Luca Salvatore

Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol

OBJECTIVES The purpose of this study was to analyze whether long-term treatment with the nonselective beta-adrenergic blocking agent carvedilol may have beneficial effects in patients with dilated cardiomyopathy (DCM), who are poor responders in terms of left ventricular (LV) function and exercise tolerance to chronic treatment with the selective beta-blocker metoprolol. BACKGROUND Although metoprolol has been proven to be beneficial in the majority of patients with heart failure, a subset of the remaining patients shows long-term survival without satisfactory clinical improvement. METHODS Thirty consecutive DCM patients with persistent LV dysfunction (ejection fraction #40%) and reduced exercise tolerance (peak oxygen consumption ,25 ml/kg/min) despite chronic (.1 year) tailored treatment with metoprolol and angiotensin-converting enzyme inhibitors were enrolled in a 12-month, open-label, parallel trial and were randomized either to continue on metoprolol (n 5 16, mean dosage 142 6 44 mg/day) or to cross over to maximum tolerated dosage of carvedilol (n 5 14, mean dosage 74 6 23 mg/day). RESULTS At 12 months, patients on carvedilol, compared with those continuing on metoprolol, showed a decrease in LV dimensions (end-diastolic volume 28 6 7 vs. 17 6 6 ml/m 2 ,p 5 0.053; end-systolic volume 27 6 5 vs. 16 6 4 ml/m 2 ,p 5 0.047), an improvement in LV ejection fraction (17 6 3% vs. 21 6 2%, p 5 0.045), a reduction in ventricular ectopic beats (212 6 9 vs. 162 6 50 n/h, p 5 0.05) and couplets (20.5 6 0.4 vs. 11.5 6 0.6 n/h, p 5 0.048), no significant benefit on symptoms and quality of life and a negative effect on peak oxygen consumption (20.6 6 0.6 vs. 11.3 6 0.5 ml/kg/min, p 5 0.03). CONCLUSIONS In DCM patients who were poor responders to chronic metoprolol, carvedilol treatment was associated with favorable effects on LV systolic function and remodeling as well as on ventricular arrhythmias, whereas it had a negative effect on peak oxygen consumption. (J Am Coll Cardiol 1999;33:1926 ‐34)

Metoprolol in dilated cardiomyopathy: Is it possible toidentify factors predictive of improvement?

Background: Some controlled clinical trials showed a beneficial effect of beta-blockers on symptoms, exercise tolerance, and left ventricular function in dilated cardiomyopathy. The purpose of this study was to investigate if there are clinical variables at baseline that could predict a favorable response to long-term metoprolol therapy.

Malfunction of cardiac devices after radiotherapy without direct exposure to ionizing radiation: mechanisms and experimental data

AIMS Malfunctions of cardiac implantable electronical devices (CIED) have been described after high-energy radiation therapy even in the absence of direct exposure to ionizing radiation, due to diffusion of neutrons (n) causing soft errors in inner circuits. The purpose of the study was to analyse the effect of scattered radiation on different types and models of CIED and the possible sources of malfunctions. METHODS AND RESULTS Fifty-nine explanted CIED were placed on an anthropomorphous phantom of tissue-equivalent material, and a high-energy photon (15 MV) radiotherapy course (total dose = 70 Gy) for prostate treatment was performed. All devices were interrogated before and after radiation. Radiation dose, the electromagnetic field, and neutron fluence at the CIED site were measured. Thirty-four pacemakers (PM) and 25 implantable cardioverter-defibrillators (ICD) were analysed. No malfunctions were detected before radiation. After radiation a software malfunction was evident in 13 (52%) ICD and 6 (18%) PM; no significant electromagnetic field or photon radiations were detected in the thoracic region. Neutron capture was demonstrated by the presence of the (198)Au((197)Au + n) or (192)Ir((191)Ir + n) isotope activation; it was significantly greater in ICD than in PM and non-significantly greater in damaged devices. A greater effect in St Jude PM (2/2 damaged), Boston (9/11), and St Jude ICD (3/6) and in older ICD models was observed; the year of production was not relevant in PM. CONCLUSION High-energy radiation can cause different malfunctions on CIED, particularly ICD, even without direct exposure to ionizing radiation due to scattered radiation of neutrons produced by the linear accelerator.

