Francesco Pelliccia

Acute Anti-Ischemic Effect of Testosterone in Men With Coronary Artery Disease

BACKGROUNDnThe role of testosterone on the development of coronary artery disease in men is controversial. The evidence that men have a greater incidence of coronary artery disease than women of a similar age suggests a possible causal role of testosterone. Conversely, recent studies have shown that the hormone improves endothelium-dependent relaxation of coronary arteries in men. Accordingly, the aim of the present study was to evaluate the effect of acute administration of testosterone on exercise-induced myocardial ischemia in men.nnnMETHODS AND RESULTSnAfter withdrawal of antianginal therapy, 14 men (mean age, 58+/-4 years) with coronary artery disease underwent 3 exercise tests according to the modified Bruce protocol on 3 different days (baseline and either testosterone or placebo given in a random order). The exercise tests were performed 30 minutes after administration of testosterone (2.5 mg IV in 5 minutes) or placebo. All patients showed at least 1-mm ST-segment depression during the baseline exercise test and after placebo, whereas only 10 patients had a positive exercise test after testosterone. Chest pain during exercise was reported by 12 patients during baseline and placebo exercise tests and by 8 patients after testosterone. Compared with placebo, testosterone increased time to 1-mm ST-segment depression (579+/-204 versus 471+/-210 seconds; P<0. 01) and total exercise time (631+/-180 versus 541+/-204 seconds; P<0. 01). Testosterone significantly increased heart rate at the onset of 1-mm ST-segment depression (135+/-12 versus 123+/-14 bpm; P<0.01) and at peak exercise (140+/-12 versus 132+/-12 bpm; P<0.01) and the rate-pressure product at the onset of 1-mm ST-segment depression (24 213+/-3750 versus 21 619+/-3542 mm Hgxbpm; P<0.05) and at peak exercise (26 746+/-3109 versus 22 527+/-5443 mm Hgxbpm; P<0.05).nnnCONCLUSIONSnShort-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.

Predictors of sudden death in idiopathic dilated cardiomyopathy

Survival in idiopathic dilated cardiomyopathy (IDC) has long been related only to left ventricular performance,1 yet there is now evidence that patients with IDC might die suddenly and unexpectedly.2,3 Although sudden death in IDC is most likely the result of a terminal malignant arrhythmia, the predictive value of complex ventricular ectopic complexes and of clinical and hemodynamic features is still controversial.4–6 We reviewed our experience with 104 consecutive patients with IDC to investigate which factors are most closely associated with sudden death.

Pathologic evidence of extensive left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (also known as arrhythmogenic right ventricular dysplasia) is characterized by adipose or fibroadipose tissue replacement of the right ventricular myocardium, whereas the left ventricle is substantively spared. Two cases of the disease with evidence of extensive left ventricular involvement at pathologic examination are described. Hearts from two patients who died suddenly showed full-thickness right ventricular fatty infiltration associated with extensive left ventricular involvement (greater than 50% of myocardial thickness). These findings might explain the reported clinical features of left ventricle dysfunction in a subset of patients with arrhythmogenic right ventricular cardiomyopathy. In view of the biventricular involvement of the disease, it should simply be termed arrhythmogenic cardiomyopathy.

Comorbidities Frequency in Takotsubo Syndrome: An International Collaborative Systematic Review Including 1109 Patients

BACKGROUNDnTo identify predisposing factors that can result in the onset of takotsubo syndrome, we performed an international, collaborative systematic review focusing on clinical characteristics and comorbidities of patients with takotsubo syndrome.nnnMETHODSnWe searched and reviewed cited references up to August 2013 to identify relevant studies. Corresponding authors of selected studies were contacted and asked to provide additional quantitative details. Data from each study were extracted by 2 independent reviewers. The cumulative prevalence of presenting features and comorbidities was assessed. Nineteen studies whose authors sent the requested information were included in the systematic review, with a total of 1109 patients (951 women; mean age, 59-76 years). Evaluation of risk factors showed that obesity was present in 17% of patients (range, 2%-48%), hypertension in 54% (range, 27%-83%), dyslipidemia in 32% (range, 7%-59%), diabetes in 17% (range, 4%-34%), and smoking in 22% (range, 6%-49%). Emotional stressors preceded takotsubo syndrome in 39% of patients and physical stressors in 35%. The most common comorbidities were psychological disorders (24%; range, 0-49%), pulmonary diseases (15%; range, 0-22%), and malignancies (10%; range, 4%-29%). Other common associated disorders were neurologic diseases (7%; range, 0-22%), chronic kidney disease (7%; range, 2%-27%), and thyroid diseases (6%; range, 0-37%).nnnCONCLUSIONSnPatients with takotsubo syndrome have a relevant prevalence of cardiovascular risk factors and associated comorbidities. Such of associations needs to be evaluated in further studies.

