Grigorios Giamouzis

State-of-the-Art PaperThe Sympathetic Nervous System in Heart Failure: Physiology, Pathophysiology, and Clinical Implications

Heart failure is a syndrome characterized initially by left ventricular dysfunction that triggers countermeasures aimed to restore cardiac output. These responses are compensatory at first but eventually become part of the disease process itself leading to further worsening cardiac function. Among these responses is the activation of the sympathetic nervous system (SNS) that provides inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure, but eventually accelerates disease progression affecting survival. Activation of SNS has been attributed to withdrawal of normal restraining influences and enhancement of excitatory inputs including changes in: 1) peripheral baroreceptor and chemoreceptor reflexes; 2) chemical mediators that control sympathetic outflow; and 3) central integratory sites. The interface between the sympathetic fibers and the cardiovascular system is formed by the adrenergic receptors (ARs). Dysregulation of cardiac beta(1)-AR signaling and transduction are key features of heart failure progression. In contrast, cardiac beta(2)-ARs and alpha(1)-ARs may function in a compensatory fashion to maintain cardiac inotropy. Adrenergic receptor polymorphisms may have an impact on the adaptive mechanisms, susceptibilities, and pharmacological responses of SNS. The beta-AR blockers and the inhibitors of the renin-angiotensin-aldosterone axis form the mainstay of current medical management of chronic heart failure. Conversely, central sympatholytics have proved harmful, whereas sympathomimetic inotropes are still used in selected patients with hemodynamic instability. This review summarizes the changes in SNS in heart failure and examines how modulation of SNS activity may affect morbidity and mortality from this syndrome.

Digoxin Therapy Does Not Improve Outcomes in Patients With Advanced Heart Failure on Contemporary Medical Therapy

Background—The impact of digoxin on outcomes of patients with advanced heart failure (HF) receiving optimal contemporary therapy is not known. Methods and Results—We retrospectively reviewed data of 455 advanced HF patients referred for transplant evaluation (age, 52±12 years; ejection fraction, 18.3±8%); 227 (49.9%) were on digoxin at baseline. Primary outcome was death (n=101), urgent transplantation (n=14), or ventricular assist device implantation (n=4); secondary outcomes included HF and all-cause hospitalizations. Digoxin use was evaluated (1) in the original cohort; (2) in a propensity score–matched subset (n=322); (3) as a time-dependent covariate; and (4) after adjustment for Seattle Heart Failure Score. Patients were on optimal therapy: angiotensin-II modulation, 92.5%; β-blockers, 91.2%; aldosterone antagonists, 45.6%; and devices, 71.0%. After a median of 27 months, 83 of 277 (36.6%) patients treated with digoxin versus 36 of 228 (15.8%) patients without digoxin met primary outcome (hazard ratio [HR], 2.28; 95% CI, 1.51 to 3.43; P<0.001). This risk persisted in the matched subset (HR, 1.73; 95% CI, 1.09 to 2.75; P=0.021) and with time-varying digoxin use (HR, 2.05; 95% CI, 1.23 to 3.41; P=0.011). Digoxin was associated with higher risk among patients in sinus rhythm compared with atrial fibrillation. Digoxin was not associated with improvement in either all-cause or HF hospitalization rates. These results were similar across sex and race and when adjusted for Seattle Heart Failure Score and renal function. Conclusion—This study suggests that digoxin therapy may be of no benefit in patients with advanced HF referred for cardiac transplantation who received optimal medical therapy. Treatment with digoxin should be used cautiously in such patients because of risk for adverse outcomes.

Natriuretic peptide-guided levosimendan therapy for heart failure: A promising new approach

We read with great interest the letter by Cavusoglu et al. demonstrating that in patients with acute decompensated heart failure (ADHF) levosimendan treatment leads to a significant reduction in NT-proBNP levels for at least up to 48 h [1]. These results are in concordance with previous studies [2–6]. Such a trend was not seen with dobutamine infusion. Considering the now well accepted prognostic importance of natriuretic peptide levels in patients with heart failure, it would have been of great interest if the investigators had measured the levels of NT-proBNP longitudinally over time for a longer duration to document the overall magnitude and duration of NT-proBNP suppression by a single 24-h levosimendan infusion. Moreover, a concomitant group of patients receiving only diuretic therapy would have further helped navigate the difficult and largely unanswered question of how to optimally manage patients with ADHF. Nevertheless, the investigators do provide important new insights into the neurohormonal modulation by levosimendan that raises important novel therapeutic questions. Of great interest is the fact that none of the patients were receiving treatment with a β-blocker agent prior to the administration of the study drug. Although from an ideal

