Standard Heart Failure Therapy Research Articles

93 Optimal medical therapy in heart failure: is there space for additional heart rate control?

IntroductionCurrent evidence suggests that heart rate (HR) may serve both as a modifiable risk factor, and as a disease modifying variable in patients with impaired left ventricular (LV) systolic function....

Postpartale Kardiomyopathie

A 27-year-old woman was admitted to the emergency room because of dyspnoea. Two months earlier she had given birth to a healthy young boy via cesarean section. Computed tomography showed acute embolism in both pulmonary arteries. Chest X-ray and echocardiography revealed an enlarged left ventricle, a highly reduced left ventricular function and thrombosis in the left ventricle. The patient was treated with extensive medical heart failure therapy, and also with bromocriptine for eight weeks. Six months later, left ventricular ejection fraction had significantly improved. Peri- or postpartum cardiomyopathy (PPCM) is a rare, potentially life-threatening heart disease, which is characterized by sudden onset of heart failure between the final weeks of pregnancy and up to six months after childbirth. Early diagnosis is crucial for the patient's prognosis. Recent pilot studies on the effect of adding bromocriptine to standard heart failure therapy indicated an improvement of prognosis and myocardial function. In this case significant improvement of left ventricular function was thus achieved.

Ambulatory blood pressure monitoring, 2D-echo and clinical variables relating to cardiac events in ischaemic cardiomyopathy following cardioverter-defibrillator implantation

Evaluation of ambulatory blood pressure monitoring (ABPM), two-dimensional (2D) echo and clinical variables in predicting cardiac death and acute decompensated heart failure in patients with ischaemic cardiomyopathy and receiving a cardioverter-defibrillator implantation. We studied 180 consecutive patients (169 men) on an out-patient basis, with systolic dysfunction (ejection fraction ≤35%) and previous myocardial infarction. All received a cardioverter defibrillator (ICD) (116 dual chamber, 36 monocameral and 28 biventricular), for primary prevention of sudden death and standard medical therapy for heart failure. Mean follow-up was 11.7 months. Two-dimensional echo was performed just before ICD implantation, ABPM and haematological samples 2 weeks later. Age, ejection fraction, creatinine, haemoglobin concentration, mean 24-h systolic blood pressure, mean 24-h diastolic blood pressure, mean 24-h heart rate, brain natriuretic peptide, QRS duration, % paced beats, ventricular scar, biventricular pacing, sex and diabetes were considered. Cox proportional hazards regression analysis was used to explore the relationship between events. ROC curves were built for each independent variable. Events occurred in 47 patients (26%); 7 deaths for refractory heart failure and 40 hospitalizations for acute decompensated heart failure. Low mean 24-h systolic blood pressure [hazard ratio 0.96, 95% confidence interval (CI) 0.93-0.99, P = 0.02], high creatinine (hazard ratio 1.61, 95% CI 1.06-2.47, P = 0.01), low haemoglobin concentration (hazard ratio 0.81, 95% CI 0.65-0.99, P = 0.04) and older age (hazard ratio 1.04, 95% CI 1.01-1.08, P = 0.02) were independent predictors of events. Ambulatory systolic blood pressure, haemoglobin, creatinine and age can stratify risk of death and acute decompensated heart failure in patients with ischaemic cardiomyopathy and ICD in whom 2D-echo ejection fraction is not predictive.

Implantable Cardioverter-Defibrillator therapy for primary prevention of sudden cardiac death in patients with severe Chagas cardiomyopathy

