Ron M. Oren

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.

Effects of heart failure on baroreflex control of sympathetic neural activity

Baroreflex control of heart rate, vascular resistance and norepinephrine is impaired in patients with heart failure, but recent animal studies demonstrate preserved baroreflex control of sympathetic nerve activity in this disorder. Studies were therefore performed to compare baroreflex control of efferent sympathetic nerve activity to muscle in 10 normal subjects (age mean +/- SEM 21 +/- 1 years) and in 11 patients with moderate to severe heart failure (age 48 +/- 5 years, New York Heart Association class II to IV, left ventricular ejection fraction 19 +/- 2%, pulmonary capillary wedge pressure 27 +/- 2 mm Hg, cardiac index 2.04 +/- 0.22 liters/min/m2). Baroreflex activation was produced by intravenous infusion of phenylephrine (0.5 to 2.0 micrograms/kg/min) and deactivation by infusion of nitroprusside (0.4 to 2.5 micrograms/kg/min). During phenylephrine infusion, comparable increases in mean arterial pressure were produced in normal subjects (89 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01) and in patients with heart failure (90 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01). The patients with heart failure exhibited significantly attenuated (p less than 0.01 for normal vs heart failure) decreases in heart rate (93 +/- 5 to 90 +/- 6 beats/min, p = not significant [NS]) compared with normal subjects (67 +/- 3 to 58 +/- 4 beats/min, p less than 0.01) and tended to demonstrate attenuated sympathoinhibitory responses to this pressor stimulus. More strikingly, patients with heart failure demonstrated significant impairment of baroreflex responses during nitroprusside-induced baroreceptor deactivation. In normal subjects, nitroprusside produced a decrease in mean arterial (90 +/- 2 to 80 +/- 3 mm Hg, p less than 0.001) and right atrial (4 +/- 1 to 2 +/- 1 mm Hg, p less than 0.01) pressures with a resultant reflex increase in heart rate (68 +/- 3 to 81 +/- 4 beats/min, p less than 0.001) and muscle sympathetic nerve activity (326 +/- 74 to 746 +/- 147 U/min, p less than 0.01). In patients with heart failure (n = 10), nitroprusside produced comparable (p = NS for normal vs heart failure) decreases in mean arterial (89 +/- 2 to 77 +/- 2 mm Hg, p less than 0.001) and right atrial (6 +/- 1 to 1 +/- 1 mm Hg, p less than 0.001) pressures, but did not significantly alter heart rate (91 +/- 6 to 97 +/- 4 beats/min, p = NS) or sympathetic nerve activity (936 +/- 155 to 1179 +/- 275 U/min, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: Results from efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) program

BACKGROUND The postdischarge rehospitalization and death rates are high in patients with acute heart failure (HF) syndromes despite optimization of standard therapy for chronic HF. To the best of our knowledge, there has been no systematic analysis of the causes of death and rehospitalization in this patient population. METHODS This was a prespecified analysis of adjudicated cause-specific all-cause mortality and cardiovascular (CV) hospitalization in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, a randomized, double-blind, placebo-controlled study in patients hospitalized with worsening HF and left ventricular ejection fraction < or =40% comparing tolvaptan, an oral vasopressin receptor antagonist to placebo, in addition to standard care. RESULTS Of the 4,133 randomized, there were 5,239 rehospitalizations and 1,080 deaths during a median of 9.9 months. Of all deaths, 41.0% were due to HF, 26.0% due to sudden cardiac death (SCD), 2.6% due to acute myocardial infarction (MI), 2.2% due to stroke, and 13.2% due to non-CV causes. Of all hospitalizations, 39.2% were non-CV, whereas 46.3% were for HF, and a minority of hospitalizations was due to stroke, MI, arrhythmia, or other CV causes. CONCLUSIONS Despite close follow-up and evidence-based therapy within a clinical trial, rehospitalization and death remain high. Although most deaths were from HF, one quarter of patients had SCD. In addition, there were almost as many non-CV hospitalizations as HF hospitalizations. Knowledge of the causes of death and rehospitalization may be essential for proper management and early initiation of therapy.

