Mark E. Dunlap

Effect of Nesiritide in Patients with Acute Decompensated Heart Failure

BACKGROUND Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Mortality and Morbidity Reduction With Candesartan in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction Results of the CHARM Low-Left Ventricular Ejection Fraction Trials

Background—Patients with symptomatic chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) have a high risk of death and hospitalization for CHF deterioration despite therapies with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and even an aldosterone antagonist. To determine whether the angiotensin-receptor blocker (ARB) candesartan decreases cardiovascular mortality, morbidity, and all-cause mortality in patients with CHF and depressed LVEF, a prespecified analysis of the combined Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) low LVEF trials was performed. CHARM is a randomized, double-blind, placebo-controlled, multicenter, international trial program. Methods and Results—New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of ≤40% were randomized to candesartan or placebo in 2 complementary parallel trials (CHARM-Alternative, for patients who cannot tolerate ACE inhibitors, and CHARM-Added, for patients who were receiving ACE inhibitors). Mortality and morbidity were determined in 4576 low LVEF patients (2289 candesartan and 2287 placebo), titrated as tolerated to a target dose of 32 mg once daily, and observed for 2 to 4 years (median, 40 months). The primary outcome (time to first event by intention to treat) was cardiovascular death or CHF hospitalization for each trial, with all-cause mortality a secondary end point in the pooled analysis of the low LVEF trials. Of the patients in the candesartan group, 817 (35.7%) experienced cardiovascular death or a CHF hospitalization as compared with 944 (41.3%) in the placebo group (HR 0.82; 95% CI 0.74 to 0.90; P<0.001) with reduced risk for both cardiovascular deaths (521 [22.8%] versus 599 [26.2%]; HR 0.84 [95% CI 0.75 to 0.95]; P=0.005) and CHF hospitalizations (516 [22.5%] versus 642 [28.1%]; HR 0.76 [95% CI 0.68 to 0.85]; P<0.001). It is important to note that all-cause mortality also was significantly reduced by candesartan (642 [28.0%] versus 708 [31.0%]; HR 0.88 [95% CI 0.79 to 0.98]; P=0.018). No significant heterogeneity for the beneficial effects of candesartan was found across prespecified and subsequently identified subgroups including treatment with ACE inhibitors, β-blockers, an aldosterone antagonist, or their combinations. The study drug was discontinued because of adverse effects by 23.1% of patients in the candesartan group and 18.8% in the placebo group; the reasons included increased creatinine (7.1% versus 3.5%), hypotension (4.2% versus 2.1%), and hyperkalemia (2.8% versus 0.5%), respectively (all P<0.001). Conclusion—Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF ≤40% when added to standard therapies including ACE inhibitors, β-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.

Aortic Diameter, Wall Stiffness, and Wave Reflection in Systolic Hypertension

Systolic hypertension is associated with increased pulse pressure (PP) and increased risk for adverse cardiovascular outcomes. However the pathogenesis of increased PP remains controversial. One hypothesis suggests that aortic dilatation, wall stiffening and increased pulse wave velocity result from elastin fragmentation, leading to a premature reflected pressure wave that contributes to elevated PP. An alternative hypothesis suggests that increased proximal aortic stiffness and reduced aortic diameter leads to mismatch between pressure and flow, giving rise to an increased forward pressure wave and increased PP. To evaluate these two hypotheses, we measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension. Antihypertensive medications were withdrawn for at least 1 week before study. Patients with PP above the median (75 mm Hg) had lower aortic diameter (2.94±0.36 versus 3.13±0.28 cm, P<0.001) and higher aortic wall stiffness (elastance-wall stiffness product: 16.1±0.7 versus 15.7±0.7 ln[dyne/cm], P<0.001) with no difference in augmentation index (19.9±10.4 versus 17.5±10.0%, P=0.12). Aortic diameter and wall stiffness both increased with advancing age (P<0.001). However, an inverse relation between PP and aortic diameter remained significant (P<0.001) in models that adjusted for age, sex, height, and weight and then further adjusted for aortic wall stiffness, augmentation index, and mean arterial pressure. Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection.

