Lynne E. Wagoner

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness

CONTEXT Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. OBJECTIVE To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. DESIGN, SETTING, AND PARTICIPANTS The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. MAIN OUTCOME MEASURES The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. RESULTS Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 micromol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. CONCLUSIONS Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.

The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure.

The beta2-adrenergic receptor (beta2AR), an important modulator of cardiac inotropy and chronotropy, has significant genetic heterogeneity in the population. Because dysfunctional betaARs play a role in the pathogenesis of the failing ventricle, we tested the hypothesis that beta2AR polymorphisms alter the outcome of congestive heart failure. 259 patients with NYHA functional class II-IV heart failure due to ischemic or dilated cardiomyopathy were genotyped and prospectively followed, with the endpoint defined as death or cardiac transplantation. The allele frequencies between this group and those of 212 healthy controls also were compared and did not differ between the groups. However, those with the Ile164 polymorphism displayed a striking difference in survival with a relative risk of death or cardiac transplant of 4.81 (P < 0.001) compared with those with the wild-type Thr at this position. Age, race, gender, functional class, etiology, ejection fraction, and medication use did not differ between these individuals and those with the wild-type beta2AR, and thus the beta2AR genotype at position 164 was the only clear distinguishing feature between the two groups. The 1-yr survival for Ile164 patients was 42% compared with 76% for patients harboring wild-type beta2AR. In contrast, polymorphisms at amino acid positions 16 (Arg or Gly) or 27 (Gln or Glu), which also alter receptor phenotype, did not appear to have an influence on the course of heart failure. Taken together with cell-based and transgenic mouse results, this study establishes a paradigm whereby genetic variants of key signaling elements can have pathophysiologic consequences within the context of a disease. Furthermore, patients with the Ile164 polymorphism and heart failure may be candidates for earlier aggressive intervention or cardiac transplantation.

β 1 -adrenergic receptor polymorphisms confer differential function and predisposition to heart failure

Catecholamines stimulate cardiac contractility through β1-adrenergic receptors (β1-ARs), which in humans are polymorphic at amino acid residue 389 (Arg/Gly). We used cardiac-targeted transgenesis in a mouse model to delineate mechanisms accounting for the association of Arg389 with human heart failure phenotypes. Hearts from young Arg389 mice had enhanced receptor function and contractility compared with Gly389 hearts. Older Arg389 mice displayed a phenotypic switch, with decreased β-agonist signaling to adenylyl cyclase and decreased cardiac contractility compared with Gly 389 hearts. Arg389 hearts had abnormal expression of fetal and hypertrophy genes and calcium-cycling proteins, decreased adenylyl cyclase and Gαs expression, and fibrosis with heart failure This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to β-receptor blockade were greater in Arg389 mice, and homozygosity for Arg389 was associated with improvement in ventricular function during carvedilol treatment in heart failure patients. Thus the human Arg389 variant predisposes to heart failure by instigating hyperactive signaling programs leading to depressed receptor coupling and ventricular dysfunction, and influences the therapeutic response to β-receptor blockade.

Validation and Potential Mechanisms of Red Cell Distribution Width as a Prognostic Marker in Heart Failure

BACKGROUND Adverse outcomes have recently been linked to elevated red cell distribution width (RDW) in heart failure. Our study sought to validate the prognostic value of RDW in heart failure and to explore the potential mechanisms underlying this association. METHODS AND RESULTS Data from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) registry, a prospective, multicenter cohort of ambulatory patients with heart failure supported multivariable modeling to assess relationships between RDW and outcomes. The association between RDW and iron metabolism, inflammation, and neurohormonal activation was studied in a separate cohort of heart failure patients from the United Investigators to Evaluate Heart Failure (UNITE-HF) Biomarker registry. RDW was independently predictive of outcome (for each 1% increase in RDW, hazard ratio for mortality 1.06, 95% CI 1.01-1.12; hazard ratio for hospitalization or mortality 1.06; 95% CI 1.02-1.10) after adjustment for other covariates. Increasing RDW correlated with decreasing hemoglobin, increasing interleukin-6, and impaired iron mobilization. CONCLUSIONS Our results confirm previous observations that RDW is a strong, independent predictor of adverse outcome in chronic heart failure and suggest elevated RDW may indicate inflammatory stress and impaired iron mobilization. These findings encourage further research into the relationship between heart failure and the hematologic system.

Polymorphisms of the β2-Adrenergic Receptor Determine Exercise Capacity in Patients With Heart Failure

Abstract—The β2-adrenergic receptor (β2AR) exists in multiple polymorphic forms with different characteristics. Their relevance to heart failure (HF) physiology is unknown. Cardiopulmonary exercise testing was performed on 232 compensated HF patients with a defined β2AR genotype. Patients with the uncommon Ile164 polymorphism had a lower peak Vo2 (15.0±0.9 mL · kg−1 · min−1) than did patients with Thr164 (17.9±0.9 mL · kg−1 · min−1, P<0.0001). The percentage achieved of predicted peak Vo2 was also lower in patients with Ile164 (62.3±4.5% versus 71.5±5.1%, P=0.045). The relative risk of a patient having a Vo2 ≤14 mL · kg−1 · min−1 who had Ile164 was 8.0 (P=0.009). Catheterization-based invasive exercise testing revealed depressed changes in the exercise-induced cardiac index, systemic vascular resistance, stroke volume, and Vo2 in patients with Ile164. The polymorphisms at position 16 also impacted exercise capacity: peak Vo2 for Arg16 versus Gly16 was 17.0±0.8 versus 15.6±0.5 mL · kg−1 · min−1, respe...

