Anju Nohria

CLINICAL ASSESSMENT IDENTIFIES HEMODYNAMIC PROFILES THAT PREDICT OUTCOMES IN PATIENTS ADMITTED WITH HEART FAILURE

OBJECTIVES This study was designed to determine the relevance of a proposed classification for advanced heart failure (HF). Profiles based on clinical assessment of congestion and perfusion at the time of hospitalization were compared with subsequent outcomes. BACKGROUND Optimal design of therapy and trials for advanced HF remains limited by the lack of simple clinical profiles to characterize patients. METHODS Prospective analysis was performed for 452 patients admitted to the cardiomyopathy service at the Brigham and Womens Hospital with a diagnosis of HF. Patients were classified by clinical assessment into four profiles: profile A, patients with no evidence of congestion or hypoperfusion (dry-warm, n = 123); profile B, congestion with adequate perfusion (wet-warm, n = 222); profile C, congestion and hypoperfusion (wet-cold, n = 91); and profile L, hypoperfusion without congestion (dry-cold, n = 16). Other standard predictors of outcome were included and patients were followed for the end points of death (n = 117) and death or urgent transplantation (n = 137) at one year. RESULTS Survival analysis showed that clinical profiles predict outcomes in HF. Profiles B and C increase the risk of death plus urgent transplantation by univariate (hazard ratio [HR] 1.83, p = 0.02) and multivariate analyses (HR 2.48, p = 0.003). Moreover, clinical profiles add prognostic information even when limited to patients with New York Heart Association (NYHA) class III/IV symptoms (profile B: HR 2.23, p = 0.026; profile C: HR 2.73, p = 0.009). CONCLUSIONS Simple clinical assessment can be used to define profiles in patients admitted with HF. These profiles predict outcomes and may be used to guide therapy and identify populations for future investigation.

Cardiorenal Interactions: Insights From the ESCAPE Trial

OBJECTIVES We examined the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) database to understand the impact and pathophysiology of renal dysfunction in patients hospitalized with advanced decompensated heart failure (HF). BACKGROUND Baseline renal insufficiency (RI) (estimated glomerular filtration rate [eGFR] <60 ml/min) and worsening renal function (WRF) (upward arrow serum creatinine [SCr] >or=0.3 mg/dl) during treatment of decompensated HF are associated with adverse outcomes. METHODS We used a Cox proportional hazards model to evaluate the impact of renal function on 6-month outcomes. Renal parameters were correlated with hemodynamic measurements. The impact of a strategy using pulmonary artery catheter (PAC) guidance on WRF and outcomes in patients with baseline RI was compared with treatment based on clinical assessment alone. RESULTS Baseline and discharge RI, but not WRF, were associated with an increased risk of death and death or rehospitalization. Among the hemodynamic parameters measured in patients randomized to the PAC arm (n = 194), only right atrial pressure correlated weakly with baseline SCr (r = 0.165, p = 0.03). There was no correlation between baseline hemodynamics or change in hemodynamics and WRF. A PAC-guided strategy was associated with less average increase in creatinine but did not decrease the incidence of defined WRF during hospitalization or affect renal function after discharge relative to clinical assessment alone. CONCLUSIONS Among patients with advanced decompensated HF, baseline RI impacts outcomes more than WRF. Poor forward flow alone does not appear to account for the development of RI or WRF in these patients. The addition of hemodynamic monitoring to clinical assessment does not prevent WRF or improve renal function after discharge.

Development of circulatory-renal limitations to angiotensin-converting enzyme inhibitors identifies patients with severe heart failure and early mortality ☆