Effect of Cheyne-Stokes Respiration on Muscle Sympathetic Nerve Activity in Severe Congestive Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy☆

Severe congestive heart failure (CHF) is associated with Cheyne-Stokes (C-S) respiration, which may be an index of poorer prognosis. The mechanisms linking C-S respiration to poorer functional status and prognosis in patients with CHF are unknown. We tested the hypothesis that C-S respiration increases muscle sympathetic nerve activity (MSNA) in 9 patients with CHF. Oxygen saturation was 96 +/- 1% during normal breathing and 91 +/- 1% after the apneic episodes (p < 0.05). Mean blood pressure was 79 +/- 8 mm Hg during normal breathing and 85 +/- 8 mm Hg during C-S respiration (p = 0.001). C-S respiration increased MSNA burst frequency (from 45 +/- 5 bursts/min during normal breathing to 50 +/- 5 bursts/min during C-S respiration; p < 0.05) and total integrated nerve activity (to 117 +/- 7%; p < 0.05). We also studied an additional 5 patients in whom C-S breathing was constant, without any periods of spontaneous normal breathing. In these patients, MSNA was higher (65 +/- 5 bursts/min) than MSNA in patients in whom C-S breathing was only intermittent (45 +/- 5 bursts/min; p < 0.05). In all 14 patients, the effects of different phases of C-S respiration were examined. MSNA was highest during the second half of each apnea (increasing to 152 +/- 14%; p < 0.01) and blood pressure was highest during mild hyperventilation occurring after termination of apnea (p < 0.0001). We conclude that C-S respiration decreases oxygen saturation, increases MSNA, and induces transient elevations in blood pressure in patients with CHF.

Evidence for a Central Origin of the Low-Frequency Oscillation in RR-Interval Variability

BACKGROUND Short-term variability of RR interval and blood pressure occurs predominantly at low frequency (LF; approximately 0.1 Hz) and high frequency (approximately 0.25 Hz). The arterial baroreflex is thought to be the predominant determinant of the LF component of RR variability. Patients with severe congestive heart failure (CHF) have an attenuated or absent LF oscillation in RR variability. The left ventricular assist device (LVAD) offers a unique possibility for analysis of spectral oscillations in RR interval independent of any effects of blood pressure that influence these oscillations via the baroreflex. METHODS AND RESULTS We performed spectral analysis of RR, blood pressure, and respiration in 2 patients with CHF before and after LVAD implantation. LF components of the RR-interval and blood pressure variability were absent in both CHF patients before LVAD implantation. After LVAD implantation, spectral analysis of the RR interval showed restoration of a clear and predominant LF oscillation in the native hearts of both patients, with no such oscillation evident in the blood pressure profile. CONCLUSIONS During total circulatory support with the LVAD, the LF oscillation in RR interval of the native heart, absent in CHF, is restored. This LF oscillation in RR interval occurs in the absence of LF oscillations in blood pressure and thus is unlikely to be explained by baroreflex mechanisms. Hence, the absence of LF oscillation in the RR interval in CHF is functional and is reversible by LVAD circulation. The presence of a predominant LF oscillation in RR interval independent of any oscillation in blood pressure suggests that the LF oscillation is a fundamental property of central autonomic outflow.

A comparative analysis of the results from 4 trials of β-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS

