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Rossi A.,University of Verona | Dini F.L.,University of Pisa | Faggiano P.,University of Brescia | Agricola E.,Istituto Scientifico San Raffaele | And 7 more authors.
Heart | Year: 2011

Background: Functional mitral regurgitation (FMR) is a common finding in patients with heart failure (HF), but its effect on outcome is still uncertain, mainly because in previous studies sample sizes were relatively small and semiquantitative methods for FMR grading were used. Objective: To evaluate the prognostic value of FMR in patients with HF. Methods and results: Patients with HF due to ischaemic and non-ischaemic dilated cardiomyopathy (DCM) were retrospectively recruited. The clinical end point was a composite of all-cause mortality and hospitalisation for worsening HF. FMR was quantitatively determined by measuring vena contracta (VC) or effective regurgitant orifice (ERO) or regurgitant volume (RV). Severe FMR was defined as ERO >0.2 cm 2 or RV >30 ml or VC >0.4 cm. Restrictive mitral filling pattern (RMP) was defined as E-wave deceleration time <140 ms. The study population comprised 1256 patients (mean age 67±11; 78% male) with HF due to DCM: 27% had no FMR, 49% mild to moderate FMR and 24% severe FMR. There was a powerful association between severe FMR and prognosis (HR=2.0, 95% CI 1.5 to 2.6; p<0.0001) after adjustment of left ventricular ejection fraction and RMP. The independent association of severe FMR with prognosis was confirmed in patients with ischaemic DCM (HR=2.0, 95% CI 1.4 to 2.7; p<0.0001) and nonischaemic DCM (HR=1.9, 95% CI 1.3 to 2.9; p=0.002). Conclusion: In a large patient population it was shown that a quantitatively defined FMR was strongly associated with the outcome of patients with HF, independently of LV function. Source

Chan P.S.,University of Missouri - Kansas City | Khumri T.,University of Missouri - Kansas City | Chung E.S.,Ohio Heart and Vascular Center | Ghio S.,Fondazione IRCCS Policlinico S. Matteo | And 4 more authors.
JACC: Cardiovascular Imaging | Year: 2010

Objectives: This study sought to assess the prognostic utility of echocardiographic dyssynchrony for health status improvement after cardiac resynchronization therapy (CRT). Background: Echocardiographic measures of dyssynchrony have been proposed for patient selection for CRT, but prospective validation studies are lacking. Methods: A prospective cohort of 324 patients from 53 centers with moderate to severe heart failure, left ventricular dysfunction, QRS <130 ms, and available echocardiographic and health status information were identified from the PROSPECT (Predictors of Response to Cardiac Re-Synchronization Therapy) trial, which evaluated the prognostic utility of dyssynchrony measures in CRT recipients. The association of 12 echocardiographic dyssynchrony parameters with 6-month improvement in health status, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), was assessed both as a continuous variable and by responder status (ΔKCCQ <+10 points reflecting moderate to large improvement). Results: Of 12 pre-defined dyssynchrony parameters, only 3 were consistently reported: interventricular mechanical delay (IVMD), left ventricular filling time relative to the cardiac cycle (LVFT), and left ventricular pre-ejection interval. After multivariable adjustment, IVMD (+5.18, 95% confidence interval [CI]: +0.76 to +9.60; p = 0.02) and LVFT (+5.19, 95% CI: +0.45 to +0.94; p = 0.03) were independently associated with 6-month improvements in KCCQ. Patients with 6-month improvements in KCCQ had lower subsequent mortality (adjusted hazard ratio [HR] for each 5-point improvement: 0.83; 95% CI: 0.72 to 0.93; p = 0.03). Additionally, IVMD was associated with CRT responder status (for ΔKCCQ <+10 points: odds ratio [OR]: 1.85; 95% CI: 1.12 to 3.05; p = 0.03), whereas LVFT was not (OR: 1.63; 95% CI: 0.85 to 3.11; p = 0.14). Patients classified as health status responders had a 76% lower subsequent risk of all-cause mortality (adjusted HR: 0.24; 95% CI: 0.07 to 0.84; p = 0.03). Conclusions: The presence of pre-implantation IVMD and LVFT was associated with 6-month health status improvement, and IVMD was associated with a significant CRT response. These echocardiographic factors may help clinicians counsel patients regarding their likelihood of symptomatic improvement with CRT. (PROSPECT: Predictors of Response to Cardiac Re-Synchronization Therapy; NCT00253357) © 2010 American College of Cardiology Foundation. Source