OBJECTIVES This study examined the hypothesis that patients who develop angiotensin-converting enzyme inhibitor intolerance attributable to circulatory-renal limitations (CRLimit) have more severe underlying disease and worse outcome. BACKGROUND Although the renin-angiotensin system contributes to the progression of heart failure (HF), it also supports the failing circulation. Patients with the most severe disease may not tolerate inhibition of this system. METHODS Consecutive inpatient admissions to the cardiomyopathy service of the Brigham and Womens Hospital between 2000 and 2002 were reviewed retrospectively for initial profiles, discharge medications, and documented reasons for discontinuation of angiotensin-converting enzyme inhibitors. Outcomes of death and transplantation were determined. RESULTS Of the 259 patients, 86 were not on an angiotensin-converting enzyme inhibitor at discharge. Circulatory-renal limitations of symptomatic hypotension, progressive renal dysfunction, or hyperkalemia were documented in 60 patients (23%); other adverse effects, including cough, in 24 patients; and absent reasons in 2 patients. Compared with patients on angiotensin-converting enzyme inhibitors, patients with CRLimit were older (60 vs. 55 years; p = 0.006), with longer history of HF (5 vs. 2 years; p = 0.009), lower systolic blood pressure (104 vs. 110 mm Hg; p = 0.05), lower sodium (135 vs. 138 mEql/l; p = 0.002), and higher initial creatinine (2.5 vs. 1.2 mg/dl; p = 0.0001). Mortality was 57% in patients with CRLimit and 22% in the patients on angiotensin-converting enzyme inhibitors during a median 8.5-month follow-up (p = 0.0001). CONCLUSIONS Development of CRLimit to angiotensin-converting enzyme inhibitor intolerance identifies patients with severe disease who are likely to die during the next year. New treatment strategies should be targeted to this population.

Rho Kinase Inhibition Improves Endothelial Function in Human Subjects With Coronary Artery Disease

Investigations from basic biology suggest that activation of the Rho/Rho kinase pathway reduces the bioavailability of nitric oxide (NO) and thereby promotes atherosclerosis and its clinical complications. Yet, little information is available about the relationship of the Rho/Rho kinase pathway to NO bioavailability in humans with atherosclerosis. Accordingly, we determined whether inhibition of Rho kinase augments NO bioavailability and improves endothelial function in human subjects with coronary artery disease (CAD). Thirteen CAD subjects and 16 age- and sex-matched healthy controls were randomly assigned to receive the Rho kinase inhibitor, fasudil, or placebo for 1 month each in a double-blind crossover trial. Flow-mediated, endothelium-dependent and nitroglycerin-induced, endothelium-independent vasodilation were assessed by brachial artery ultrasonography. Rho kinase activity was measured in peripheral leukocytes. Fasudil increased endothelium-dependent vasodilation in CAD subjects from 9.4±1.9% to 13.4±1.9% (P=0.001) but not in healthy controls (from 11.3±1.4% to 7.7±1.1%; P=0.07). Endothelium-independent vasodilation was not affected by fasudil in either CAD or healthy subjects. Fasudil reduced Rho kinase activity by 59±18% in CAD subjects (P=0.001) but not in healthy subjects (by 3±6%; P=0.60). The change in endothelium-dependent vasodilation achieved with fasudil relative to placebo was inversely proportional to Rho kinase inhibition (ie, greater Rho kinase inhibition was associated with larger improvement in endothelium-dependent vasodilation) (r=−0.48; P=0.01). These findings suggest that Rho/Rho kinase activation promotes endothelial dysfunction in humans with atherosclerosis. Inhibition of the Rho/Rho kinase pathway should provide a useful strategy to restore NO bioavailability in humans with atherosclerosis.

Value of Clinician Assessment of Hemodynamics in Advanced Heart Failure The ESCAPE Trial

Background—We determined whether estimated hemodynamics from history and physical examination (H&P) reflect invasive measurements and predict outcomes in advanced heart failure. The role of the H&P in medical decision making has declined in favor of diagnostic tests, perhaps because of the lack of evidence for utility. Methods and Results—We compared H&P estimates of filling pressures and cardiac index with invasive measurements in 194 patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. H&P estimates were compared with 6-month outcomes in 388 patients enrolled in ESCAPE. Measured right atrial pressure was <8 mmHg in 82% of patients with right atrial pressure estimated from jugular veins as <8 mmHg, and was >12 mmHg in 70% of patients when estimated as >12 mmHg. From the H&P, only estimated right atrial pressure ≥12 mmHg (odds ratio, 4.6; P<0.001) and orthopnea ≥2 pillows (odds ratio, 3.6; P<0.05) were associated with pulmonary capillary wedge pressure ≥30 mmHg. Estimated cardiac index did not reliably reflect the measured cardiac index (P=0.09), but “cold” versus “warm” profile was associated with lower median measured cardiac index (1.75 versus 2.0 L/(min·m2); P=0.004). In Cox regression analysis, discharge “cold” or “wet” profile conveyed a 50% increased risk of death or rehospitalization. Conclusions—In advanced heart failure, the presence of orthopnea and increased jugular venous pressure is useful to detect increased pulmonary capillary wedge pressure, and a global assessment of inadequate perfusion (“cold” profile) is useful to detect reduced cardiac index. Hemodynamic profiles estimated from the discharge H&P identify patients at increased risk of early events.