Ganglionic Mechanisms Contribute to Diminished Vagal Control in Heart Failure

BACKGROUND Previous work has shown that spontaneous and stimulated vagal activity is diminished in heart failure (HF) despite upregulation of functional postsynaptic cholinergic mechanisms. We therefore examined function of the postganglionic neuron in the paced canine model of HF as a possible site for diminished control. METHODS AND RESULTS We measured sinus cycle length changes in response to electrical stimulation of preganglionic and postganglionic parasympathetic neurons innervating the sinoatrial node in control and HF dogs (both, n=8). Cervical vagus stimulation (preganglionic) demonstrated attenuated responses in the HF group at all levels of stimulation (P<0.05). Stimulation of the right atrial fat pad, containing both postganglionic nerves and terminals of preganglionic neurons, showed no such difference between control and HF (200+/-25 versus 192+/-18 ms). To ensure that preganglionic input and different levels of baseline sympathetic activity did not contribute to the group difference, similar stimulations were done in the presence of ganglionic and beta-adrenergic blockade. Under these conditions, postganglionic stimulation showed smaller changes in sinus cycle length, but the HF group response remained significantly higher than in controls (76+/-10 versus 20+/-2 ms; P<0. 01), indicating that the difference was independent of preganglionic input and sympathetic activity. CONCLUSIONS A component of attenuated parasympathetic control in HF is located within the peripheral efferent limb. This defect is located within the parasympathetic ganglion. Future work should be focused on determining mechanisms of attenuated ganglionic transmission so that means targeted at restoring vagal activity can be developed.

Characterization of health‐related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM

Limited comparative studies assessing the health‐related quality of life (HRQL) in heart failure (HF) patients with preserved vs. low ejection fraction (LVEF) have been disparate.

Sympathetically Mediated Changes in Capacitance Redistribution of the Venous Reservoir as a Cause of Decompensation

“To be accepted as a paradigm, a theory must seem better than its competitors, but it need not, and in fact never does, explain all the facts with which it can be confronted.” Thomas Kuhn, The Structure of Scientific Revolutions ### Heard on Rounds “A 57-year-old patient with a history of heart failure states that she began experiencing worsening shortness of breath 4 days prior to admission, with lower extremity edema developing 1 day prior to admission. She is compliant with her medications, though has had similar admissions previously. She states that her weight at home increased by “a couple of pounds” 2 days ago and that she increased her diuretic dose but her symptoms worsened. She says that she generally adheres to her low salt diet, but admits to eating pretzels 5 days ago. The physical examination showed BP 136/84, HR 94, weight 3 lbs above baseline, elevated JVP, basilar rales, and 1+ pedal edema.” As the intern finishes the presentation, the Senior expresses surprise that the patients weight had increased only 3 pounds, and comments about salt and volume overload leading to acute decompensated heart failure (ADHF). The Attending adds that recent data reveal that many patients presenting with ADHF have minimal or no weight gain, but that there is no clear mechanism to explain this phenomenon. They set in place plans for diuresis, increasing vasodilators, and further patient education. On the surface, there is nothing remarkable about this case, and the usual approaches to treat this entity have remained remarkably consistent since the advent of loop diuretics over 50 years ago: salt restriction, patient education, uptitration of medications if not already at optimal doses, and diuresis. However, approximately 1 in 4 such patients are readmitted to the hospital within 30 days,1 and the disease continues to progress. It is clear …

DITPA (3,5-diiodothyropropionic acid), a thyroid hormone analog to treat heart failure: Phase II trial veterans affairs cooperative study

Background— In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results— This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure–specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (−20%), low-density lipoprotein cholesterol (−30%), and body weight (−11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions— DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.