NGAL and ST2 levels in ambulatory patients with chronic heart failure. Clinical and echocardiographic correlates

Abstract Aim. Neutrophil gelatinase-associated lipocalin (NGAL) and ST2 receptor, a member of the interleukin-1 receptor family, are novel biomarkers with a potential role in the diagnosis and risk stratification of patients with chronic heart failure (CHF). There is however scarce data on their relation with clinical characteristics and cardiac function in patients with CHF. Methods. Consecutive ambulatory patients with CHF were studied. All patients underwent clinical and echocardiographic assessment, and blood samples were collected for the estimation of ST2 and NGAL serum levels during the same assessment. Results. A total of 76 patients (79% male, mean age: 63 ± 14 years), with CHF and left ventricular ejection fraction of 28 ± 7% were included. Median NGAL was 0.16 (0.09–0.275) mg/L and median ST2 was 0.0125 (0.0071–0.0176) mg/L. No association between NGAL and ST2 was observed. Multivariate analysis revealed tissue Doppler-derived right ventricular systolic velocity as an independent predictor of ST2, and the duration of HF and serum creatinine levels as independent predictors of NGAL. Conclusions. NGAL levels depend on the renal function and the duration of HF, while ST2 levels are affected by the right but not the left ventricular function and show no association with clinical indices of HF.

A Struggle to SURVIVE: To Abandon or not to Abandon Levosimendan?

To the Editor: The recently published SURVIVE trial showed that despite an initial reduction in plasma B-type natriuretic peptide (BNP) level seen in patients with acute decompensated heart failure (ADHF) receiving levosimendan compared with patients receiving dobutamine, levosimendan did not significantly reduce all-cause mortality at 180 days [1]. Moreover, most of the pre-specified subgroup analyses, with one exception, showed no difference in survival between patients in the levosimendan or the dobutamine group. Patients with a prior history of heart failure in the levosimendan group, however, had a trend towards lower mortality at 31 days (59 vs 78 p=0.05). The favorable neurohormonal response following levosimendan administration is known from previous single center studies [2, 3]. The magnitude of levosimendan-induced reduction in plasma BNP levels at 48 h was recently recognised as a predictor of 6-month survival [4]. Similarly, in general lower BNP levels at the time of discharge are associated with improved post-discharge outcomes [5]. We propose that a reduction in early BNP levels with levosimendan suggests a strongly signal towards the potential beneficial effect of this agent in ADHF, however, it may be unrealistic to expect such benefits to last for 180 days post-discharge. An interesting finding in the SURVIVE trial is the trend over time for difference between the levosimendan vs. the dobutamine deaths (29 vs 40, p=0.17 at 5, 59 vs 69, p=0.33 at 14, and 139 vs 138, p=0.91 at 90 days). These data suggest an interesting possibility that if intermittent levosimendan infusions were given serially overtime to maintain optimal hemodynamics and BNP levels at outpatient, it may attenuate progressive cardiac worsening and improve outcomes. A recent study reported that serial levosimendan administrations improved left ventricular performance and modulated beneficially neurohormonal and immune activation in decompensated chronic heart failure without increasing myocardial injury [6]. The issues surrounding the arrhythmic risks with levosimendan still persist, however baseline β-blocker therapy may play a significant role in this respect as they attenuate the sympathetic hyperactivity and decrease the high arrhythmic risks seen with levosimendan. Indeed preadmission beta-blocker therapy and continuation of these agents during hospitalization for ADHF has been shown to significantly improve outcomes for these patients [7]. The trend towards progressive amelioration of benefit with levosimendan over time and preliminary data showing benefit with intermittent serial outpatient infusions both suggest that further larger studies are needed to truly realize the potential role of this agent in patient with chronic heart failure. Cardiovasc Drugs Ther (2007) 21:401–402 DOI 10.1007/s10557-007-6046-y

Ranolazine Added to Amiodarone Facilitates Earlier Conversion of Atrial Fibrillation Compared to Amiodarone-Only Therapy: AMIODARONE PLUS RANOLAZINE FOR ATRIAL FIBRILLATION

Amiodarone (AMIO) is for many years effectively used to control ventricular rate during atrial fibrillation (AF) and to convert it into sinus rhythm. However, due to its delayed onset of action, ranolazine (RAN), a new antianginal agent with atrial‐selective electrophysiologic properties, has recently been attempted as add‐on therapy with AMIO to facilitate AF conversion.