Alterations in Ca2+ cycling proteins and Gαq signaling after left ventricular assist device support in failing human hearts

OBJECTIVE Left ventricular assist device support mechanically unloads the failing ventricle with resultant improvement in cardiac geometry and function in patients with end-stage heart failure. Activation of the G alpha q signaling pathway, including protein kinase C, appears to be involved in the progression of heart failure. Similarly down-regulation of Ca2+ cycling proteins may contribute to contractile depression in this clinical syndrome. Thus we examined whether protein kinase C activation and decreased Ca2+ cycling protein levels could be reversed by left ventricular assist device support. METHODS Left ventricular myocardial specimens were obtained from seven patients during placement of left ventricular assist device and heart transplantation. We examined changes in protein levels of G alpha q, phospholipase C beta 1, regulators of G protein signaling (RGS), sarcoplasmic reticulum Ca2+ ATPase, phospholamban and translocation of protein kinase C isoforms (alpha, beta 1, and beta 2). RESULTS The paired pre- and post-left ventricular assist device samples revealed that RGS2, a selective inhibitor of G alpha q, was decreased (P < 0.01), while the status of G alpha q, phospholipase C beta 1, RGS3 and RGS4 were unchanged after left ventricular assist device implantation. Translocation of protein kinase C isoforms remained unchanged. Left ventricular assist device support increased sarcoplasmic reticulum Ca2+ ATPase protein level (P < 0.01), while phospholamban abundance was unchanged. CONCLUSIONS We conclude that altered protein expression and stoichiometry of the major cardiomyocyte Ca2+ cycling proteins rather than reduced phospholipase C beta 1 activation may contribute to improved mechanical function produced by left ventricular assist device support in human heart failure.

Impact of cardiac resynchronization therapy on exercise performance, functional capacity, and quality of life in systolic heart failure with QRS prolongation: COMPANION trial sub-study.

BACKGROUND A total of 405 participants in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial were prospectively enrolled in an exercise sub-study designed to study the influence of cardiac resynchronization therapy (CRT) on measures of exercise capacity, functional capacity, and quality of life (QOL). METHODS AND RESULTS Substudy eligibility included New York Heart Association (NYHA) functional Class III or IV heart failure, left ventricular ejection fraction < or =0.35, QRS interval of > or =120 ms, normal sinus rhythm, a heart failure hospitalization (or equivalent) within 1 year, a peak VO2 < or =22 mL x kg x min, the ability to walk 150 to 425 meters in 6 minutes, forced expiratory volume in 1 second/forced vital capacity > or =50%, and no clinical indication for a pacemaker or implantable cardioverter-defibrillator. Patients were randomized in a 1:4 ratio to optimal medical therapy (OPT) or to OPT plus CRT. Cardiopulmonary exercise testing (peak VO2 and 6-minute walk distance [6MWD]) and assessment of NYHA functional class and QOL were assessed at baseline and at 3 and 6 months of assigned therapy. There was no significant improvement in peak VO2 at 6 months in the CRT group compared with the OPT group (+0.63 mL x kg x min) by unadjusted analysis (P = .05) or by analyses adjusted for missing data. Thus the primary end point of the study was not met. There was significantly greater improvement in the 6MWD in the CRT group compared with the OPT group at both 3 and 6 months by both statistical methods (P < or = .045). Likewise, a greater proportion of CRT patients improved by 1 or more NYHA functional classes (P < .01) at 3 months and had better QOL scores (P < .01) at 3 and 6 months compared with the OPT patients. Baseline peak VO2 predicted clinical events (time to death, time to death or first hospitalization, or time to death and first heart failure hospitalization: P < .05) in CRT participants. CONCLUSION CRT patients with moderate to advanced symptoms of systolic heart failure and prolonged QRS intervals benefit from the addition of CRT to OPT in terms of exercise capacity, functional status, and QOL. CRT should be considered standard therapy in this select group of heart failure patients.