Takotsubo syndrome (Stress Cardiomyopathy): An intriguing clinical condition in search of its identity

Takotsubo syndrome is a relatively frequent clinical entity presenting typically as an acute coronary syndrome in the absence of obstructive coronary artery disease and characterized angiographically by transient left ventricular systolic dysfunction, sparing the basal segments of the left ventricle (apical ballooning). Takotsubo syndrome characteristically affects peri- or postmenopausal women, albeit recent series show that men also are at risk. Takotsubo syndrome is characteristically triggered by severe emotional or physical stress, which suggests a pathogenic role for increased sympathetic activity leading to myocardial perfusion abnormalities and ventricular dysfunction. The reasons why severe emotional and physical stress result in the development of takotsubo syndrome in certain individuals but not others is still a matter of speculation, but strongly suggests the existence of predisposing factors/mechanisms in certain subjects. The present article reviews the different factors that can play a role in the development of takotsubo syndrome in different patients. We propose that triggers (ie, emotional stressors, physical stressors, iatrogenic stressors, and neurologic triggers), pathogenic mechanisms (ie, increased catecholamine levels, coronary vasomotor abnormalities leading to myocardial ischemia), and predisposing factors (ie, cardiovascular risk factors, endothelial dysfunction, comorbidities) all interact in a complex fashion and possibly differently in different patients to cause takotsubo syndrome. Identifying these factors may help in preventing and managing the condition more effectively.

Angiotensin II receptor antagonism with telmisartan increases number of endothelial progenitor cells in normotensive patients with coronary artery disease: A randomized, double-blind, placebo-controlled study

INTRODUCTIONnCirculating endothelial progenitor cells (EPCs) provide an endogenous repair mechanism of the dysfunctional endothelium and therefore can play a crucial role in the pathophysiology of coronary artery disease (CAD). Angiotensin II receptor antagonism has been shown to be able to increase EPCs in hypertension but its effect in patients with CAD is unknown. Aim of this study was to evaluate whether telmisartan, an angiotensin II receptor antagonist, can modify the number of subpopulations of EPCs and may in turn affect the endothelial function of normotensive patients with CAD.nnnMETHODSnIn a prospective double-blind parallel group study, 40 normotensive patients with CAD were randomly treated with telmisartan (80 mg) or placebo for 4 weeks at time of coronary angiography. Measurements of EPCs and assessment of flow-mediated dilatation (FMD) of the brachial artery was performed before and after therapy.nnnRESULTSnAbsolute number of EPCs was similar at baseline in the telmisartan and placebo groups. After 4 weeks treatment, CD34+/KDR+/CD45- cells increased significantly in the telmisartan group (from 0.010+/-0.003 to 0.014+/-0.004%, P=0.0001) but not in the placebo group (from 0.009+/-0.004 to 0.009+/-0.005%, NS). Similarly, CD133+/KDR+/CD45- cells raised significantly with telmisartan (from 0.003+/-0.002 to 0.006+/-0.002%, P=0.0001) but not with placebo (from 0.004+/-0.003 to 0.003+/-0.002%, NS). Also, CD14+/CD45+ cells increased significantly with telmisartan (from 0.005+/-0.002 to 0.008+/-0.002%, P=0.0001) and were unchanged with placebo (0.006+/-0.002 vs. 0.005+/-0.003%, NS). FMD improved significantly in patients who received telmisartan (10.4+/-3.9%, P=0.0015 vs. baseline) but did not change in the placebo group (5.9+/-2.8%; P=0.32 vs. baseline; telmisartan vs. placebo, P=0.002). A significant positive correlation was found in the telmisartan group between the improvement in FMD and the increase in CD34+/KDR+/CD45- cells and CD133+/KDR+/CD45- cells (r=0.55, P<0.01, and r=0.49, P<0.05, respectively).nnnCONCLUSIONnAngiotensin II receptor antagonism with telmisartan increases the number of regenerative EPCs and improves endothelial function in normotensive patients with CAD. These novel effects are interrelated and can explain, at least in part, why telmisartan has beneficial cardiovascular effects independent of its blood pressure lowering action.

Effectiveness of Two-Year Clopidogrel Aspirin in Abolishing the Risk of Very Late Thrombosis After Drug-Eluting Stent Implantation (from the TYCOON (Two-Year ClOpidOgrel Need) Study)

It remains unclear whether dual antiplatelet therapy >12 months might carry a better prognosis after percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). To address the hypothesis that in the real world the risk of very late thrombosis after PCI with DESs can be decreased by an extended use of clopidogrel, we set up the Two-Year ClOpidOgrel Need (TYCOON) registry and prospectively investigated the impact on very late thrombosis of 12- versus 24-month dual antiplatelet regimens in an unselected population. The registry enrolled 897 consecutive patients who underwent PCI with stenting from January 1, 2003, to December 31, 2004, and had dual antiplatelet therapy. All patients had a 4-year clinical follow-up. In the 447 patients with DES implantation, the dual antiplatelet regimen after PCI was given for 12 months in the 173 patients treated in 2003 (12-month group) and for 24 months in the 274 patients treated in 2004 (24-month group). Comparison between groups did not reveal any significant difference in baseline clinical characteristics, angiographic and procedural features, and major adverse cardiac events. During follow-up, there were 5 cases of stent thrombosis after PCI in the 12-month DES group and 1 case in the 24-month DES group (p = 0.02). Specifically, there were 2 cases of subacute thrombosis (1 in each group), no case of late thrombosis, and 4 cases of very late thrombosis occurring at 13, 15, 17, and 23 months after DES implantation in the 12-month group only. In conclusion, a 2-year dual antiplatelet regimen with aspirin and clopidogrel can prevent the occurrence of very late stent thrombosis after PCI with DESs.