Statins inhibit Rho kinase activity in patients with atherosclerosis.

BACKGROUND In addition to inhibiting cholesterol synthesis, statins (HMG-CoA reductase inhibitors) decrease the formation of isoprenoid intermediates required for the activation of key signaling pathways, including Rho/Rho kinase (ROCK). In experimental settings, statins inhibit ROCK and reverse vascular dysfunctions in atherosclerosis, independent of cholesterol reduction. It is not known whether statins inhibit ROCK activity in humans with atherosclerosis. METHODS We investigated 35 patients with stable atherosclerosis in a randomized, double-blind study comparing treatment with high-dose (80mg/d) or low-dose (10mg/d) atorvastatin to placebo for 28 days. Blood samples for leukocyte ROCK activity, fasting lipids, and high-sensitivity C-reactive protein (hs-CRP) were obtained on days 0, 7, 14, and 28 after randomization and change over time with the two statin treatments relative to placebo was examined. RESULTS Atorvastatin 80mg/d reduced ROCK activity (p=0.002 vs. placebo). This decline was rapid and significant within 2 weeks of treatment. The inhibition of ROCK by atorvastatin (80mg/d) remained significant even after controlling for changes in low-density lipoprotein cholesterol (LDL-C) and triglycerides (p=0.01). Furthermore, there was no correlation between changes in ROCK activity and changes in LDL-C (r=0.2, p=0.25) or triglycerides (r=0.1, p=0.55). There was a modest correlation between ROCK inhibition and change in hs-CRP among patients randomized to atorvastatin 80mg/d (r=0.6, p=0.07). CONCLUSIONS These first-in-man findings demonstrate that high-dose atorvastatin rapidly inhibits the pro-atherogenic Rho/ROCK pathway, independent of cholesterol reduction. This inhibition may contribute to the clinical benefits of statins. Rho/ROCK may provide a useful therapeutic target in patients with atherosclerosis.

Patient Expectations From Implantable Defibrillators to Prevent Death in Heart Failure

BACKGROUND Indications for implantable cardioverter-defibrillators (ICDs) in heart failure (HF) are expanding and may include more than 1 million patients. This study examined patient expectations from ICDs for primary prevention of sudden death in HF. METHODS AND RESULTS Study participants (n = 105) had an EF <35% and symptomatic HF, without history of ventricular tachycardia/fibrillation or syncope. Subjects completed a written survey about perceived ICD benefits, survival expectations, and circumstances under which they might deactivate defibrillation. Mean age was 58, LVEF 21%, 40% were New York Heart Association Class III-IV, and 65% already had a primary prevention ICD. Most patients anticipated more than10 years survival despite symptomatic HF. Nearly 54% expected an ICD to save >or=50 lives per 100 during 5 years. ICD recipients expressed more confidence that the device would save their own lives compared with those without an ICD (P < .001). Despite understanding the ease of deactivation, 70% of ICD recipients indicated they would keep the ICD on even if dying of cancer, 55% even if having daily shocks, and none would inactivate defibrillation even if suffering constant dyspnea at rest. CONCLUSIONS HF patients anticipate long survival, overestimate survival benefits conferred by ICDs, and express reluctance to deactivate their devices even for end-stage disease.

