Regioselective C(sp2)-C(sp3) Coupling Mediated by Classical and Rollover Cyclometalation.

By taking advantage of a sequence of oxidative addition/reductive elimination reactions, Pt(II) cyclometalated derivatives are able to promote a rare C(sp2)-C(sp3) bond coupling, resulting in the production of novel methyl-substituted pyridines and bipyridines. Starting from 6-phenyl-2,2'-bipyridine, the step-by-step full sequence of reactions has been followed, leading to the unprecedented 3-methyl-6-phenyl-2,2'-bipyridine, which was isolated and fully characterized. The synthesis involves the following steps: (1) rollover cyclometalation to give the starting complex [Pt(N^C)(DMSO)Me]; (2) the synthesis of a more electron-rich complex [Pt(N^C)(PPh3)Me] by the substitution of DMSO with triphenylphosphine; (3) oxidative addition with methyl iodide to give the Pt(IV) complex [Pt(N^C)(PPh3)(Me)2(I)]; (4) iodide abstraction with silver tetrafluoborate to give an unstable pentacoordinate intermediate, which rapidly evolves through a carbon-carbon reductive coupling, forming a new C(sp3)-C(sp2) bond; (5) finally, the extrusion and characterization of the newly formed 3-methyl-6-phenyl-2,2'-bipyridine. The reaction has been therefore extended to a well-known classical cyclometalating ligand, 2-phenylpyridine, demonstrating that the method is not restricted to rollover derivatives. Following the same step-by-step procedure, 2-phenylpyridine was converted to 2-o-tolyl-pyridine, displaying the potential application of the method to the larger family of classical cyclometalated complexes. The application of this protocol may be useful to convert an array of heterocyclic compounds to their methyl- or alkyl-substituted analogs.

Proportion of patients needing an implantable cardioverter defibrillator on the basis of current guidelines: impact on healthcare resources in Italy and the USA. Data from the ALPHA study registry.

AIMS: Implantable cardioverter defibrillators (ICD) improve survival in selected patients with left ventricular dysfunction or heart failure (HF). The objective is to estimate the number of ICD candidates and to assess the potential impact on public health expenditure in Italy and the USA. METHODS AND RESULTS: Data from 3513 consecutive patients (ALPHA study registry) were screened. A model based on international guidelines inclusion criteria and epidemiological data was used to estimate the number of eligible patients. A comparison with current ICD implant rate was done to estimate the necessary incremental rate to treat eligible patients within 5 years. Up to 54% of HF patients are estimated to be eligible for ICD implantation. An implantation policy based on guidelines would significantly increase the ICD number to 2671 implants per million inhabitants in Italy and to 4261 in the USA. An annual increment of prophylactic ICD implants of 20% in the USA and 68% in Italy would be necessary to treat all indicated patients in a 5-year timeframe. CONCLUSION: Implantable cardioverter defibrillator implantation policy based on current evidence may have significant impact on public health expenditure. Effective risk stratification may be useful in order to maximize benefit of ICD therapy and its cost-effectiveness in primary prevention.

Predictors of mortality and hospitalization for cardiac causes in patients with heart failure and nonischemic heart disease: a subanalysis of the ALPHA study.

BACKGROUND: Several studies have searched for predictors of clinical outcome in patients with heart failure (HF). However, since they were collected in clinical trials, most data were subject to selection biases and do not specifically apply to patients with nonischemic heart disease. This study examined the impact of several variables on combined all-cause mortality and hospitalization for cardiac causes, in consecutive ambulatory patients with HF included in the ALPHA registry. METHODS AND RESULTS: This analysis included 446 patients with HF and nonischemic heart disease, in New York Heart Association functional class II or III, and a left ventricular (LV) ejection fraction below 40%. In 126 patients (73%) the disease was idiopathic dilated cardiomyopathy, in 72 (16%) hypertensive, in nine (2%) valvular, and in 39 (9%) of other etiologies. The median age was 61 years (range 51-69 years) and 349 (78%) patients were men. Over a median follow-up of 31 months (range 23-40), 82 patients (18%) died or were hospitalized for cardiac causes. In a proportional hazard (Cox) regression model, maximal oxygen consumption (HR 0.9, P = 0.001), LV end-diastolic diameter (HR 1.07, P < 0.001), resting systolic blood pressure (HR 0.97, P < 0.005), and hemoglobin (HR 0.86, P < 0.05) were independent predictors of the combined study endpoint. CONCLUSIONS: In an unselected population of patients with HF and nonischemic heart disease, a reduced exercise capacity, large LV end-diastolic diameter, low systolic blood pressure, and hemoglobin were correlated with long-term all-cause mortality or hospitalization for cardiac causes. These observations may help stratifying and tailoring the treatment of patients with HF and nonischemic heart disease.

Atrial fibrillation in heart failure patients: prevalence in daily practice and effect on the severity of symptoms. Data from the ALPHA study registry.

BACKGROUND: Estimates of the prevalence of atrial fibrillation (AF) in heart failure (HF) originate from patients enrolled in clinical trials. AIMS: To assess the prevalence and clinical correlates of AF among HF patients in everyday clinical practice from HF patients screened for the T-wave ALternans in Patients with Heart fAilure (ALPHA) study; to investigate the correlation between AF and functional status. METHODS AND RESULTS: Consecutive patients (N=3513) seen at nine Heart Failure Clinics were studied; 21.4% were in AF. AF prevalence was greater with increasing age (OR 1.04/year, p<0.001) in non-ischaemic cardiomyopathy (OR 2.34, p<0.001) and with increasing NYHA class (p<0.0001). Multiple logistic regression predictors of AF were age >70 years (OR 2.35), NYHA class II III or IV vs class I (OR 1.8, 4.4 and 3.1) and non-ischaemic cardiomyopathy (OR 3.2). A logistic model indicated that AF was associated with a 2.5 OR of being in NYHA class III-IV vs I-II while accounting for age, gender, left ventricular ejection fraction (LVEF), and aetiology of HF. CONCLUSIONS: The prevalence of AF in HF patients exceeds 20%, and increases with age and functional class. The presence of AF leads to a more severe NYHA class, indicating that AF contributes to the severity of heart failure.