Long-Term Trandolapril Treatment Is Associated With Reduced Aortic Stiffness The Prevention of Events With Angiotensin-Converting Enzyme Inhibition Hemodynamic Substudy

The Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial evaluated angiotensin-converting enzyme inhibition with trandolapril versus placebo added to conventional therapy in patients with stable coronary disease and preserved left ventricular function. The PEACE hemodynamic substudy evaluated effects of trandolapril on pulsatile hemodynamics. Hemodynamic studies were performed in 300 participants from 5 PEACE centers a median of 52 months (range, 25 to 80 months) after random assignment to trandolapril at a target dose of 4 mg per day or placebo. Central pulsatile hemodynamics and carotid–femoral pulse wave velocity were assessed by using echocardiography, tonometry of the carotid and femoral arteries, and body surface transit distances. Patients randomly assigned to trandolapril tended to be older (mean±SD: 64.2±7.9 versus 62.9±7.7 years; P=0.14), with a higher body mass index (28.5±4.0 versus 27.8±3.9 kg/m2; P=0.09) and lower ejection fraction (57.1±8.1% versus 58.7±8.4%; P<0.01). At the time of the hemodynamic substudy, the trandolapril group had lower mean arterial pressure (93.1±10.2 versus 96.3±11.3 mm Hg; P<0.01) and lower carotid-femoral pulse wave velocity (geometric mean [95% CI]: 10.4 m/s [10.0 to 10.9 m/s] versus 11.2 m/s [10.7 to 11.8 m/s]; P=0.02). The difference in carotid–femoral pulse wave velocity persisted (P<0.01) in an analysis that adjusted for baseline characteristics and follow-up mean pressure. In contrast, there was no difference in aortic compliance, characteristic impedance, augmentation index, or total arterial compliance. Angiotensin-converting enzyme inhibition with trandolapril produced a modest reduction in carotid–femoral pulse wave velocity, a measure of aortic wall stiffness, beyond what would be expected from blood pressure lowering or differences in baseline characteristics alone.

Evidence for impaired vagus nerve activity in heart failure

Parasympathetic control of the heart via the vagus nerve is the primary mechanism that regulates beat-to-beat control of heart rate. Additionally, the vagus nerve exerts significant effects at the AV node, as well as effects on both atrial and ventricular myocardium. Vagal control is abnormal in heart failure, occurring at early stages of left ventricular dysfunction, and this reduced vagal function is associated with worse outcomes in patients following myocardial infarction and with heart failure. While central control mechanisms are abnormal, one of the primary sites of attenuated vagal control is at the level of the parasympathetic ganglion. It remains to be seen whether or not preventing or treating abnormal vagal control of the heart improves prognosis.

6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure.

OBJECTIVES The goal of this study was to compare the prognostic efficacy of the 6-min walk (6MW) and cardiopulmonary exercise (CPX) tests in stable outpatients with chronic heart failure (HF). BACKGROUND CPX and 6MW tests are commonly applied as prognostic gauges for systolic HF patients, but few direct comparisons have been conducted. METHODS Stable New York Heart Association (NYHA) functional class II and III systolic HF patients (ejection fraction ≤ 35%) from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial were studied. 6MW distance (6MWD) and CPX indices (peak oxygen consumption [VO(2)] and ventilatory equivalents for exhaled carbon dioxide [VE/VCO(2)] slope) were compared as predictors of all-cause mortality/hospitalization and all-cause mortality over 2.5 years of mean follow-up. RESULTS A total of 2,054 HF-ACTION participants underwent both CPX and 6MW tests at baseline (median age 59 years; 71% male; 64% NYHA functional class II and 36% NYHA functional class III/IV). In unadjusted models and in models that included key clinical and demographic covariates, C-indices of 6MWD were 0.58 and 0.65 (unadjusted) and 0.62 and 0.72 (adjusted) in predicting all-cause mortality/hospitalization and all-cause mortality, respectively. C-indices for peak VO(2) were 0.61 and 0.68 (unadjusted) and 0.63 and 0.73 (adjusted). C-indices for VE/VCO(2) slope were 0.56 and 0.65 (unadjusted) and 0.61 and 0.71 (adjusted); combining peak VO(2) and VE/VCO(2) slope did not improve the C-indices. Overlapping 95% confidence intervals and modest integrated discrimination improvement values confirmed similar prognostic discrimination by 6MWD and CPX indices within adjusted models. CONCLUSIONS In systolic HF outpatients, 6MWD and CPX indices demonstrated similar utility as univariate predictors for all-cause hospitalization/mortality and all-cause mortality. However, 6MWD or CPX indices added only modest prognostic discrimination to models that included important demographic and clinical covariates.