Gary S. Francis

Importance of Venous Congestion for Worsening of Renal Function in Advanced Decompensated Heart Failure

OBJECTIVES To determine whether venous congestion, rather than impairment of cardiac output, is primarily associated with the development of worsening renal function (WRF) in patients with advanced decompensated heart failure (ADHF). BACKGROUND Reduced cardiac output is traditionally believed to be the main determinant of WRF in patients with ADHF. METHODS A total of 145 consecutive patients admitted with ADHF treated with intensive medical therapy guided by pulmonary artery catheter were studied. We defined WRF as an increase of serum creatinine >/=0.3 mg/dl during hospitalization. RESULTS In the study cohort (age 57 +/- 14 years, cardiac index 1.9 +/- 0.6 l/min/m(2), left ventricular ejection fraction 20 +/- 8%, serum creatinine 1.7 +/- 0.9 mg/dl), 58 patients (40%) developed WRF. Patients who developed WRF had a greater central venous pressure (CVP) on admission (18 +/- 7 mm Hg vs. 12 +/- 6 mm Hg, p < 0.001) and after intensive medical therapy (11 +/- 8 mm Hg vs. 8 +/- 5 mm Hg, p = 0.04). The development of WRF occurred less frequently in patients who achieved a CVP <8 mm Hg (p = 0.01). Furthermore, the ability of CVP to stratify risk for development of WRF was apparent across the spectrum of systemic blood pressure, pulmonary capillary wedge pressure, cardiac index, and estimated glomerular filtration rates. CONCLUSIONS Venous congestion is the most important hemodynamic factor driving WRF in decompensated patients with advanced heart failure.

Cardiac troponins in renal insufficiency: review and clinical implications.

Patients with renal insufficiency may have increased serum troponins even in the absence of clinically suspected acute myocardial ischemia. While cardiovascular disease is the most common cause of death in patients with renal failure, we are just beginning to understand the clinical meaning of serum troponin elevations. Serum troponin T is increased more frequently than troponin I in patients with renal failure, leading clinicians to question its specificity for the diagnosis of myocardial infarction. Many large-scale trials demonstrating the utility of serum troponins in predicting adverse events and in guiding therapy and intervention in acute coronary syndromes have excluded patients with renal failure. Despite persistent uncertainty about the mechanism of elevated serum troponins in patients with reduced renal function, data from smaller groups of renal failure patients have suggested that troponin elevations are associated with added risk, including an increase in mortality. It is possible that increases in serum troponin from baseline in patients with renal insufficiency admitted to hospital with acute coronary syndrome may signify myocardial necrosis. Further studies are needed to clarify this hypothesis.

Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function?

OBJECTIVES This study sought to determine whether changes in intra-abdominal pressure (IAP) with aggressive diuretic or vasodilator therapy are associated with improvement in renal function in acute decompensated heart failure (ADHF). BACKGROUND Elevated IAP (>or=8 mm Hg) is associated with intra-abdominal organ dysfunction. There is potential for ascites and visceral edema causing elevated IAP in patients with ADHF. METHODS Forty consecutive patients admitted to a specialized heart failure intensive care unit for management of ADHF with intensive medical therapy were studied. The IAP was measured using a simple transvesical technique at time of admission and before removal of the pulmonary artery catheter. RESULTS In our study cohort (mean age 59 +/- 13 years, mean left ventricular ejection fraction 19 +/- 9%, baseline serum creatinine 2.0 +/- 0.9 mg/dl), the mean baseline IAP was 8 +/- 4 mm Hg, with 24 (60%) patients having elevated IAP. Elevated IAP was associated with worse renal function (p = 0.009). Intensive medical therapy resulted in improvement in both hemodynamic measurements and IAP. A strong correlation (r = 0.77, p < 0.001) was observed between reduction in IAP and improved renal function in patients with baseline elevated IAP. However, changes in IAP or renal function did not correlate with changes in any hemodynamic variable. CONCLUSIONS Elevated IAP is prevalent in patients with ADHF and is associated with impaired renal function. In the setting of intensive medical therapy for ADHF, changes in IAP were better correlated with changes in renal function than any hemodynamic variable.