Sudden cardiac death (SCD) affects about half of patients who died of Chagas disease followed at a referral center, and may victim up to 20% of patients without any evidence of heart disease [1]. In the vast majority of cases, SCD is caused by either sustained ventricular tachycardia (VT) degenerating into ventricular fibrillation (VF) or direct VF [1]. In patients with non-Chagas disease dilated cardiomyopathy and left ventricular ejection fraction b35%, Implantable CardioverterDefibrillator (ICD) delivered-therapy has been recommended by international guidelines to avert SCD [2]. Conversely, the impact of ICD therapy in patients with Chagas cardiomyopathy and a left ventricular ejection fraction b35% is unknown. Accordingly, we report herein our initial experience with ICD-delivered therapy in patients with severe Chagas cardiomyopathy. From January, 2006 to December, 2009, a total of 32 patients routinely followed at the Cardiomyopathy Outpatient Service of our Institution received ICD therapy for primary prevention of SCD. The study was approved by the Local Ethical Committee (protocol 3626/ 2010). Inclusion criteria were a left ventricular ejection fraction b35% at radionuclide ventriculography, receiving standard therapy for chronic systolic heart failure, and to have a reasonable expectation of 1-year survival after device implantation [2]. All patients were on New York Heart Association class II at the time of ICD implantation and none had syncope before device implantation. Nineteen (59%) patients had a positive serology for Chagas disease and were considered to have Chagas cardiomyopathy, whereas the remaining 13 (41%) patients had non-Chagas disease dilated cardiomyopathy. Device therapy consisted of antitachycardia pacing (ATP) or shock. ATP was the initial therapy for VT. Shock was the initial therapy when heart rate was higher than 200 beats per minute (VF zone), when ATP accelerated VT heart rate, or when ATP failed to abolish VT. Baseline characteristics of the study population are given in Table 1. It is noteworthy that 87% patients were on Beta-Blocker therapy. Sustained VT was detected in 4 (21%) of 19 patients with Chagas cardiomyopathy and in 2 (15%) patients with non-Chagas cardiomyopathy (pN0.05). VF was observed in 4 Chagas cardiomyopathy (21%) patients and in 2 (15%) non-Chagas cardiomyopathy patients (pN0.05). Overall, 10 (31%) patients were shocked. In total, shock occurrence was necessary to terminate 136 out of 172 (79%) episodes of VT/VF. Inappropriate shock occurred in 4 (12%) patients; 2 (10%) in Chagas and 2 (14%) in non-Chagas cardiomyopathy patients (pN0.05). A total of 101 episodes of VFwere observed in 6 patients. Median of episodes per patient was 6.5 (3, 38). Ninety-four episodes of VF were observed in four Chagas and 7 episodes of VF in two non-Chagas cardiomyopathy patients (p=0.03). Median time to first event was 78 (34, 151) days in Chagas and 173 (71, 593) days in non-Chagas cardiomyopathy patients (pb0.005). Median time to VF was 80 (22, 147) days in Chagas cardiomyopathy patients and 151 (43, 804) days in non-Chagas cardiomyopathy patients (pb0.005). Probability of freedom from shock occurrence was similar in Chagas and non-Chagas cardiomyopathy patients (Fig. 1). Median follow upwas 292 (78, 845) days in Chagas and 654 (158, 987) days in non-Chagas cardiomyopathy patients (pb0.005). Three (9%) patients died during the study period; 2 in Chagas and 1 in non-Chagas patients (pN0.05). The frequency of shock occurrence observed in our Chagas cardiomyopathy cohort in this study was similar to that reported in patients with non-Chagas cardiomyopathy [3]. The lower mortality rate observed in our study in comparison to studies of secondary prevention of SCD [4] in Chagas disease patients may partially be explained by the lower frequency of shock occurrence. Also, the frequency of shock episodes observed in this investigation was lower than that seen in Chagas disease patients receiving ICD therapy for secondary prevention of SCD [4–6]. This can account, at least in part, for the similarity of mortality rate observed in our study in comparison to that seen in non-Chagas cardiomyopathy patients [7]. The higher frequency of VF episodes/per patient observed in Chagas cardiomyopathy patients in this study can also reflect the characteristics of the pathogenesis of Chagas disease [8]. In patients with Chagas cardiomyopathy, foci of confluent fibrosis intermingled with mononuclear cell infiltrate disseminated throughout the myocardium are frequently seen. Moreover, myocardial ischemia

Rationale and design of the multicentre, randomized, double‐blind, placebo‐controlled Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT)