S3 Detection as a Diagnostic and Prognostic Aid in Emergency Department Patients With Acute Dyspnea

STUDY OBJECTIVE Dyspneic emergency department (ED) patients present a diagnostic dilemma. Recent technologic advances have made it possible to capture information about pathologic heart sounds at ECG recording. This study evaluates the effect of an S3 captured by acoustic cardiography on emergency physician diagnostic accuracy and confidence in their diagnosis of acute decompensated heart failure, as well as the patients prognosis. METHODS Dyspneic ED patients older than 40 years who were not dialysis dependent were prospectively enrolled in this multinational study. Treating emergency physicians, initially blinded to all laboratory and acoustic cardiography results, estimated acute decompensated heart failure probability from 0% to 100% on a visual analog scale. The emergency physician repeated the visual analog scale after acoustic cardiography results were provided. Physician diagnostic accuracy for and confidence in acute decompensated heart failure were evaluated against a reference standard diagnosis, as determined by 2 independent cardiologists blinded to acoustic cardiography. Patients were followed through 90 days to determine the relationship of the S3 to adverse events. RESULTS Nine hundred ninety-five patients with acoustic cardiography results were enrolled from March to October 2006 at 7 US and 2 international sites. Median age was 63 years, 55% were men, and 44% were white. The reference diagnosis was acute decompensated heart failure in 41.5%. After initial history and physical examination, the treating physicians initial sensitivity, specificity, and accuracy for acute decompensated heart failure as a possible diagnosis were 89.0% (95% confidence interval [CI] 85.5% to 91.8%), 58.2% (95% CI 54.0% to 62.2%), and 71.0% (95% CI 68.4% to 73.8%), respectively. Acoustic cardiography had an accuracy of 68% (95% CI 65.4% to 71.3%), sensitivity of 40.2% (95% CI 35.5% to 45.1%), and specificity of 88.5% (95% CI 85.5% to 90.9%). Emergency physician confidence and diagnostic accuracy were influenced by adding information about the presence or absence of S3. In a multivariable model, the S3 added no independent prognostic information for 30-day (odds ratio 1.20; 95% CI 0.67 to 2.14) or 90-day events (odds ratio 1.22; 95% CI 0.78 to 1.90). CONCLUSION In patients presenting with acute dyspnea, the acoustic cardiography S3 was specific for acute decompensated heart failure and affected physician confidence but did not improve diagnostic accuracy for acute decompensated heart failure, largely because of its low sensitivity. Further, the acoustic cardiography S3 provided no significant independent prognostic information.

Sympathetic nervous system function as measured by I-123 metaiodobenzylguanidine predicts transplant-free survival in heart failure patients with idiopathic dilated cardiomyopathy ☆

BACKGROUND Heightened activity of the sympathetic nervous system in heart failure patients is a major contributor to disease progression and death. I-123 metaiodobenzylguanidine (MIBG) provides an accurate, noninvasive method to assess cardiac sympathetic nerve activity. METHODS Thirty-seven patients with New York Heart Association class II, III, or IV heart failure underwent baseline measurement of I-123 MIBG heart-to-mediastinum ratios, maximum oxygen consumption, radionuclide left ventricular ejection fraction, and plasma norepinephrine levels. Patients were followed 48.8+/-8.6 months to endpoints of cardiac death or transplantation. The heart-to-mediastinum ratio of I-123 MIBG activity measured 15 minutes after injection was the only independent predictor of transplant-free survival (P<.0001). I-123 MIBG imaging at 15 minutes identified patients with subsequent cardiac transplantation or death with a sensitivity of 92% and specificity of 72%, whereas the corresponding values for maximum oxygen consumption were 75% and 56%. By Kaplan-Meier survival analysis, the time to a cardiac endpoint was significantly shorter in patients with a 15-minute I-123 MIBG heart-to-mediastinum ratio below the group mean ratio of 1.536, compared with patients with a preserved I-123 MIBG ratio. Maximum oxygen consumption was not predictive of time to cardiac transplant or death. CONCLUSIONS In this study of patients with congestive heart failure resulting from dilated cardiomyopathy, a 15-minute heart-to-mediastinum ratio of I-123 MIBG activity provided more accurate prediction of cardiac transplantation or death than other standard clinical tests.

The cellular pathophysiology of progression to heart failure

Congestive heart failure is the final common pathway of diverse etiologies that result in impaired systolic and diastolic function, deleterious activation of neurohumoral pathways, and high morbidity and mortality. Many studies published in 1995 significantly added to our understanding of the pathophysiologies of heart failure at the cellular level. Because a common accompaniment to all forms of low output heart failure are hypertrophy and contractile dysfunction of the cardiomyocyte, applications of the techniques of molecular and cell biology to animal models that demonstrate this phenomenon are providing new insights into the mechanisms responsible for this important clinical problem. In the past year, critical information was derived from animal models that mimic human cardiac hypertrophy and failure. Likewise, genetically engineered mice in which a gene product of interest is overexpressed or eliminated provided critical information, in particular regarding the roles of phospholamban and beta-adrenergic receptor kinase 1 in mediating the contractile responses of the heart to beta-adrenergic stimulation. Furthermore, study of human myocardial tissue from patients with end-stage cardiomyopathy continues to provide insight into the diverse etiologies of heart failure. The recent applications of the techniques of molecular and cell biology to this clinical problem are likely to accelerate our understanding of the complex mechanisms responsible for this syndrome.