Antonio Sanzo

Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure

AIMS In chronic heart failure (CHF), reduced vagal activity correlates with increased mortality and acute decompensation. Experimentally, chronic vagus nerve stimulation (VNS) improved left ventricular (LV) function and survival; clinically, it is used for the treatment of drug-refractory epilepsy. We assessed safety and tolerability of chronic VNS in symptomatic CHF patients, using a novel implantable nerve stimulation system. The secondary goal was to obtain preliminary data on clinical efficacy. METHODS AND RESULTS This multi-centre, open-label phase II, two-staged study (8-patient feasibility phase plus 24-patient safety and tolerability phase) enrolled 32 New York Heart Association (NYHA) class II-IV patients [age 56 ± 11 years, LV ejection fraction (LVEF) 23 ± 8%]. Right cervical VNS with CardioFit (BioControl Medical) implantable system started 2-4 weeks after implant, slowly raising intensity; patients were followed 3 and 6 months thereafter with optional 1-year follow-up. Overall, 26 serious adverse events (SAEs) occurred in 13 of 32 patients (40.6%), including three deaths and two clearly device-related AEs (post-operative pulmonary oedema, need of surgical revision). Expected non-serious device-related AEs (cough, dysphonia, and stimulation-related pain) occurred early but were reduced and disappeared after stimulation intensity adjustment. There were significant improvements (P < 0.001) in NYHA class quality of life, 6-minute walk test (from 411 ± 76 to 471 ± 111 m), LVEF (from 22 ± 7 to 29 ± 8%), and LV systolic volumes (P = 0.02). These improvements were maintained at 1 year. CONCLUSIONS This open-label study shows that chronic VNS in CHF patients with severe systolic dysfunction may be safe and tolerable and may improve quality of life and LV function. A controlled clinical trial appears warranted.

Long term vagal stimulation in patients with advanced heart failure: first experience in man.

Experimentally, vagal stimulation (VS) is protective in chronic heart failure (HF). In man, VS is used in refractory epilepsy but has never been used in cardiovascular diseases. Increased sympathetic and reduced vagal activity predict increased mortality in HF.

Chronic vagal stimulation in patients with congestive heart failure

Increased sympathetic and reduced vagal activity predict increased mortality in patients with congestive heart failure (CHF). Experimentally, vagal stimulation (VS) is protective both during acute myocardial ischemia and in chronic heart failure. In man, VS is used in refractory epilepsy but has never been used in cardiovascular diseases. Thus, there is a strong rationale to investigate the effects of chronic VS in patients with CHF. We assesses the feasibility and safety of chronic VS with CardioFit (BioControl Medical), a VS implantable system delivering pulses synchronous with heart beats to the right cervical vagus nerve in a preliminary pilot study in eight advanced CHF patients with favorable results, and subsequently in a larger multicenter study. Overall, 32 patients have been successfully implanted (mostly in NYHA Class III; mean age 56 years, ischemic etiology in 69%; prior implantable cardioverter-defibrillator (ICD) in 63%; concomitant beta blocker and angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) in 100%). Preliminary results confirm feasibility of the study, an acceptable side effect profile and promising preliminary efficacy data. Several mechanisms may contribute to the beneficial effect observed in patients with heart failure. Should these results be confirmed in larger controlled studies, chronic vagal stimulation could be a further treatment option for CHF patients, possibly integrated with defibrillator and resynchronization therapies.

T-wave alternans in risk stratification of patients with nonischemic dilated cardiomyopathy: Can it help to better select candidates for ICD implantation?