Hospitalizations for acute heart failure syndromes (AHFS) are associated with high post-discharge mortality and readmission rates in spite of available therapies. Renin-angiotensin-aldosterone system (RAAS) antagonists improve outcomes in outpatients with heart failure (HF) and reduced ejection fraction, however these therapies have not been tested in AHFS. Aliskiren is a direct renin inhibitor (DRI) that is known to enhance RAAS inhibition, which may result in improved clinical outcomes in AHFS. The aim of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) study is to evaluate the effect of aliskiren on cardiovascular death and HF in AHFS patients. ASTRONAUT will be an event-driven trial with an estimated enrolment of 1782 patients hospitalized with worsening chronic HF, a left ventricular ejection fraction ≤40%, and an estimated glomerular filtration rate ≥40 mL/min/1.73 m(2). Patients will be randomized 1:1 in a double-blind fashion to receive aliskiren or placebo, in addition to standard HF therapy. The primary endpoint will be a composite of time to either cardiovascular death or first occurrence of HF re-hospitalization. Aliskiren is a DRI with a favourable neurohormonal and haemodynamic profile that may benefit patients hospitalized with worsening HF. Given the neurohormonal abnormalities that are present during and after hospitalization for AHFS, it is hypothesized that adding aliskiren to standard therapy will reduce post-discharge mortality and re-hospitalization. NCT00894387.

Current outcome of heart transplantation: a 10-year single centre perspective and review

Heart transplantation (HTx), the gold standard therapy for advanced heart failure, is limited by donor availability; alternative therapies are now becoming available. We examined the outcome of HTx with current immunosuppressive and adjunctive therapy. We analysed the outcome of 399 consecutive patients who underwent transplantation at our centre (1995-2007). Prior to HTx 23% (98) required inotropic support, 8.5% (34) an intra-aortic balloon pump and 11% (43) a ventricular assist device. Actuarial patient survival was 86% at 30 days, 79% at 1 year and 62% at 10 years. Survival was similar regardless of the heart failure severity, P=0.22. The cumulative incidence of allograft vasculopathy, Costanzo grade≥2, was 7% at 5 years and 23% by 10 years with an 11% cumulative probability of requiring a percutaneous coronary intervention by 10 years. Allograft function was preserved with a mean±SD left ventricular ejection fraction of 73±7% at 1 year and 74±8% at 10 years. The cumulative incidence of malignancy by 10 years was 27% (skin malignancy 13% and post transplant lymphoproliferative diseases 10%). The cumulative incidence of developing chronic kidney disease (CKD) with an estimated glomerular filtration rate≤45 ml/min/1.73 m2 was 42% at 1 year, 62% at 5 years and 72% at 10 years and of requiring long-term renal replacement therapy was 10.6% at 10 years. HTx provided good medium-term survival for patients with advanced heart failure, independent of its severity. The incidence of allograft vasculopathy was lower than reported previously but malignancy and CKD remain cause for concern.

Intolerance to β‐blockade in a mouse model of δ‐sarcoglycan‐deficient muscular dystrophy cardiomyopathy

Patients with mutations predisposing to cardiomyopathy often have routine assessments of left ventricular function. It is unclear whether asymptomatic mild cardiomyopathy should be treated with standard heart failure therapies. We tested the effect of metoprolol on cardiac haemodynamics and pathology in two animal models for muscular dystrophy and cardiomyopathy. Treatment started at an early stage in the development of the cardiomyopathy. Metoprolol was given orally (2.5 mg/kg/day) over 8 weeks to mdx mice (model for Duchenne muscular dystrophy) and δ-sarcoglycan-deficient (Sgcd(null)) mice (model for Limb girdle muscular dystrophy type 2F). In vivo pressure-volume loops, fibrosis, in vivo myocyte sarcolemmal injury, and β-adrenergic receptor mRNA were assessed. In β-blocked mdx mice, there was a beneficial reduction in afterload and restored contractility resulting in an increased stroke volume. In contrast, in Sgcd(null) mice, there was marked deterioration in haemodynamics (prolonged relaxation, Tau, and reduced stroke volume). Furthermore, challenging the β-blocked Sgcd(null) mice with the β-adrenergic agonist dobutamine led to markedly increased mortality. Patterns of sarcolemmal injury or β-adrenergic receptor mRNA could not account for this, though the acute rise in markers of active relaxation suggested abnormally high levels of intracellular calcium. β-Blockers may not necessarily be beneficial in all cardiomyopathies, even when given at an early stage of development. Clinical trials of β-blockers in muscular dystrophy-associated cardiomyopathy may need to stratify patients by genotype.