Long term survival effect of metoprolol in dilated cardiomyopathy

Objective To evaluate the additive effect of metoprolol treatment on long term incidence of fatal and non-fatal cardiac events in idiopathic dilated cardiomyopathy. Design 586 patients with idiopathic dilated cardiomyopathy were prospectively enrolled in a multicentre registry and followed up for a mean (SD) of 52 (32) months. Metoprolol, carefully titrated to the maximum tolerated dose, was added to conventional heart failure treatment in 175 patients. Results Survival and transplant-free survival at seven years were significantly higher in the 175 metoprolol treated patients than in the remaining 411 on standard treatment (81%v 60%, p < 0.001, and 69% v 49%, p < 0.001, respectively). By multivariate analysis, metoprolol independently predicted survival and transplant-free survival (relative risk reduction values for all cause mortality and combined mortality or transplantation 51% (95% confidence interval 21% to 69%), p = 0.002, and 34% (5% to 53%), p = 0.01, respectively). New York Heart Association class, left ventricular end diastolic diameter, and pulmonary wedge pressure were also predictive. Seven year survival (80% v 62%, p = 0.004) and transplant-free survival (68% v 51%, p = 0.005) were significantly higher in 127 metoprolol treated cases than in 127 controls selected from the entire control cohort and appropriately matched. Metoprolol was associated with a 30% reduction in all cause mortality (7% to 48%, p = 0.015) and a 26% reduction in mortality or transplantation (7% to 41%, p = 0.009). Conclusions—The addition of metoprolol to standard heart failure treatment, including angiotensin converting enzyme inhibitors, was effective in the long term, reducing both all cause mortality and transplantation in patients with idiopathic dilated cardiomyopathy.

Management of Bradyarrhythmias in Emergency

The sudden appearance in patients of changes in heart rhythm is a situation that requires rapid diagnosis and treatment in emergency departments and intensive care units. The slowdown and block of cardiac impulse conduction form the basis of symptomatic bradycardia.

Guidelines for the Management of Patients with Heart Failure

Chronic congestive heart failure (HF) is a highly disabling, costly, and deadly syndrome which affects a hundred million people worldwide [1]. Large clinical trials have shown that drugs which antagonise the renin–angiotensin–aldosterone system [angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), aldosterone receptor antagonists] and sympathetic nervous system (beta-blockers) are highly effective in reducing the rates of mortality and morbidity in patients with left ventricular (LV) chamber dilation/systolic dysfunction cardiomyopathies, whether of ischaemic or non-ischaemic aetiology (Tables 1–3) [2–5]. Although no survival benefit has been documented with diuretics and digoxin, the former remain a cornerstone in the treatment of HF patients as the most efficacious means of counteracting fluid retention [6], while the latter can be of value to achieve further improvements in symptoms and quality of life [7]. In addition, several randomised controlled trials have recently demonstrated the effectiveness of implantable cardioverter defibrillator (ICD) therapy for the primary and secondary prevention of unexpected cardiac sudden death (Table 4) [8–10]. Despite the availability of these useful therapies, HF patients continue to be affected by progressively worsening symptoms, the need for recurrent high-cost hospitalisations, poor quality of life, and shortened life expectancy [11]. It is indisputable that the persistence of high morbidity and mortality rates can be explained, at least in part, by the fact that treatments proven to be effective in randomised controlled trials have not been applied to all suitable patients encountered in the clinical arena [12]. Following from this, guidelines for the management of the syndrome have emerged in the last years as an helpful tool to translate scientific evidence into daily practice, providing indications for a more appropriate use of currently available therapeutic strategies [13, 14].

185 Effect of carvedilol versus metoprolol immediate release on 24-hour heart rate in patients with idiopathic dilated cardiomyopathy. A 1-year cross-over study

Death or CV Hospitalisation 963 1016 0.93 0.097 Death or CV Hospitalisation (63.7%) (66.9%) (0.85-1.01) Death or WHF Hospitalization 774 841 0.89 0.019 Death or WHF Hospitalization (51.2%) (55.4%) (0.81-0.98) Death or WHF (Investigator 865 924 0.91 0.046 assessment) (57.2%) (60.9%) (0.83-1.00) CV death, transplant, non-fatal 745 815 0.88 0.013 MI or WHF (49.3%) (53.7%) (0.80-0.97) CV death or H for non-fatal MI, WHE unstable angina, atrial fibrillation 821 885 0.90 0.023 or ventricuIar arrhythmia (54.3%) (58.3%) (0.81-0.99) New-onset diabetes 122/1151 149/1147 0.78 0.040 (10.6%) ( 1 3 % ) (0.6i-0.99) Withdrawal from study medication 762 827 0.91 0.063 for any reason (50.4%) (54.5%) (0.83-1,01)

ACE-Inhibitors, β-Blockers, Spironolactone: Do We Need Many More Drugs to Treat Chronic Heart Failure?

Over the last two decades, considerable insights into the pathophysiology of chronic congestive heart failure (HF) have been gained to suggest that the overstimulation of biologically active pathways - primarily the reninangiotensin-aldosterone and sympathoadrenergic systems - may play a key role in determining the progression of the syndrome [1]. Supporting this concept, a large body of evidence has been accumulated to show that drugs possessing the ability to counteract these up-regulated neuroendocrine mechanisms may represent an effective therapeutic strategy to improve the course of the disease [2-7].