A.A. Voors

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.).

Pregnancy and delivery in women after Fontan palliation.

Objectives: To evaluate the outcome of pregnancy in women after Fontan palliation and to assess the occurrence of infertility and menstrual cycle disorders. Design and patients: Two congenital heart disease registries were used to investigate 38 female patients who had undergone Fontan palliation (aged 18–45 years): atriopulmonary anastomosis (n  =  23), atrioventricular connection (n  =  5) and total cavopulmonary connection (n  =  10). Results: Six women had 10 pregnancies, including five miscarriages (50%) and one aborted ectopic pregnancy. During the remaining four live-birth pregnancies clinically significant complications were encountered: New York Heart Association class deterioration; atrial fibrillation; gestational hypertension; premature rupture of membranes; premature delivery; fetal growth retardation and neonatal death. Four of seven women who had attempted to become pregnant reported female infertility: non-specified secondary infertility (n  =  2), uterus bicornis (n  =  1) and related to endometriosis (n  =  1). Moreover, several important menstrual cycle disorders were documented. In particular, the incidence of primary amenorrhoea was high (n  =  15, 40%), which resulted in a significant increase in age at menarche (14.6 (SD 2.1) years, p < 0.0001, compared with the general population). Conclusion: Women can successfully complete pregnancy after adequate Fontan palliation without important long-term sequelae, although it is often complicated by clinically significant (non-)cardiac events. In addition, subfertility or infertility and menstrual disorders were common.

Pregnancy, fertility, and recurrence risk in corrected tetralogy of Fallot.

Objective: To determine in women with surgically corrected tetralogy of Fallot the risk of pregnancy for mother and fetus, whether fertility was compromised, and the recurrence risk of congenital heart disease. Design: Data were collected from 83 patients through interviews and review of medical records. Results: In 29 patients 63 pregnancies were observed, of which 13 ended in an abortion. Fifty successful pregnancies were observed in 26 patients. During six successful pregnancies (12%) complications (symptomatic right sided heart failure, arrhythmias, or both) occurred. Both patients who developed symptomatic heart failure had severe pulmonary regurgitation. No clear relation between offspring mortality, premature birth or being small for gestational age, and cardiac characteristics of the mother was identified. Fifty seven patients were childless (41 (72%) voluntarily). Recurrence risk for congenital heart disease was 2.2%. Infertility was uncommon. Conclusions: Although complications did occur in five of 26 (19%) of the patients with a corrected tetralogy of Fallot, pregnancy was generally well tolerated in this largest report so far. No obvious predictors for maternal events or child outcome were determined, except for a possible relation between severe pulmonary regurgitation and symptomatic heart failure.

Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function).

OBJECTIVES This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). BACKGROUND Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. METHODS A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine ≥0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7. RESULTS At baseline, mean ± SD estimated creatinine clearance was 51.0 ± 20.5 ml/min in the placebo group and 50.4 ± 20.0 ml/min in the rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44). CONCLUSIONS In this large, phase III clinical trial, the adenosine A(1) receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458).

Non-cardiac complications during pregnancy in women with isolated congenital pulmonary valvar stenosis

Background: Information on the outcome of pregnancy in patients with pulmonary valvar stenosis is scarce, mostly limited to cardiac complications observed during pregnancy. Objectives: To investigate the magnitude and determinants of non-cardiac and fetal risks during pregnancy of women with isolated pulmonary valvar stenosis. Methods: Using the nationwide registry (CONgenital CORvitia), 106 women with (un-)corrected pulmonary valvar stenosis receiving care in six tertiary medical centres in The Netherlands were included. A total of 51 women had 108 pregnancies, including 21 (19%) miscarriages and 6 elective abortions. Results: In the 81 completed (>20 weeks of gestation) pregnancies, we observed a high number of hypertension-related disorders (n = 12, 15%, including pre-eclampsia (n = 4) and eclampsia (n = 2)), premature deliveries (n = 14, 17%, including one twin) and thromboembolic events (n = 3, 3.7%). Furthermore, recurrence of congenital heart defects in the offspring was detected in three children (3.7%, pulmonary valvar stenosis (n = 2) and complete transposition of the great arteries in combination with anencephaly). In addition to the intrauterine fetal demise of the transposition child, three other children died shortly after birth owing to immaturity, hydrocephalus combined with prematurity and meningitis (overall offspring mortality, 4.8%). Conclusion: In this largest report on pregnancy in women with (un-) corrected isolated pulmonary valvar stenosis, an excessive number of (serious) non-cardiac complications and mortality were observed in the offspring.

Use of cystatin C levels in estimating renal function and prognosis in patients with chronic systolic heart failure

Background Estimates of glomerular filtration rate (GFR), including creatinine and creatinine based formulae, are inaccurate in extremes of GFR and substantially biased in patients with chronic heart failure (CHF). Objective To investigate whether serum cystatin C levels would be a better, more accurate and simple alternative for estimation of GFR and prognosis in CHF. Design Cohort study. Setting Chronic heart failure. Patients, interventions and main outcome measure In 102 CHF patients, the correlation between GFR as estimated by 125I-iothalamate clearance (GFRIOTH), the modification of diet in renal disease formula (GFRMDRD) and cystatin C was investigated. The combined endpoint consisted of the first occurrence of all cause mortality, heart transplantation or admission for CHF within 24 months. Results Mean age was 58±12 years; 77% were male. Mean left ventricular ejection fraction was 28±9%. Mean GFRIOTH was 75±27 ml/min/1.73 m2, while median cystatin C levels were 0.80 (0.69–1.02) mg/l. GFRIOTH was strongly correlated with all renal function estimates, including 1/cystatin C (r=0.867, p<0.001). GFRIOTH was better predicted by 1/cystatin C compared to 1/serum creatinine (z=3.12, p=0.002), but equally predicted compared to GFRMDRD (z=0.92, p=0.356). Serum 1/cystatin C was a strong independent predictor of prognosis (HR: 2.27 per SD increase, 95% CI 1.12 to 4.63), comparable to GFRMDRD. Conclusions Cystatin C is an accurate and easy estimate of renal function with prognostic properties superior to serum creatinine and similar to creatinine based formulae in patients with CHF.