BACKGROUND Recent large randomized, controlled trials (BEST [Beta-blocker Evaluation of Survival Trial], CIBIS-II [Cardiac Insufficiency Bisoprolol Trial II], COPERNICUS [Carvedilol Prospective Randomized Cumulative Survival Study], and MERIT-HF [Metoprolol Randomized Intervention Trial in Congestive Heart Failure]) have addressed the usefulness of beta-blockade in the treatment of advanced heart failure. CIBIS-II, COPERNICUS, and MERIT-HF have shown that beta-blocker treatment with bisoprolol, carvedilol, and metoprolol XL, respectively, reduce mortality in advanced heart failure patients, whereas BEST found a statistically nonsignificant trend toward reduced mortality with bucindolol. We conducted a post hoc analysis to determine whether the response to beta-blockade in BEST could be related to differences in the clinical and demographic characteristics of the study populations. We generated a sample from BEST to resemble the patient cohorts studied in CIBIS-II and MERIT-HF to find out whether the response to beta-blocker therapy was similar to that reported in the other trials. These findings are further compared with COPERNICUS, which entered patients with more severe heart failure. METHODS To achieve conformity with the entry criteria for CIBIS-II and MERIT-HF, the BEST study population was adjusted to exclude patients with systolic blood pressure <100 mm Hg, heart rate <60 bpm, and age >80 years (exclusion criteria employed in those trials). The BEST comparison subgroup (BCG) was further modified to more closely reflect the racial demographics reported for patients enrolled in CIBIS-II and MERIT-HF. The association of beta-blocker therapy with overall survival and survival free of cardiac death, sudden cardiac death, and progressive pump failure in the BCG was assessed. RESULTS In the BCG subgroup, bucindolol treatment was associated with significantly lower risk of death from all causes (hazard ratio (HR)=0.77 [95% CI=0.65, 0.92]), cardiovascular death (HR=0.71 [0.58, 0.86]), sudden death (HR=0.77 [0.59, 0.999]), and pump failure death (HR=0.64 [0.45, 0.91]). CONCLUSIONS Although not excluding the possibility of differences resulting from chance alone or to different properties among beta-blockers, this study suggests the possibility that different heart failure population subgroups may have different responses to beta-blocker therapy.

Tonic chemoreflex activation does not contribute to elevated muscle sympathetic nerve activity in heart failure

BACKGROUND Sympathetic activation in heart failure may be due to an increase in sympathetic excitatory influences or to a decrease in inhibitory signals to the brain stem. Chemoreflex sensitivity may be increased in patients with heart failure. The present study tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in heart failure. METHODS AND RESULTS We recorded sympathetic nerve activity to muscle circulation from the peroneal nerve of 12 chronic heart failure patients while the patients were breathing room air and during deactivation of the chemoreceptors while the patients were breathing a 100% O2 gas mixture. All patients except 2 were in class III of the New York Heart Association functional classification. Left ventricular ejection fraction defined by radionuclide ventriculography was 24 +/- 2% (mean +/- SE). We also obtained measurements of resting sympathetic nerve activity in 9 healthy control subjects to document that sympathetic nerve activity was elevated in heart failure subjects. Resting sympathetic nerve activity was 59 +/- 5 bursts/min in heart failure patients versus 36 +/- 4 bursts/min in control subjects (P < .01). In heart failure patients, oxygen administration increased oxygen saturation from 94 +/- 0.9% to 99 +/- 0.3% (P < .0001). This increase in oxygen saturation did not affect resting muscle sympathetic nerve activity (798 +/- 122 U/min while patients breathed room air and 824 +/- 35 U/min during 100% O2 breathing) or blood pressure. CONCLUSIONS Increased efferent sympathetic activity to muscle circulation in patients with heart failure is not explained by tonic activation of excitatory chemoreflex afferents.

Naloxone potentiates cardiopulmonary baroreflex sympathetic control in normal humans.

Naloxone, an opioid antagonist, augments baroreflex mechanisms in animals; this occurrence suggests that endogenous opioids blunt baroreflex responses. Limited human studies suggest an inhibitory action of endogenous opioids on baroreflex-mediated vagal responses during arterial baroreceptor deactivation. To evaluate the potential effect of endogenous opioids on cardiopulmonary baroreflex mechanisms in humans, we measured arterial and central venous pressures, heart rate, and efferent muscle sympathetic nerve activity (MSNA, by peroneal microneurography) during unloading of cardiopulmonary baroreceptors with incremental lower body negative pressure (LBNP, from 0 to -15 mm Hg) and during the cold pressor test in 21 normal subjects (aged 24 +/- 1 [mean +/- SEM] years). In 14 subjects, we performed LBNP before and after naloxone (0.15 mg/kg i.v.) and placebo (n = 11) on separate days. In six of these 14 subjects and an additional seven subjects (n = 13), studies were also performed before and after administration of a lower dose of naloxone (0.075 mg/kg i.v.) on separate days. Neither dose of naloxone significantly altered control arterial or central venous pressures or heart rate. Control MSNA was reduced after the higher but not after the lower dose of naloxone. Comparable reductions in central venous pressure were produced by LBNP in all groups before and after naloxone or placebo, whereas LBNP did not alter arterial pressure. Cardiopulmonary baroreflex sympathetic sensitivity, which was derived as the slope of the linear regression relation between percent change in total MSNA (units) per absolute change in central venous pressure (mm Hg) during incremental LBNP, was significantly augmented after both the high dose (from 18.6 +/- 4.7%/mm Hg to 39.3 +/- 8.1%/mm Hg, p = 0.001) and low dose of naloxone, whereas placebo had no effect. MSNA responses to the cold pressor test were not altered by either dose of naloxone. Thus, naloxone selectively potentiates cardiopulmonary baroreflex regulation of sympathetic neural activity in normal humans. These findings suggest that endogenous opioids exert a tonic inhibitory effect on sympathetic responses to orthostatic stress in normal humans.

