Prognostic Implications of Defibrillation Threshold Testing in Patients With Hypertrophic Cardiomyopathy.

INTRODUCTION: In hypertrophic cardiomyopathy (HCM) patients the need for defibrillation threshold (DFT) testing at the time of ICD implantation is debated. Moreover, its prognostic implications have never been explored. In a cohort of HCM patients we sought to (a) investigate factors prompting DFT testing, (b) evaluate ICD efficacy by testing DFT, (c) compare DFT in patients with and without massive LVH, and (d) assess whether DFT testing predicts shock efficacy for spontaneous VT/VF. METHODS AND RESULTS: We retrospectively analyzed a cohort of HCM patients implanted with an ICD. DFT was tested at the discretion of the implanting physician with a 10 J safety margin. During follow-up, ICD interventions were evaluated. The study population included 66 patients. DFT was determined in 25 (38%) patients. Age (HR: 0.95; 95%CI: 0.92-0.98; P = 0.004) and massive LVH (HR: 6.0; 95%CI: 2.03-18.8; P = 0.001) affected the decision to test DFT. DFT was at least 10 J less than maximal ICD output in 25/25. Safety margin was similar among patients with and without massive LVH (15 ± 3 J vs. 14 ± 2 J; P = 0.42). During follow-up (median 53 months) 15 shocks were delivered for 12 VT/VF in 7 patients. One VF ended spontaneously after a failed shock. Of 4 unsuccessful shocks, 2 occurred in 1 patient with DFT testing and 2 were delivered in 2 patients without. All unsuccessful shocks were ≤35 J. CONCLUSION: Young age and massive LVH prompt DFT testing. Contemporary ICDs are safe and effective in HCM patients independently from the magnitude of LVH. DFT testing does not predict shock efficacy for spontaneous VT/VF.

Eligibility for the Subcutaneous Implantable Cardioverter-Defibrillator in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: High-risk hypertrophic cardiomyopathy (HCM) patients benefit from the implantable cardioverter defibrillator (ICD). The subcutaneous ICD (S-ICD) may provide comparable protection while avoiding the shortcomings of transvenous (TV) leads. We assessed S-ICD eligibility according to surface ECG screening test in a cohort of high-risk HCM patients. METHODS AND RESULTS: 47 HCM patients (3 S-ICD candidates; 41 TV-ICD patients without pacing indication; and 3 pacemaker-dependent TV-ICD patients) underwent 4 screening protocols: standard (n = 44); exercise (n = 33); continuous pacing (n = 44); alternating paced/spontaneous QRS (n = 41). Of the 44 patients in the standard screening group, 41 (93%) were eligible. Max LV thickness was inversely related to the number of qualifying leads (3 leads: 21 ± 4 mm; 2 leads: 22 ± 6 mm; 1 lead: 25 ± 6 mm; no leads: 28 ± 11 mm; P = 0.07). Of the 33 patients in the exercise group, 5 were ineligible (3 after exercise). Of these, 2 became eligible after moving sternal electrodes from the left to the right parasternal line (eligibility rate: 30/33; 91%). Of the 44 patients in the continuous pacing group, 28 (64%) were eligible, 8 of which with right parasternal electrodes. In the paced/spontaneous QRS group (n = 41), 21 patients (51%) had at least 1 eligible lead during pacing and retained compatibility on the same lead during spontaneous rhythm, 5 of which with right parasternal electrodes. CONCLUSIONS: S-ICD screening failure is low in HCM, provided that patients with severe hypertrophy are carefully evaluated. Exercise test should be performed and right parasternal leads tested. Pacemaker patients display lower eligibility rate.

RyR2 Common Gene Variant G1886S and the Risk of Ventricular Arrhythmias in ICD Patients with Heart Failure.