Value of Clinician Assessment of Hemodynamics in Advanced Heart FailureCLINICAL PERSPECTIVE

Background—We determined whether estimated hemodynamics from history and physical examination (H&P) reflect invasive measurements and predict outcomes in advanced heart failure. The role of the H&P in medical decision making has declined in favor of diagnostic tests, perhaps because of the lack of evidence for utility. Methods and Results—We compared H&P estimates of filling pressures and cardiac index with invasive measurements in 194 patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. H&P estimates were compared with 6-month outcomes in 388 patients enrolled in ESCAPE. Measured right atrial pressure was <8 mmHg in 82% of patients with right atrial pressure estimated from jugular veins as <8 mmHg, and was >12 mmHg in 70% of patients when estimated as >12 mmHg. From the H&P, only estimated right atrial pressure ≥12 mmHg (odds ratio, 4.6; P<0.001) and orthopnea ≥2 pillows (odds ratio, 3.6; P<0.05) were associated with pulmonary capillary wedge pressure ≥30 mmHg. Estimated cardiac index did not reliably reflect the measured cardiac index (P=0.09), but “cold” versus “warm” profile was associated with lower median measured cardiac index (1.75 versus 2.0 L/(min·m2); P=0.004). In Cox regression analysis, discharge “cold” or “wet” profile conveyed a 50% increased risk of death or rehospitalization. Conclusions—In advanced heart failure, the presence of orthopnea and increased jugular venous pressure is useful to detect increased pulmonary capillary wedge pressure, and a global assessment of inadequate perfusion (“cold” profile) is useful to detect reduced cardiac index. Hemodynamic profiles estimated from the discharge H&P identify patients at increased risk of early events.

Cytokines as potential vaccine adjuvants

There is a compelling clinical need for adjuvants suitable for human use to enhance the efficacy of vaccines in the prevention of life-threatening infection. Candidate populations for such vaccine-adjuvant strategies include normal individuals at the two extremes of life, as well as the ever increasing population of immunocompromised individuals. In addition, adjuvants that would increase the efficiency of vaccination with such vaccines as those directed against hepatitis B andStreptococcus pneumoniae would have an even greater general use. Cytokines, as natural peptides intimately involved in the normal immune response, have great appeal as potential adjuvants. An increasing body of work utilizing recombinant versions of interleukin-1, -2, -3, -6, -12, gamma-interferon, tumor necrosis factor, and granulocyte-monocyte-colony stimulating factor has shown that cytokines do have vaccine adjuvant activity. However, in order to optimize adjuvant effect and minimize systemic toxicity, strategies in which the cytokine is fused to the antigen, or the cytokine is presented within liposomes or microspheres appear to be necessary to make this a practical approach suitable for human use. There is much promise in this approach, but there is much work to be accomplished in order to optimize the pharmacokinetics of cytokine administration as well as its side effect profile.

The Association Between High-Dose Diuretics and Clinical Stability in Ambulatory Chronic Heart Failure Patients

OBJECTIVE In chronic heart failure (HF), diuretic doses increase as the disease progresses, often after hospitalization for instability, and have been associated with worsening renal function and increased mortality. METHODS AND RESULTS A prospective observational analysis of 183 patients in an advanced HF clinic stratified at baseline by diuretic dose (low dose < or = 80 mg, high dose > 80 mg furosemide equivalent) was performed. All patients were followed for 1 year, and the primary outcome was a combined HF event of admission for HF, cardiac transplant, mechanical cardiac support, or death. Compared with patients taking low-dose diuretics (n = 113), patients taking high-dose diuretics (n = 70) had more markers of increased cardiovascular risk and were more likely to have a history of recent instability (33% vs 4.4% in low dose, P < .001). High doses of diuretics were a strong univariate predictor of subsequent HF events (hazard ratio 3.83, 95% confidence interval 1.82-8.54); however, after adjustment for clinical stability, diuretic dose no longer remained significant (hazard ratio 1.53, 95% confidence interval 0.58-4.03). CONCLUSION High-dose diuretics may be more of a marker than a cause of instability. A history of HF stability during the past 6 months is associated with an 80% lower risk of an HF event during the next year, independently of baseline diuretic dose.