Resting and ambulatory ECG predictors of mode of death in dilated cardiomyopathy

With the purpose of verifying whether the electrocardiogram (ECG) pattern alone can predict the mode of death in dilated cardiomyopathy, data from 12-lead ECGs and 48-hour arrhythmia monitoring were evaluated in 67 patients with dilated cardiomyopathy. During a mean follow-up period of 3 +/- 2 years, death from congestive heart failure occurred in 18 patients (27%), whereas 10 (15%) died suddenly (NS). Multivariate analysis showed that left bundle branch block (p < 0.001) and left atrial enlargement (p < 0.001) were independently related to death from congestive heart failure. Ventricular arrhythmias of Lown grade 4A or 4B (p < 0.001) and repolarization time, as assessed by QTc-QRS interval (p < 0.05), were independent predictors of sudden death. It is concluded that ECG features alone may be helpful for risk factor characterization of dilated cardiomyopathy patients, provided that multiple ECG criteria are utilized at time of diagnosis.

A pilot randomized study of ranolazine for reduction of myocardial damage during elective percutaneous coronary intervention

BACKGROUNDnRanolazine is a new antianginal drug that reduces intracellular sodium and calcium accumulation during ischemia, thus potentially limiting myocardial ischemia. It remains unknown, however, if the drug can play a role in the pathophysiology of periprocedural myocardial infarction. The aim of this study was to verify in a randomized study if pretreatment with ranolazine before percutaneous coronary intervention (PCI) has any protective effect on periprocedural myocardial damage.nnnMETHODSnSeventy patients with stable angina (age 62 ± 18 years, 42 men) scheduled for elective coronary intervention entered a randomized, double-blind, placebo-controlled pilot trial. For 7 days before the procedure, 35 patients were assigned to receive ranolazine (1,000 mg twice daily) and 35 patients had placebo. Creatine kinase-MB and troponin I levels were measured at baseline and at 8 and 24 hours postprocedure.nnnRESULTSnComparison between the 2 groups did not show any difference in clinical features, extent of coronary artery disease, and technical aspects of PCI. Periprocedural myocardial infarction (ie, postprocedural increase of creatine kinase-MB ≥ 3 times above the upper limit of normal) was less commonly seen after PCI in the ranolazine than in the placebo group (6% vs 22%, P = .041). Detection of markers of myocardial injury above the upper limit of normal was less common [corrected] in the ranolazine vs placebo group: 23% vs 40% for creatine kinase-MB (P = .010) and 31% vs 48% for troponin I (P = .011). [corrected] Postprocedural peak markers levels were also significantly lower in the ranolazine vs placebo group (creatine kinase-MB: 3.1 ± 15.0 and 7.7 ± 19.1 ng/mL, P < .05; troponin I: 0.15 ± 0.35 and 0.47 ± 0.49 ng/mL, P < .05). No significant adverse effect was reported by the 2 groups of patients.nnnCONCLUSIONSnPretreatment with ranolazine 1,000 mg twice daily for 7 days significantly reduced procedural myocardial injury in elective PCI.

Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone

Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more mineralocorticoid receptor-specific. From a marginal role as a potassium-sparing diuretic, spironolactone has been shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure. Also, spironolactone is safe and protective in arterial hypertension, particularly in patients with so-called resistant hypertension. Eplerenone is the second oral aldosterone antagonist available for the treatment of arterial hypertension and heart failure. Treatment with eplerenone has been associated with decreased blood pressure and improved survival for patients with heart failure and reduced left ventricular ejection fraction. Due to the selectivity of eplerenone for the aldosterone receptor, severe adverse effects such as gynecomastia and vaginal bleeding seem to be less likely in patients who take eplerenone than in those who take spironolactone. The most common and potentially dangerous side effect of spironolactone--hyperkalemia--is also observed with eplerenone but the findings from clinical trials do not indicate more hyperkalemia induced drug withdrawals. Treatment with eplerenone should be initiated at a dosage of 25mg once daily and titrated to a target dosage of 50mg once daily preferably within 4 weeks. Serum potassium levels and renal function should be assessed prior to initiating eplerenone therapy, and periodic monitoring is recommended, especially in patients at high risk of developing hyperkalemia.