Ventilatory and Heart Rate Responses to Exercise: Better Predictors of Heart Failure Mortality Than Peak Oxygen Consumption

BACKGROUND An abnormally low chronotropic response and an abnormally high ventilatory response (V(E)/V(CO2)) to exercise are common in patients with severe heart failure, but their relative prognostic impacts have not been well explored. METHODS AND RESULTS Consecutive patients with heart failure referred for metabolic stress testing who were not taking beta-blockers or intravenous inotropes (n=470) were followed for 1.5 years. The chronotropic index was calculated while peak V(O2) and V(E)/V(CO2) were directly measured. Chronotropic index and peak V(O2) were considered abnormal if in the lowest 25th percentiles of the patient cohort, whereas V(E)/V(CO2) was considered abnormal if in the highest 25th percentile. For comparative purposes, a group of 17 healthy controls underwent metabolic testing as well. Compared with controls, heart failure patients had markedly abnormal ventilatory and chronotropic responses to exercise. In the heart failure cohort, there were 71 deaths. In univariate analyses, predictors of death included high V(E)/V(CO2) low chronotropic index, low V(O2), low resting systolic blood pressure, and older age. Nonparametric Kaplan-Meier plots demonstrated that by dividing the population according to peak V(E)/V(CO2) and peak V(O2), it is possible to identify low, intermediate, and very high risk groups. In multivariate analyses, the only independent predictors of death were high V(E)/V(CO2) (adjusted relative risk [RR] 3.20, 95% CI 1.95 to 5.26, P<0.0001) and low chronotropic index (adjusted RR 1.94, 95% CI 1.18 to 3.19, P=0.0009). CONCLUSIONS The ventilatory and chronotropic responses to exercise are powerful and independent predictors of heart failure mortality.

Plasma B-Type Natriuretic Peptide Levels in Ambulatory Patients With Established Chronic Symptomatic Systolic Heart Failure

Background—The diagnostic and prognostic values of plasma B-type natriuretic peptide (BNP) testing are established. However, the range of plasma BNP levels present in the setting of chronic, stable systolic heart failure (HF) is unclear. Methods and Results—We followed up 558 consecutive ambulatory patients with chronic, stable systolic HF (left ventricular ejection fraction <50%) treated at a specialized outpatient HF clinic between November 2001 and February 2003. Retrospective chart review was performed to determine clinical and functional data at the time of BNP testing (Biosite Triage). The clinical characteristics of patients with plasma BNP levels <100 pg/mL and those with ≥100 pg/mL were compared. In our cohort, 60 patients were considered asymptomatic, and their plasma BNP levels ranged from 5 to 572 pg/mL (median, 147 pg/mL). Of the remaining 498 symptomatic (NYHA functional class II–III) patients, 106 (21.3%) had plasma BNP levels in the “normal” diagnostic range (<100 pg/mL). Patients in this “normal BNP” subgroup were more likely to be younger, to be female, to have nonischemic pathogenesis, and to have better-preserved cardiac and renal function and less likely to have atrial fibrillation. Conclusions—In the ambulatory care setting, both symptomatic and asymptomatic patients with chronic, stable systolic HF may present with a wide range of plasma BNP levels. In a subset of symptomatic patients (up to 21% in our cohort), plasma BNP levels are below what would be considered “diagnostic” (<100 pg/mL).

Decreased SLIM1 Expression and Increased Gelsolin Expression in Failing Human Hearts Measured by High-Density Oligonucleotide Arrays