De Ferrari G.M.,Fondazione IRCCS Policlinico S. Matteo | Schwartz P.J.,Fondazione IRCCS Policlinico S. Matteo | Schwartz P.J.,University of Pavia | Schwartz P.J.,Laboratory of Cardiovascular Genetics | And 2 more authors.
Heart Failure Reviews | Year: 2011

Vagus nerve stimulation was performed experimentally for the first time more than 150 years ago. In the 1980s and 1990s, vagus nerve stimulation was shown, both in the anesthetized and in the conscious animal, to exert marked antiarrhythmic effects, particularly during acute myocardial ischemia. There is a strong rationale for a beneficial effect of augmented vagal activity in the setting of chronic heart failure. Studies in experimental models of heart failure showed that chronic vagus nerve stimulation exerts beneficial effects on left ventricular function and on survival. Vagus nerve stimulation is approved in man for refractory epilepsy and depression. The first-in-man study performed in 32 patients with chronic heart failure suggests that vagus nerve stimulation was safe and well tolerated. Six months of open-label treatment was associated with significant improvements (P < 0.001) in NYHA class, quality of life, 6-min walk test, LV ejection fraction (from 22 ± 7 to 29 ± 8%), and LV systolic volumes (P = 0.02). These improvements were maintained at 1 year. Mechanisms of action may include the following: heart rate, anti-adrenergic, anti-apoptotic, and anti-inflammatory effects as well as an increase in nitric oxide. Controlled clinical trials will start soon to assess whether vagus nerve stimulation can indeed represent a new non-pharmacological approach for the treatment of symptomatic heart failure. © 2010 Springer Science+Business Media, LLC. Source

Bhatt D.L.,Harvard University | Stone G.W.,Columbia University | Mahaffey K.W.,Duke Clinical Research Institute | Gibson C.M.,Beth Israel Deaconess Medical Center | And 20 more authors.
New England Journal of Medicine | Year: 2013

Background: The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects. Methods: In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guidelinerecommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours. Results: The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P = 0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P = 0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P = 0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups. Conclusions: Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.) Copyright © 2013 Massachusetts Medical Society. All rights reserved. Source

Calvillo L.,Center for Cardiac Arrhythmias of Genetic Origin | Spazzolini C.,Fondazione IRCCS Policlinico S. Matteo | Vullo E.,Fondazione IRCCS Policlinico S. Matteo | Vullo E.,University of Pavia | And 9 more authors.
Heart Rhythm | Year: 2014

Background The efficacy of beta-blockers for treatment of patients with long QT syndrome type 3 (LQT3) has been repeatedly questioned, and it has been suggested that they might be detrimental for this genetic subgroup of patients with long QT syndrome (LQTS). The disquieting consequence has been that cardiologists confronted with LQT3 patients often do not even attempt pharmacologic therapy and implant cardioverter-defibrillators as first-choice treatment. However, the most recent clinical data indicate high efficacy of beta-blocker therapy in LQT3 patients. Objective The purpose of this study was to test the antiarrhythmic efficacy of beta-blockers in an established experimental model for LQT3. Methods After phenotypic validation of 65 â̂†KPQ-SCN5A knock-in transgenic (TG) mice compared to 32 wild-type (WT) mice, we tested the effect of the arrhythmogenic cholinergic muscarinic agonist carbachol in 19 WT and 39 TG anesthetized mice, with and without pretreatment with propranolol given intraperitoneally. Results At the same heart rates, TG mice had a markedly longer QT interval than WT mice. Whereas carbachol had minor arrhythmic effects in the WT mice, it produced ventricular tachycardia (VT) and ventricular fibrillation (VF) in 55% of 20 TG mice. By contrast, in none of 19 TG mice pretreated with propranolol did VT/VF occur after carbachol injection. Conclusion These experimental data indicate that, contrary to previous reports, beta-blockade effectively prevents VT/VF in a validated LQT3 model. Together with the most recent clinical data, these findings indicate that there is no reason for not initiating protective therapy with beta-blockers in LQT3 patients. © 2014 Heart Rhythm Society. All rights reserved. Source

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