Prospective assessment of the occurrence of anemia in patients with heart failure: Results from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) Registry

BACKGROUND Although a potentially important pathophysiologic factor in heart failure, the prevalence and predictors of anemia have not been well studied in unselected patients with heart failure. METHODS The Study of Anemia in a Heart Failure Population (STAMINA-HFP) Registry prospectively studied the prevalence of anemia and the relationship of hemoglobin to health-related quality of life and outcomes among patients with heart failure. A random selection algorithm was used to reduce bias during enrollment of patients seen in specialty clinics or clinics of community cardiologists with experience in heart failure. In this initial report, data on prevalence and correlates of anemia were analyzed in 1,076 of the 1,082 registry patients who had clinical characteristics and hemoglobin determined by finger-stick at baseline. RESULTS Overall (n = 1,082), the registry patients were 41% female and 73% white with a mean age (+/-SD) of 64 +/- 14 years (68 +/- 13 years in community and 57 +/- 14 years in specialty sites, P < .001). Among the 1,076 patients in the prevalence analysis, mean hemoglobin was 13.3 +/- 2.1 g/dL (median 13.2 g/dL); and anemia (defined by World Health Organization criteria) was present in 34%. Age identified patients at risk for anemia, with 40% of patients >70 years affected. CONCLUSIONS Initial results from the STAMINA-HFP Registry suggest that anemia is a common comorbidity in unselected outpatients with heart failure. Given the strong association of anemia with adverse outcomes in heart failure, this study supports further investigation concerning the importance of anemia as a therapeutic target in this condition.

Prospective evaluation of the association between hemoglobin concentration and quality of life in patients with heart failure

BACKGROUND Reduced hemoglobin has been associated with adverse outcomes in heart failure, but the relationship of hemoglobin to health-related quality of life in outpatients with this syndrome has not been well studied. METHODS We used data from the prospective, observational Study of Anemia in a Heart Failure Population Registry, which randomly selected outpatients with heart failure from specialty or community cardiology clinics. Hemoglobin was determined by finger stick at baseline and during medically indicated follow-up visits. Health-related quality of life was assessed using the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire at 3-month intervals for 12 months. RESULTS Adjusted regression analysis demonstrated a significant, direct, linear relationship between hemoglobin and health-related quality of life from baseline through 12 months follow-up on all Kansas City Cardiomyopathy Questionnaire domains (all P < .001) and the Summary and Physical domains of the Minnesota Living with Heart Failure Questionnaire (all P < .05). Adjusted categorical analysis of the change in Kansas City Cardiomyopathy Questionnaire Clinical scores associated with change in hemoglobin from baseline to 6 months also showed a significant relationship between increasing hemoglobin and improved health status (5.9 +/- 1.8 units for a hemoglobin increase of >or=1 g/dL, 0.7 +/- 1.2 units for change in hemoglobin <1 g/dL, and -2.6 +/- 1.4 units for a >or=1 g/dL decrease in hemoglobin, P < .001). CONCLUSIONS These prospective, observational results indicate that reduced hemoglobin is associated with poorer quality of life in patients with heart failure. Additional studies will be required to establish if this is a cause-and-effect relationship.