BACKGROUND Prophylactic implantable cardioverter-defibrillator (ICD) therapy reduces mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF), but the absolute risk reduction is relatively small. Thus, there is a strong need to identify reliable risk stratifiers, particularly among patients with nonischemic cardiomyopathy (NIDCM), in whom the search for risk predictors has been particularly frustrating. OBJECTIVE This study sought to review data regarding T-wave alternans (TWA) in patients with NIDCM and to discuss its potential role. METHODS We included in a meta-analysis clinical trials that enrolled > or =50 NICDM patients, had a follow-up of > or =1 year, and provided detailed data on NIDCM patients, in case of mixed population. Relative risks were derived from absolute numbers of events in abnormal (positive + indeterminate test whenever possible) TWA versus normal (negative) TWA group. RESULTS Eight studies with 1,456 patients (mean age 56 years, LVEF 30%, follow-up 25 months) were included. A negative TWA test occurred in 33%, and was indeterminate in 21% of the patients. The primary end point (VT+VF+sudden or all-cause death) occurred in 14.7% abnormal versus 3.8% normal TWA patients. The relative risk for the cumulative data was found to be 2.99 (95% confidence interval: 1.88 to 4.75). The negative predictive value was 96.2%. CONCLUSION A normal TWA test identifies one-third of NIDCM patients who have a very good prognosis and are unlikely to significantly benefit from ICD therapy. A randomized clinical trial evaluating the utility of TWA in guiding therapy seems warranted, possibly a noninferiority trial of medical therapy only versus ICD in TWA-negative patients.

Identification of genetic markers for treatment success in heart failure patients: Insight from cardiac resynchronization therapy

Background—Cardiac resynchronization therapy (CRT) can improve ventricular size, shape, and mass and reduce mitral regurgitation by reverse remodeling of the failing ventricle. About 30% of patients do not respond to this therapy for unknown reasons. In this study, we aimed at the identification and classification of CRT responder by the use of genetic variants and clinical parameters. Methods and Results—Of 1421 CRT patients, 207 subjects were consecutively selected, and CRT responder and nonresponder were matched for their baseline parameters before CRT. Treatment success of CRT was defined as a decrease in left ventricular end-systolic volume >15% at follow-up echocardiography compared with left ventricular end-systolic volume at baseline. All other changes classified the patient as CRT nonresponder. A genetic association study was performed, which identified 4 genetic variants to be associated with the CRT responder phenotype at the allelic (P<0.035) and genotypic (P<0.031) level: rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11). Machine learning algorithms were used for the classification of CRT patients into responder and nonresponder status, including combinations of the identified genetic variants and clinical parameters. Conclusions—We demonstrated that rule induction algorithms can successfully be applied for the classification of heart failure patients in CRT responder and nonresponder status using clinical and genetic parameters. Our analysis included information on alleles and genotypes of 4 genetic loci, rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11), pathophysiologically associated with remodeling of the failing ventricle.

Contact Force Technology integrated with 3D Navigation System for Atrial Fibrillation Ablation: Improving Results?

ABSTRACT Introduction: Pulmonary veins isolation (PVI) by radiofrequency (RF) ablation is currently an established treatment for symptomatic, drug-resistant paroxysmal atrial fibrillation. Although the effectiveness of the therapy has been clearly demonstrated, success rate after a single procedure is still sub-optimal. The main reason for recurrences after PVI is electrical pulmonary vein-atrium reconnection. In order to increase the likelihood of permanent PVI, the creation of a transmural, durable lesion is mandatory. The main determinants of lesion size and transmurality are power, stability, duration and contact-force during RF application. In recent times, catheters with contact-force sensors have been developed and released for clinical use. Areas covered: The present review summarizes rational and clinical evidences for efficacy and safety of contact force (CF) technology integrated into 3D navigation systems for AF ablation. Expert commentary Although CF technology has a strong rational, clinical data on the superior safety and efficacy of CF technology over traditional non-CF catheters are still conflicting. The reason for that is very likely to rely on the lack of definite data on how to optimize CF parameters and how to integrate CF data with power, duration of RF applications and information on catheter stability.

Identification of Genetic Markers for Treatment Success in Heart Failure PatientsCLINICAL PERSPECTIVE: Insight From Cardiac Resynchronization Therapy

Background—Cardiac resynchronization therapy (CRT) can improve ventricular size, shape, and mass and reduce mitral regurgitation by reverse remodeling of the failing ventricle. About 30% of patients do not respond to this therapy for unknown reasons. In this study, we aimed at the identification and classification of CRT responder by the use of genetic variants and clinical parameters. Methods and Results—Of 1421 CRT patients, 207 subjects were consecutively selected, and CRT responder and nonresponder were matched for their baseline parameters before CRT. Treatment success of CRT was defined as a decrease in left ventricular end-systolic volume >15% at follow-up echocardiography compared with left ventricular end-systolic volume at baseline. All other changes classified the patient as CRT nonresponder. A genetic association study was performed, which identified 4 genetic variants to be associated with the CRT responder phenotype at the allelic (P<0.035) and genotypic (P<0.031) level: rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11). Machine learning algorithms were used for the classification of CRT patients into responder and nonresponder status, including combinations of the identified genetic variants and clinical parameters. Conclusions—We demonstrated that rule induction algorithms can successfully be applied for the classification of heart failure patients in CRT responder and nonresponder status using clinical and genetic parameters. Our analysis included information on alleles and genotypes of 4 genetic loci, rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11), pathophysiologically associated with remodeling of the failing ventricle.

