that was related to explanatory variables was summarized by the coefficient of determination (100 xR(2)) from regression models. Dyspnea at rest, dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, fatigue, and New York Heart Association class were significantly related to MLHF scores. Combined, these symptoms explained 41% of the variation in MLHF scores. Controlling for symptoms, age explained an additional 4.5% of the variation in MLHF scores, whereas race, gender, and available comorbidities each explained <1%. Pathologic measures including ejection fraction, B-type natriuretic peptide, jugular venous distension, rales, peripheral edema, systolic blood pressure, creatinine, and hemoglobin were not strongly related to symptom assessments (combined R(2) = 17%) or MLHF scores (combined R(2) = 7%). CONCLUSION: Symptoms of heart failure explain a substantial proportion of the variation in the effects of heart failure on patients' quality of life as measured by the MLHF score. The effects of heart failure on quality of life can vary with age independently of symptoms. Pathologic measures of heart failure including some well-known correlates of the risk of hospitalization and death are not strongly related to symptoms or quality of life. Further studies are needed to understand the relationships between heart failure pathology and symptoms and to identify determinants of the effects of heart failure on patients' quality of life that were not related to symptoms.

Age Factors↗
PubMed2006

The prognostic value of big endothelin-1 in more than 2,300 patients with heart failure enrolled in the Valsartan Heart Failure Trial (Val-HeFT).

BACKGROUND: Endothelin is elevated in heart failure and contributes to neurohormonal activation, hemodynamic deterioration, and cardiovascular remodeling. Here, we examined its prognostic value in a large population of patients with chronic heart failure. METHODS AND RESULTS: Big endothelin-1 (Big ET-1) and 4 other neurohormones were measured at study entry in 2359 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) and their concentrations related to outcome over a median follow-up of 23 months. Baseline concentration of Big ET-1 (median 0.80 pmol/L) was proportional to severity of disease (New York Heart Association class, left ventricular structure and function). High circulating concentrations of brain natriuretic peptide (BNP), creatinine and bilirubin, advanced New York Heart Association class, elevated body mass index, and the presence of atrial fibrillation were independently associated to higher concentrations of Big ET-1. Big ET-1 (ranking second just behind BNP among neurohormonal factors) was an independent predictor of outcome defined as all-cause mortality (hazard ratio 1.49, 95% CI 1.20-1.84, P = .0003) or the combined endpoint of mortality and morbidity (hazard ratio 1.43, 95% CI 1.20-1.69, P < .0001) and provided incremental prognostic value compared with BNP. CONCLUSIONS: In a large population of patients with symptomatic heart failure, the circulating concentration of Big ET-1, a precursor of the paracrine and bioactive peptide ET-1, was an independent marker of mortality and morbidity. In this setting, BNP remained the strongest neurohormonal prognostic factor.

Aged↗
PubMed2006

The use of race and ethnicity in medicine: lessons from the African-American Heart Failure Trial.

Race or ethnic identity, despite its imprecise categorization, is a useful means of identifying population differences in mechanisms of disease and treatment effects. Therefore, race and other arbitrary demographic and physiological variables have appropriately served as a helpful guide to clinical management and to clinical trial participation. The African-American Heart Failure Trial was carried out in African-Americans with heart failure because prior data had demonstrated a uniquely favorable effect in this subpopulation of the drug combination in BiDil. The remarkable effect of the drug in reducing mortality in this study has illuminated an important new mechanism of therapy for heart failure. Application of these findings need not be confined to the population studied, but the observation highlights the need for more precise ways to identify individual responsiveness to therapy.

Black or African American↗
PubMed2005

Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care-data from Val-HeFT.

BACKGROUND: Clinical trials emphasize mortality and morbidity endpoints. AIMS: To bring relevance of trial results to point of care by examining the prognostic and therapeutic value of individual signs and symptoms (S&S). METHODS: We analysed data from 5010 patients with stable chronic heart failure and left ventricular dysfunction who were participants in the Val-HeFT study. Individual S&S were stratified by severity. Treatment differences between valsartan and placebo were analysed by S&S strata at baseline and endpoint by logistical regression, and an overall S&S score by ANCOVA. Hazard ratios of S&S strata were calculated for mortality and heart failure hospitalisation. Prognostic contributions of S&S to other variables were determined by multivariate analysis. RESULTS: At endpoint, there were significantly fewer valsartan and more placebo patients with severe symptoms. Over time, improvement in the S&S overall score was significantly more favourable for valsartan than placebo. S&S strata were significantly predictive of risk for hospitalisation and death. S&S were each independent and incremental predictors of mortality compared to other variables. Symptom strata separated out moderately symptomatic patients with a mortality rate which was intermediate between that for NYHA Class II and III. CONCLUSION: Risk stratification of individual S&S defined prognosis, identified patients with an intermediate mortality between Class II and III, and treatment benefits of valsartan over placebo.

Aged↗
PubMed2005

C-reactive protein in heart failure: prognostic value and the effect of valsartan.

BACKGROUND: The role of C-reactive protein (CRP) in heart failure is not well studied. We assessed the prognostic value of CRP in patients randomized in Val-HeFT (Valsartan Heart Failure Trial) and studied changes in CRP that were associated with valsartan. METHODS AND RESULTS: Characteristics of patients with baseline CRP levels above and below the median value were compared. Univariable and multivariable Cox proportional hazards regression models were used to examine the relationship of CRP to mortality and morbidity. Interactions were tested to determine whether differences in CRP changes from baseline to 4 and 12 months between groups randomly assigned to valsartan or placebo depended on baseline ACE inhibitor use. Median plasma CRP was 3.23 mg/L (interquartile range 1.42 to 7.56 mg/L), which is higher than in the general population. Patients with CRP above the median had features of more severe heart failure than those with CRP levels below the median. The cumulative likelihood of death and first morbid event increased with increasing quartile of CRP. Relative to the lowest CRP quartile, the risk of mortality (hazard ratio 1.51, 95% CI 1.2 to 1.9) and first morbid event (hazard ratio 1.53, 95% CI 1.28 to 1.84) was increased in the highest CRP quartile in multivariable models. CRP added incremental prognostic information to that provided by brain natriuretic peptide alone. CRP did not change significantly over time in the placebo group; however, after 12 months, valsartan was associated with a decrease in CRP in patients not receiving ACE inhibitors but not in those receiving ACE inhibitors at 12 months. CONCLUSIONS: CRP is increased in heart failure. Higher levels are associated with features of more severe heart failure and are independently associated with mortality and morbidity. The ability of treatments to reduce CRP levels and the prognostic importance of reducing CRP require further study.

Aged↗