Background—Failing human hearts are characterized by altered cytoskeletal and myofibrillar organization, impaired signal transduction, abnormal protein turnover, and impaired energy metabolism. Thus, expression of multiple classes of genes is likely to be altered in human heart failure. Methods and Results—We used high-density oligonucleotide arrays to explore changes in expression of ≈7000 genes in 2 nonfailing and 2 failing human hearts with diagnoses of end-stage ischemic and dilated cardiomyopathy, respectively. We report altered expression of (1) cytoskeletal and myofibrillar genes (striated muscle LIM protein-1 [SLIM1], myomesin, nonsarcomeric myosin regulatory light chain-2 [MLC2], and &bgr;-actin); (2) genes responsible for degradation and disassembly of myocardial proteins (&agr;1-antichymotrypsin, ubiquitin, and gelsolin); (3) genes involved in metabolism (ATP synthase &agr;-subunit, succinate dehydrogenase flavoprotein [SDH Fp] subunit, aldose reductase, and TIM17 preprotein translocase); (4) genes responsible for protein synthesis (elongation factor-2 [EF-2], eukaryotic initiation factor-4AII, and transcription factor homologue-HBZ17); and (5) genes encoding stress proteins (&agr;B-crystallin and &mgr;-crystallin). In 5 additional failing hearts and 4 additional nonfailing controls, we then compared expression of proteins encoded by the differentially expressed genes, &agr;B-crystallin, SLIM1, gelsolin, &agr;1-antichymotrypsin, and ubiquitin. In each case, changes in protein expression were consistent with changes in transcript measured by microarray analysis. Gelsolin protein expression was also increased in cardiomyopathic hearts from tropomodulin-overexpressing (TOT) mice and rac1-expressing (racET) mice. Conclusions—Altered expression of the genes identified in this study may contribute to development of the heart failure phenotype and/or represent compensatory mechanisms to sustain cardiac function in failing human hearts.

Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction - The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial

Background—A prior diagnosis of diabetes mellitus is associated with adverse outcomes after acute myocardial infarction (MI), but the risk associated with a new diagnosis of diabetes in this setting has not been well defined. Methods and Results—We assessed the risk of death and major cardiovascular events associated with previously known and newly diagnosed diabetes by studying 14 703 patients with acute MI enrolled in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Patients were grouped by diabetic status: previously known diabetes (insulin use or diagnosis of diabetes before MI, n=3400, 23%); newly diagnosed diabetes (use of diabetic therapy or diabetes diagnosed at randomization [median 4.9 d after infarction], but no known diabetes at presentation, n=580, 4%); or no diabetes (n=10 719). Patients with newly diagnosed diabetes were younger and had fewer comorbid conditions than did patients with previously known diabetes. At 1 year after enrollment, patients with previously known and newly diagnosed diabetes had similarly increased adjusted risks of mortality (hazard ratio [HR] 1.43; 95% confidence interval [CI], 1.29 to 1.59 and HR, 1.50; 95% CI, 1.21 to 1.85, respectively) and cardiovascular events (HR, 1.37; 95% CI, 1.27 to 1.48 and HR, 1.34; 95% CI, 1.14 to 1.56). Conclusions—Diabetes mellitus, whether newly diagnosed or previously known, is associated with poorer long-term outcomes after MI in high-risk patients. The poor prognosis of patients with newly diagnosed diabetes, despite having baseline characteristics similar to those of patients without diabetes, supports the idea that metabolic abnormalities contribute to their adverse outcomes.

The prognostic value of estimated creatinine clearance alongside functional capacity in ambulatory patients with chronic congestive heart failure

OBJECTIVES The goal of this study was to determine the prognostic significance of estimated creatinine clearance (CrCl) in relation to 6-min walk distance in ambulatory patients with congestive heart failure (HF). BACKGROUND Although measurement of renal function is integral to the management of chronic congestive HF, its prognostic implications are not well described and have not been formally evaluated relative to measures of functional capacity. METHODS We analyzed outcomes of the 585 participants of the 6-min walk substudy of the Digitalis Investigation Group (DIG) trial. The CrCl was estimated using the Cockcroft-Gault equation. Predictors of all-cause mortality were identified using semiparametric Cox proportional hazards regression and completely parametric hazard analyses. RESULTS Most subjects (85%) were New York Heart Association functional class II and III. Mean age was 65 (+/-12) years and mean ejection fraction (EF) 35% (+/-13%). There were 153 (26%) deaths during a median of 2.6 years of follow-up. Mortality by increasing quartiles of estimated CrCl was 37% (18 to 48 ml/min), 29% (47 to 64 ml/min), 18% (64 to 86 ml/min), and 21% (86 to 194 ml/min) with corresponding hazard ratios (HRs) relative to the top quartile of 2.1 (95% confidence interval [CI], 1.4 to 3.3), 1.6 (95% CI, 1.0 to 2.5), and 0.9 (95% CI, 0.5 to 1.5), respectively. In Cox regression analyses, independent predictors of mortality were estimated CrCl (adjusted HR [quartile 1:quartile 4] 1.5; 95% CI, 1.1 to 2.1), 6-min walk distance < or =262 m [adjusted HR, 1.63; 95% CI, 1.12 to 2.27]), EF, recent hospitalization for worsening HF, and need for diuretic treatment. Parametric (hazard) analysis confirmed consistent effects of estimated CrCl on mortality in several subgroups including that of patients with EF >45%. CONCLUSION In ambulatory patients with congestive HF, estimated CrCl predicts all-cause mortality independently of established prognostic variables.