Identification of Genetic Markers for Treatment Success in Heart Failure PatientsCLINICAL PERSPECTIVE

Background—Cardiac resynchronization therapy (CRT) can improve ventricular size, shape, and mass and reduce mitral regurgitation by reverse remodeling of the failing ventricle. About 30% of patients do not respond to this therapy for unknown reasons. In this study, we aimed at the identification and classification of CRT responder by the use of genetic variants and clinical parameters. Methods and Results—Of 1421 CRT patients, 207 subjects were consecutively selected, and CRT responder and nonresponder were matched for their baseline parameters before CRT. Treatment success of CRT was defined as a decrease in left ventricular end-systolic volume >15% at follow-up echocardiography compared with left ventricular end-systolic volume at baseline. All other changes classified the patient as CRT nonresponder. A genetic association study was performed, which identified 4 genetic variants to be associated with the CRT responder phenotype at the allelic (P<0.035) and genotypic (P<0.031) level: rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11). Machine learning algorithms were used for the classification of CRT patients into responder and nonresponder status, including combinations of the identified genetic variants and clinical parameters. Conclusions—We demonstrated that rule induction algorithms can successfully be applied for the classification of heart failure patients in CRT responder and nonresponder status using clinical and genetic parameters. Our analysis included information on alleles and genotypes of 4 genetic loci, rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11), pathophysiologically associated with remodeling of the failing ventricle.

NEGATIVE T WAVES AFTER REPERFUSED MYOCARDIAL INFARCTION ARE A MARKER OF MYOCARDIAL STUNNING AND PREDICT REGIONAL RECOVERY OF CONTRACTILE FUNCTION

Background: ST elevation myocardial infarction (MI) typically evolves with negative T waves. The signiicance and clinical correlate of these “post-ischemic” T waves is uncertain. This study tested the hypothesis that in patients with a reperfused MI, prevailing negative voltages in the ST-T segment correlate with myocardial stunning and with late recovery of contractile function (CF). Methods: We enrolled 32 patients with anterior MI, treated with primary PCI (age 57±12 years, peak CK 2860 ± 1555 U/L, LVEF 43± 8%). ECGs were digitized with a dedicated system (ECGScan v3, AMPS-LLC) and analyzed with a semi-automated on-screen software (CalECG v2, AMPS-LLC) which quantiies the area of positive and negative waves during repolarization from J point to T-wave end in each cardiac lead. Regional CF was assessed blindly by means of 1.5 T cardiac MR 4 days and 4 months after MI. Recovery of CF was evaluated comparing percentage thickening between the 2 tests. We prospectively correlated repolarization in V3 and V4 48 h after MI (peak of negative T waves) and speciically the ratio of negative/total area (%negTA) with the recovery of CF in the anterior middle and apical LV (segments 7 and 13, corresponding to leads V3 and V4), estimated as sum of the differences in % thickening in both segments. Results: Repolarization analysis showed that %negTA was 54±32% (median 53%) and 62±31% (median 70%) in V3 and V4, respectively. Acute CMR showed an ischemic area corresponding to 39 ± 14% of LV mass. Segments 7 and 13 were ischemic in all patients and showed an average thickening of 12.2±12.5% and 8.4±8.7%, respectively. CMR after 4 months showed a signiicant recovery of regional thickening to 27.8±14.3% and 17.3±15.1% in segment 7 and 13, respectively. Contractile recovery correlated signiicantly with %negTA in both V3 and V4 (r=0.50, p=0.004 and r=0.46, p=0.009). Compared to patients with less negative T waves, those with %negTA >50% in V3 and >70% in V4 had a total recovery of 34±27 vs 13±14% (p<0.01) and of 41±25 vs 10±13% (p<0.001), respectively.