Double-Blind Placebo-Controlled Comparison of Enoximone and Dobutamine Infusions in Patients With Moderate to Severe Chronic Heart Failure

Few data exist on the safety of transferring patients to standard oral therapy for chronic heart failure (CHF) after acute management with inotropic agents. This study compares hemodynamic responses and cardiac dysrhythmic effects of continuous infusion of enoximone, dobutamine, or placebo in patients with moderate to severe CHF. The authors enrolled 136 patients who were randomly assigned to either open-label dobutamine or double-blind enoximone vs placebo. After 24 hours of treatment, the study was unblinded. Patients receiving placebo completed the study. Patients receiving enoximone or dobutamine received the infusion for an additional 24 hours and were then switched to standard oral therapy for 72 hours. Compared with placebo, both enoximone and dobutamine increased cardiac index and decreased pulmonary capillary wedge pressure (PCWP). Compared with dobutamine, enoximone significantly increased cardiac index after the first 24 hours of infusion and significantly decreased PCWP throughout the infusion period. There was no difference in the incidence of arrhythmias between enoximone and dobutamine. More patients (65%) tolerated the switch to oral therapy in the enoximone group compared with dobutamine (49%; P =.12). Enoximone is effective in improving the hemodynamics in patients with moderate to severe CHF and is tolerated at least as well as dobutamine.

Heart Transplantation for Heart Failure in Children

Heart transplantation has become standard therapy for end-stage heart failure in children with cardiomyopathy as well as complex congenital heart disease, and has a significant effect on survival and quality of life. The indications for listing and referral for transplantation are outlined. Evaluation for heart transplantation is discussed, including full pretransplant assessment. ABO incompatible listing and HLA sensitization are discussed, and listing algorithms are outlined for different countries.

Rosuvastatin added to standard heart failure therapy improves cardiac remodelling in heart failure rats with preserved ejection fraction

Although statins may provide potential therapeutic pathways for patients with heart failure with preserved ejection fraction (HFpEF), no studies have evaluated statins in combination with standard HF therapy, which would reflect clinical practice more closely. To address this question, we evaluated whether rosuvastatin added to a standard HF therapy provides additional improvement in cardiac structure and function in rats with hypertensive heart failure (SHHF). Two-month-old SHHF rats were randomly assigned to four groups: (i) non-treated SHHF rats; (ii) rosuvastatin-treated SHHF rats; (iii) SHHF rats treated with quinapril plus torasemide plus carvedilol (considered as standard HF therapy); and (iv) SHHF rats treated with the combination of standard HF therapy and rosuvastatin. The administration of a standard anti-hypertensive HF therapy to SHHF rats for 17 months attenuated left ventricular (LV) chamber dilatation, cardiac hypertrophy, fibrosis, and inflammation compared with non-treated SHHF rats. Rosuvastatin alone prevented LV dilatation and cardiac inflammation similar to standard HF therapy-treated SHHF, despite being unable to normalize blood pressure (BP) or influence cardiac hypertrophy. However, and importantly, the addition of rosuvastatin to the standard HF therapy further prevented LV dilatation, preserved cardiac function, and normalized inflammation. These data show that the use of rosuvastatin plus a standard HF therapy results in a significant additional improvement in HF and cardiac remodelling in a rat model of HFpEF. These beneficial effects were independent of BP and plasma lipid changes, and seem to be due, at least in part, to decreased myocardial inflammation.