Ambulatory Ventricular Arrhythmias in Patients With Heart Failure Do Not Specifically Predict an Increased Risk of Sudden Death

BACKGROUND Ventricular arrhythmias are a frequent finding in congestive heart failure (CHF) patients and a cause of concern for physicians caring for them. Previous studies have reached conflicting conclusions regarding the importance of ventricular arrhythmias as predictors of sudden death in patients with CHF. This study examined the independent predictive value of ventricular arrhythmias for sudden death and all-cause mortality in PROMISE (Prospective Randomized Milrinone Survival Evaluation). METHODS AND RESULTS Ventricular arrhythmias were analyzed and quantified by use of prespecified criteria on baseline ambulatory ECGs from 1080 patients with New York Heart Association (NYHA) class III/IV symptoms and a left ventricular ejection fraction </=35% enrolled in PROMISE. The relationship of ventricular arrhythmias and other clinical parameters to overall mortality and sudden death classified by an independent, blinded mortality committee was determined. There were 290 deaths, of which 139 were classified as sudden. Of the several measures of ventricular ectopy that were univariate predictors, the frequency of nonsustained ventricular tachycardia (NSVT) was the most powerful predictor and remained a significant independent predictor when included with other clinical variables in multivariate models of both sudden death mortality and non-sudden death mortality. However, multiple logistic analysis with models including the clinical variables with and without the NSVT variable demonstrated that the frequency of NSVT did not add significant information beyond the clinical variables. CONCLUSIONS This study demonstrates that ventricular arrhythmias do not specifically predict sudden death in patients with moderate-to-severe heart failure. Thus, the finding of asymptomatic NSVT on ambulatory ECG does not identify specific candidates for antiarrhythmic or device therapy.

Sodium Nitroprusside for Advanced Low-Output Heart Failure

OBJECTIVES This study was designed to examine the safety and efficacy of sodium nitroprusside (SNP) for patients with acute decompensated heart failure (ADHF) and low-output states. BACKGROUND Inotropic therapy has been predominantly used in the management of patients with ADHF presenting with low cardiac output. METHODS We reviewed all consecutive patients with ADHF admitted between 2000 and 2005 with a cardiac index < or =2 l/min/m(2) for intensive medical therapy including vasoactive drugs. Administration of SNP was chosen by the attending clinician, nonrandomized, and titrated to a target mean arterial pressure of 65 to 70 mm Hg. RESULTS Compared with control patients (n = 97), cases treated with SNP (n = 78) had significantly higher mean central venous pressure (15 vs. 13 mm Hg; p = 0.001), pulmonary capillary wedge pressure (29 vs. 24 mm Hg; p = 0.001), but similar demographics, medications, and renal function at baseline. Use of SNP was not associated with higher rates of inotropic support or worsening renal function during hospitalization. Patients treated with SNP achieved greater improvement in hemodynamic measurements during hospitalization, had higher rates of oral vasodilator prescription at discharge, and had lower rates of all-cause mortality (29% vs. 44%; odds ratio: 0.48; p = 0.005; 95% confidence interval: 0.29 to 0.80) without increase in rehospitalization rates (58% vs. 56%; p = NS). CONCLUSIONS In patients with advanced, low-output heart failure, vasodilator therapy used in conjunction with optimal current medical therapy during hospitalization might be associated with favorable long-term clinical outcomes irrespective of inotropic support or renal dysfunction and remains an excellent therapeutic choice in hospitalized ADHF patients.