Acute heart failure: Multiple clinical profiles and mechanisms require tailored therapy

Acute heart failure (HF) is the most common diagnosis at discharge in patients aged >65years. It carries a dismal prognosis with a high in-hospital mortality and very high post-discharge mortality and re-hospitalization rates. It is a complex clinical syndrome that cannot be described as a single entity as it varies widely with respect to underlying pathophysiologic mechanisms, clinical presentations and, likely, treatments. It is the aim of this paper to describe some of the main clinical presentations of acute HF. Amongst them, we will consider de novo HF versus acutely decompensated chronic HF, HF caused, and/or worsened, by myocardial ischemia, acute HF with low, normal, or high systolic blood pressure, acute HF caused by lung congestion or fluid retention or fluid redistribution to the lungs, and acute HF with comorbidities (diabetes, anemia, renal insufficiency, etc.). Different pathophysiologic mechanisms and clinical presentations may coexist in the same patient. Identification and, whenever possible, treatment of underlying pathophysiologic mechanisms may become important for acute HF management.

Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure

Adeno-associated virus serotype 1 (AAV1) has many advantages as a gene therapy vector, but the presence of pre-existing neutralizing antibodies (NAbs) is an important limitation. This study was designed to determine: (1) characteristics of AAV NAbs in human subjects, (2) prevalence of AAV1 NAbs in heart failure patients and (3) utility of aggressive immunosuppressive therapy in reducing NAb seroconversion in an animal model. NAb titers were assessed in a cohort of heart failure patients and in patients screened for a clinical trial of gene therapy with AAV1 carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a). AAV1 NAbs were found in 59.5% of 1552 heart failure patients. NAb prevalence increased with age (P=0.001) and varied geographically. The pattern of NAb titers suggested that exposure is against AAV2, with AAV1 NAb seropositivity due to crossreactivity. The effects of immunosuppression on NAb formation were tested in mini-pigs treated with immunosuppressant therapy before, during and after a single AAV1/SERCA2a infusion. Aggressive immunosuppression did not prevent formation of AAV1 NAbs. We conclude that immunosuppression is unlikely to be a viable solution for repeat AAV1 dosing. Strategies to reduce NAbs in heart failure patients are needed to increase eligibility for gene transfer using AAV vectors.

Telomere length and outcome in heart failure

Abstract Background. Telomeres are causally involved in senescence. Senescence is a potential factor in the pathogenesis and progression of heart failure. In heart failure telomeres are shorter, but the prognostic value associated with telomere length has not been defined. Methods. Telomere length was prospectively determined by quantitative polymerase chain reaction in 890 patients with New York Heart Association (NYHA) functional class II to IV heart failure. After 18 months, we examined the association between telomere length and the predefined primary end-point: time to death or hospitalization for heart failure. Results. Mean age of the patients was 71 years, 39% were women, 51% were in NYHA class II, and 49% were in class III/IV. A total of 344 patients reached the primary end-point (130 deaths and 214 hospitalizations). Patients with shorter telomeres were at an increased risk of reaching the primary end-point (hazard ratio 1.79; 95% confidence interval (CI) 1.21–2.63). In multivariate analysis shorter telomere length remained associated with a higher risk for death or hospitalization (hazard ratio, 1.74; 95% CI 1.07–2.95) after adjustment for age of heart failure onset, gender, hemoglobin, renal function, and N-terminal pro-B-type natriuretic peptide level, a history of stroke, atrial fibrillation, and diabetes. Conclusions. Shorter length of telomeres predicts the occurrence of death or hospitalization in patients with chronic heart failure.

Central sleep apnoea syndrome in chronic heart failure: an underestimated and treatable comorbidity

Chronic heart failure is a clinical syndrome with a high mortality and morbidity. Despite optimal therapy, five-year survival is still only 50%. Central sleep apnoea syndrome is seen in approximately 40% of patients with congestive heart failure. Sleep apnoea syndrome can be divided into two forms in these patients: obstructive sleep apnoea syndrome (OSAS) and central sleep apnoea syndrome (CSAS, Cheyne-Stokes respiration), of which CSAS is the most common. CSAS is a form of sleep apnoea in congestive heart failure which is driven by changes in pCO2. As a consequence of apnoea-hypopnoea an imbalance in myocardial oxygen delivery/consumption ratio will develop, sympathetic and other neurohormonal systems will be activated and right and left ventricular afterload will be increased. Sleep apnoea is associated with an increased mortality in patients with systolic heart failure. Treatment of sleep apnoea increases left ventricular ejection fraction and transplant-free survival. Because of its high prevalence, poor quality of life, poor outcome, and the beneficial effects of treatment, physicians treating patients with heart failure should be aware of central sleep apnoea. There are different treatment options, but the exact effects and indications of each option have not yet been fully determined. Further studies should be done to further investigate its prevalence, and to establish the most adequate therapy for the individual patient. (Neth Heart J 2010;18:260-3.)