Optimal Antagonism of the Renin-Angiotensin-Aldosterone System

The cardiovascular and cardiorenal disease continuum comprises the transition from cardiovascular risk factors to endothelial dysfunction and atherosclerosis, to clinical complications such as myocardial infarction (MI) and stroke, to the development of persistent target-organ damage and, ultimately, to chronic congestive heart failure (CHF), end-stage renal disease or premature death. The renin-angiotensin-aldosterone system (RAAS) is involved in all steps along this pathway, and RAAS blockade with ACE inhibitors or angiotensin AT(1)-receptor antagonists (angiotensin receptor blockers; ARBs) has turned out to be beneficial for patient outcomes throughout the disease continuum. Both ACE inhibitors and ARBs can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. These drugs have further been shown to reduce end-organ damage in the heart, kidneys and brain. Aldosterone antagonists such as spironolactone and eplerenone are increasingly recognized as a third class of RAAS inhibitor with potent risk-reducing properties, especially but not solely with respect to the inhibition of cardiac remodelling and the possible prevention of heart failure. In secondary prevention, head-to-head comparisons of ACE inhibitors and ARBs, such as the recent ONTARGET study, provided evidence that, in addition to better tolerability, ARBs are non-inferior to ACE inhibitors in the prevention of clinical endpoints such as MI and stroke in cardiovascular high-risk patients. However, the combination of both ramipril and telmisartan at the maximally tolerated dosage achieved no further benefits and was associated with more adverse events such as symptomatic hypotension and renal dysfunction. In acute MI complicated by heart failure, the VALIANT trial has shown similar effects of ACE inhibition with captopril and ARB treatment with valsartan, but dual RAAS blockade did not further reduce events. In CHF, meta-analyses of RESOLVD, ValHeFT and CHARM-ADDED have shown that combined RAAS inhibition with an ACE inhibitor and ARB significantly reduced the morbidity endpoint in certain patient subgroups compared with standard therapy. However, in clinical practice, dual RAAS blockade is rarely employed, as seen, for instance, in the CORONA trial. The RALES and EPHESUS trials, investigating the effects of aldosterone blockade on cardiovascular outcomes in CHF patients, revealed that the addition of an aldosterone antagonist to standard heart failure therapy conferred powerful relative risk reductions for both morbidity and mortality. Future studies will elucidate whether this also holds true for patients who are asymptomatic or who have heart failure with preserved ejection fraction. In selected patients with renal disease, several studies have suggested that combined RAAS blockade brings about additional renoprotective antiproteinuric effects independent of blood pressure reduction, and large trials with robust endpoints are underway. In summary, combined therapy with several RAAS inhibitors is not recommended for all patients along the cardiorenovascular continuum. Patients with CHF with incomplete neuroendocrine blockade, as indicated, for example, by repetitive cardiac decompensation or refractory symptoms, might benefit from dual therapy as long as safety issues are well controlled. Finally, novel pharmacological agents such as the direct renin inhibitor aliskiren may provide additional therapeutic tools, but their role has yet to be established.

066 Vasodilatory capacity at peak exercise in treated heart failure patients are not diminished

Background Previous received dogma has propagated the concept that heart failure (HF) patients have compromised vasodilatory capacity during exercise through various vascular mechanisms, thereby reducing their exercise capacity through peripheral (vascular) factors rather than central (cardiac) factors. We tested whether such a concept is still valid in modern HF patients receiving current standard HF therapies. Methods and Results We recruited 150 female participants (133 normal healthy controls, age 48.5±13.1 (SD) years; 17 DCM patients, age 41.5±14.2 years) with no known coronary or other vascular diseases, and compared their central haemodynamic responses during volitional maximal exercise. The exercise capacity of controls spanned the same ranges as those of the HF patients. All patients performed symptom-limited cardiopulmonary exercise testing (CPX) with breath-by-breath analyses of respiratory gases and non-invasive haemodynamic measurements employing standard auscultatory sphygmomanometric and rebreathing methods. The patients performed a total of 30 CPX9s. The peak O2 consumption spanned from 1.20 to 2.45 L/min in DCM patients and from 1.15 to 2.44 L/min in controls. As shown in the figure, at peak exercise the systemic vascular resistances (SVR) of DCM patients were lower (532±154 dyn.s.cm-5) than those of controls (654±118 dyn.s.cm-5). Conclusion With modern HF therapy, the lower peak exercise SVR in HF patients compared to normal healthy controls demonstrates that there is no evidence of compromised systemic vasodilatory capacities in HF patients. The long-held dogma of vasodilatory incapacity in HF propagated >3 decades ago is no longer valid nowadays.

Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS‐HF)

In chronic heart failure (HF), aldosterone antagonists have been shown to improve survival in patients with low ejection fraction and moderate-to-severe symptoms [New York Heart Association (NYHA) classes III and IV]. Efficacy of these agents was also shown when they were administered to patients with left ventricular dysfunction and signs and symptoms of CHF early after acute myocardial infarction. It is not known whether the selective aldosterone antagonist eplerenone can improve outcomes in mildly symptomatic patients. The Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF) was designed to evaluate the effect of eplerenone on mortality and morbidity in patients with chronic systolic HF in NYHA class II. Methods Approximately 3100 patients with ejection fraction < or =30% and estimated glomerular filtration rate > or =30 mL/min/1.73 m(2) will be recruited. Patients are randomized 1:1 to double-blind eplerenone or placebo in addition to standard chronic HF therapy. Doses are adjusted from 25 mg every other day to 50 mg daily, depending on serum potassium. The primary endpoint is a composite of time to cardiovascular death or first hospital admission for worsening HF, whichever occurs first. The study will be complete when approximately 813 subjects experience a primary endpoint. Clinical Trials.gov. NCT00232180.