ADHERENCE, PREDICTORS OF ADHERENCE AND OUTCOMES ASSOCIATED WITH SELF-CARE RECOMMENDATIONS AMONG HEART FAILURE PATIENTS

Abstract Category: 24. Myocardial Function/Heart Failure—Clinical Nonpharmacological TreatmentSession-Poster Board Number: 1160-25Authors: Catherine Norton, Vasiliki Georgiopoulou, Andreas Kalogeropoulos, Lucy Fike, Grigorios Giamouzis, Sonjoy Laskar, Robert Cole, Andrew Smith, Wilson W.H. Tang, Sandra Dunbar, Javed Butler, Emory University School of Medicine, Atlanta, GA, Cleveland Clinic Foundation, Cleveland, OH Background: Cumulative adherence with self-care recommendations and association with outcomes is not well described in heart failure (HF) patients.Methods: We used self-report to evaluate adherence to eight HF self-care recommendations (exercise, medications, alcohol and smoking habits, diet, weight and symptom monitoring) among 286 patients with HF (age, 56±11.6 years; 34.3% female; 46.2% black). Adherence was defined as optimal (overall ≥80%) or ideal (≥80% adherence to each recommendation). Outcomes included death or transplant or ventricular assist device placement; rates of emergency department visits, hospitalizations, and length of stay; health status using the Kansas City Cardiomyopathy Questionnaire.Results: Mean follow-up was 525±295 days. Adherence to individual recommendations ranged from 89% for medication to 26% for exercise. Optimal adherence was reported by 34% of patients whereas only 11% indicated ideal adherence. Education was the only sociodemographic variable associated with adherence (odds ratio [OR] 1.15; 95% confidence interval [CI] 1.05-1.25 for optimal; and OR 1.15; 95% CI 1.02-1.30 for ideal adherence per year of education). Patients with optimal or ideal adherence had better clinical outcomes (Table); however, only ideal adherence was associated with better quality of life.Conclusions: In this HF cohort, better adherence with self-care recommendations was associated with improved clinical outcomes. However, adherence was suboptimal for most patients. Optimal AdherenceDeath/Left Ventricular Assist Device/Transplant, % 8.0 9.2 0.73All cause hospitalizations, per 1000 patient-days 2.8 2.0 0.07HF hospitalizations, per 1000 patient-days 1.2 0.9 0.12Emergency department visits, per 1000 patient-days 1.3 0.8 0.02Hospital length of stay, per 1000 patient-days 13.8 8.8 0.06Hospital length of stay - HF only, per 1000 patient-days 8.5 5.5 0.13Kansas City Cardiomyopathy Questionnaire Overall Summary Score 65.2±23.2 67.9±24.3 0.37Ideal AdherenceDeath/Left Ventricular Assist Device/Transplant, % 8.3 9.4 0.83All cause hospitalizations, per 1000 patient-days 2.7 1.5 0.09HF hospitalizations, per 1000 patient-days 1.2 0.4 0.08Emergency department visits, per 1000 patient-days 1.2 0.8 0.33Hospital length of stay, per 1000 patient-days 13.6 3.0 0.02Hospital length of stay - HF only, per 1000 patient-days 8.3 0.8 0.04Kansas City Cardiomyopathy Questionnaire Overall Summary Score 65.1±23.5 74.3±23.5 0.04

Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure

Digoxin is recommended for patients with left ventricular systolic dysfunction who continue to have New York Heart Association functional class II–IV symptoms despite appropriate medical therapy and optimization of volume status. Diuretics are the mainstay of therapy for the removal of excess fluid in patients with heart failure (HF). They are equally important for use in patients with decompensated HF as well as in those with stable chronic HF to maintain euvolemia. This chapter will review the pharmacokinetics and appropriate use criteria of available cardiac glycosides and diuretics as well as drugs that are used primarily for their vasodilator properties in patients with HF. Newer agents such as Arginine Vasopressin Receptor Antagonists and Adenosine A1 Receptor Antagonists are also reviewed.