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

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. 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. 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. 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.

Himalayan P waves

A 22-year-old man presented with a history of breathlessness of around 6 months duration. The breathlessness was particularly prominent on walking. He had noted that his fingers were of a bluish hue over the prior 2 months. He denied any history of chest pain, syncope, cyanotic spells or arthritis during his childhood. The patient had a blood pressure of 114/74 mm of Hg, and the pulse rate was 75 beats/min and regular. The patient was tachypneic (rate, 24 breaths/min) and appeared cyanotic. Clubbing was present. Auscultation of the heart revealed a widely split second heart sound and a pansystolic murmur in the tricuspid area. The ECG revealed extremely tall ‘P’ waves, the so called Himalayan P waves, most prominently in leads II, III, aVF and V1. The P wave was most prominent in lead II where it was even taller than the QRS. These changes are suggestive of gross enlargement of the right atrium. The ECG also reveals a right bundle branch-like pattern in V1 preceded by a small q wave (Fig. 1). The Himalayan P waves are a result of a massively dilatated right atrium. These are classical for an Ebstein anomaly, although they have also been reported in a few other conditions such as tricuspid atresia and combined tricuspid and pulmonary stenosis [1–3]. In this case, the ECG picture and the clinical evidence of TR point to the diagnosis of an Ebstein anomaly and an echocardiography confirmed the diagnosis. The patient was started on standard heart failure therapy. On improvement, he was referred for tricuspid valve (TV) replacement. An Ebstein anomaly is a congenital defect of the TV characterized by downward displacement of the TV into the right ventricle. This results in atrialization of a portion of the right ventricle. The accompanying TR also contributes to the massive dilatation of the right atrium. The clinical presentation of an Ebstein anomaly is variable; around 50% patients present in infancy with features of cyanosis, heart failure and a cardiac murmur. In some patients, as in the present case, symptoms appear during teenage years or early adulthood. The symptoms may include exertional dyspnea, fatigue, palpitations (supraventricular tachycardia, associated Wolf Parkinson White syndrome), cyanosis or syncope. Echocardiography can help in establishing the diagnosis of an Ebstein anomaly in the majority of cases. The findings in such a case would include a dilatated right atrium, presence of tricuspid regurgitation and displacement of the leaflets of the TV [4]. An MRI may be used for diagnosis if images from echocardiography are not clear. Cardiac catheterization is rarely needed, but may be risky due to possible cardiac rhythm disturbances.

Evaluation of Bromocriptine in the Treatment of Acute Severe Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease that occurs in previously healthy women. We identified prolactin, mainly its 16-kDa angiostatic and proapoptotic form, as a key factor in PPCM pathophysiology. Previous reports suggest that bromocriptine may have beneficial effects in women with acute onset of PPCM. A prospective, single-center, randomized, open-label, proof-of-concept pilot study of women with newly diagnosed PPCM receiving standard care (PPCM-Std; n=10) versus standard care plus bromocriptine for 8 weeks (PPCM-Br, n=10) was conducted. Because mothers receiving bromocriptine could not breast-feed, the 6-month outcome of their children (n=21) was studied as a secondary end point. Blinded clinical, hemodynamic, and echocardiographic assessments were performed at baseline and 6 months after diagnosis. Cardiac magnetic resonance imaging was performed 4 to 6 weeks after diagnosis in PPCM-Br patients. There were no significant differences in baseline characteristics, including serum 16-kDa prolactin levels and cathepsin D activity, between the 2 study groups. PPCM-Br patients displayed greater recovery of left ventricular ejection fraction (27% to 58%; P=0.012) compared with PPCM-Std patients (27% to 36%) at 6 months. One patient in the PPCM-Br group died compared with 4 patients in the PPCM-Std group. Significantly fewer PPCM-Br patients (n=1, 10%) experienced the composite end point of poor outcome defined as death, New York Heart Association functional class III/IV, or left ventricular ejection fraction <35% at 6 months compared with the PPCM-Std patients (n=8, 80%; P=0.006). Cardiac magnetic resonance imaging revealed no intracavitary thrombi. Infants of mothers in both groups showed normal growth and survival. In this trial, the addition of bromocriptine to standard heart failure therapy appeared to improve left ventricular ejection fraction and a composite clinical outcome in women with acute severe PPCM, although the number of patients studied was small and the results cannot be considered definitive. Larger-scale multicenter and blinded studies are in progress to test this strategy more robustly.

Bromocriptine treatment associated with recovery from peripartum cardiomyopathy in siblings: two case reports

IntroductionPeripartum cardiomyopathy is a rare form of cardiomyopathy, with heterogeneous presentation occurring in women between one-month antepartum and six months postpartum. It carries a poor prognosis and a high risk of mortality.Case presentationWe report the development of peripartum cardiomyopathy in two sisters, 27- and 35-year-old African women, one of whom presented with a large left ventricular thrombus. Subsequently, both patients were treated with bromocriptine, heparin and standard therapy for heart failure (angiotensin converting enzyme inhibitors, beta-blockers and diuretics). During follow-up, the left ventricular thrombus observed in one patient degraded. Neither patient experienced a thrombotic event, and both experienced continuous improvements in cardiac function and New York Heart Association stage.ConclusionThe development of peripartum cardiomyopathy in two sisters indicates that there may be a genetic basis for this type of cardiomyopathy, and that women with a positive family history for peripartum cardiomyopathy may have an increased risk of developing the disease. This is also the first report of a patient experiencing degradation of a large left ventricular thrombus under standard therapy for heart failure with bromocriptine. It suggests that the use of bromocriptine in association with adequate anti-coagulation and heart failure therapy may be beneficial and safe.

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway.

Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC-induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-beta-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38alpha MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC-induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38alpha MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.

Myostatin

Cachexia in chronic heart failure (HF) is a major clinical problem that is still underestimated for its impact on morbidity, mortality, and healthcare expenditures. The pathophysiology of cardiac cachexia is characterized by a catabolic/anabolic imbalance. An important player in the development of muscle wasting and cachexia in HF may be myostatin. Article see p 419 Myostatin, also known as growth differentiation factor-8 (GDF-8), is a member of the transforming growth factor-β superfamily and was identified in 1997.1 In humans, myostatin is expressed almost exclusively in skeletal muscle and is essential for normal regulation of muscle mass through its actions as a negative regulator of muscle bulk.2 Gene disruption, either natural or by targeted mutation, leads to a marked increase in muscle mass due to hypertrophy and hyperplasia.1 This was clearly evident in a child with a mutation in the myostatin gene who had the ability to hold two 3-kg dumbbells at the age of 4 years.3 Myostatin has been shown to be upregulated in human immunodeficiency virus– and cancer-associated cachexia,4 with advanced age,5 and in chronic HF.6 In each of these conditions, a loss of skeletal muscle mass occurs that leads to a disproportionate loss of exercise tolerance and an early increase in muscle fatigue. Human cardiovascular studies concerning myostatin are generally lacking. Before the report by Heineke et al7 in this issue of Circulation , 2 animal studies reported increased myostatin expression in the peri-infarct zone in sheep8 and in a rat model of volume overload induced by an aortocaval shunt.9 Importantly, the expression remained increased after 4 weeks in the shunt model. In 2008, Hoenig10 presented a hypothesis that myostatin acts as a mediator of cardiac cachexia, insulin resistance, and osteoporosis in chronic HF. To date, it …

Myocarditis

Myocarditis is an uncommon, potentially life-threatening disease that presents with a wide range of symptoms in children and adults. Viral infection is the most common cause of myocarditis in developed countries, but other etiologies include bacterial and protozoal infections, toxins, drug reactions, autoimmune diseases, giant cell myocarditis, and sarcoidosis. Acute injury leads to myocyte damage, which in turn activates the innate and humeral immune system, leading to severe inflammation. In most patients, the immune reaction is eventually down-regulated and the myocardium recovers. In select cases, however, persistent myocardial inflammation leads to ongoing myocyte damage and relentless symptomatic heart failure or even death. The diagnosis is usually made based on clinical presentation and noninvasive imaging findings. Most patients respond well to standard heart failure therapy, although in severe cases, mechanical circulatory support or heart transplantation is indicated. Prognosis in acute myocarditis is generally good except in patients with giant cell myocarditis. Persistent, chronic myocarditis usually has a progressive course but may respond to immunosuppression.