BACKGROUND: Cardiac ryanodine receptor 2 (RyR2) is critical to the electrical homeostasis of cardiomyocytes. Its gene variant rs3766871 entails channel destabilization and enhanced intracellular Ca(2+) oscillation, thus promoting cardiac arrhythmias. We investigated whether the RyR2 rs3766871 variant is associated with aborted sudden cardiac death or ICD therapy for ventricular tachycardia (VT)/fibrillation (VF) in heart failure (HF) patients implanted with a cardioverter defibrillator (ICD). METHODS AND RESULTS: A total of 183 HF patients with primary or secondary prevention ICD were divided in 2 groups. A VT/VF group was composed of secondary prevention patients and primary prevention patients with appropriate ICD intervention for VT/VF. An ICD control group was composed of primary prevention patients free from any appropriate ICD intervention after 43 ± 25 months follow-up. Study subjects were genotyped with respect to the rs3766871 RyR2 gene variant. Hazard ratios (HRs) were derived from Cox proportional-hazards regression analysis. In all, 56 patients constituted the VT/VF group and 127 patients the ICD control group. Male sex (HR: 3.02; 95% CI: 0.99-9.18; P = 0.05), atrial fibrillation (AF; HR: 2.33; 95% CI: 0.89-6.10; P = 0.08), and underuse of ß-blockers (HR: 2.08; 95% CI: 0.84-5.15; P = 0.11) were associated with the VT/VF phenotype. Prevalence of the rs3766871 minor allele was 2.8% in ICD control patients and 8.0% in the VT/VF group (P = 0.02). After adjustment for age, sex, AF, and use of ß-blockers, the rs3766871 minor allele was associated with increased risk of VT/VF (HR: 3.49; 95% CI: 1.14-10.62; P = 0.02). CONCLUSIONS: Our study identifies a significant role of RyR2 rs3766871 minor allele for increased susceptibility to VT/VF in a population of ICD patients with HF.

Clinical impact of nonsustained ventricular tachycardia recorded by the implantable cardioverter-defibrillator in patients with hypertrophic cardiomyopathy.

BACKGROUND: Nonsustained ventricular tachycardia (NSVT) is a risk factor for sudden death (SD) in hypertrophic cardiomyopathy (HCM). Implantable cardioverter-defibrillators (ICDs) enable accurate assessment of NSVT burden and characteristics. In a cohort of HCM patients with ICD, we characterized Holter- and ICD-retrieved NSVT and evaluated their relationship with prognosis. METHODS AND RESULTS: We studied a cohort of consecutive HCM patients who underwent Holter ECG before receiving a primary prevention ICD. Patients were followed from ICD implantation to the first appropriate ICD therapy. We evaluated the association of NSVT characteristics with ICD interventions. Study cohort included 51 HCM patients (28 males, mean age: 48 ± 15 years). Thirty-four patients (66%) had NSVT at pre-ICD Holter ECG. Out of 17 patients with negative baseline Holter, 7 (41%) showed ICD-NSVT. In patients with both Holter- and ICD-NSVT, these latter were faster (199 ± 27 bpm vs. 146 ± 24 bpm; P < 0.001) and longer (16 ± 8 beats vs. 10 ± 11 beats; P = 0.008) than Holter-NSVT. During follow-up (38 ± 24 months), 11 patients (22%) experienced appropriate ICD therapy. NSVT length in beats (hazard ratio [HR]: 1.05; 95% CI: 1.00-1.10; P = 0.02) but not heart rate (HR: 1.00; 95% CI: 0.98-1.02; P = 0.86) predicted ICD intervention. A simple index of NSVT severity (heart rate × length in beats/100 >28) predicted ICD intervention (HR: 5.45; 95% CI: 1.10-27.32; P = 0.03). CONCLUSIONS: Long-lasting and rapid NSVT recorded during continuous rhythm monitoring predict appropriate ICD intervention in high-risk HCM patients. Further studies should assess whether prolonged rhythm monitoring may assist in evaluating patients at intermediate risk of SD, in which the decision to implant an ICD needs to be individualized.

Osteopontin and galectin-3 predict the risk of ventricular tachycardia and fibrillation in heart failure patients with implantable defibrillators.

BACKGROUND: Myocardial extracellular matrix remodelling provides electrical heterogeneity entailing ventricular tachycardia/fibrillation (VT/VF) in heart failure (HF) patients. Osteopontin (OPN) and Galectin-3 (Gal-3) are fibrosis markers and may reflect the extension of the arrhythmogenic substrate. We assessed whether plasma OPN and Gal-3 predict the risk of sustained VT/VF in a cohort of HF patients with implantable cardioverter-defibrillator (ICD). METHODS: A total of 75 HF patients underwent pre-ICD implantation clinical evaluation and assessment of plasma OPN and Gal-3. The primary endpoint was the time to the occurrence of the first sustained VT/VF. Hazard ratios (HR) were derived from Cox proportional-hazards analysis. RESULTS: Patients with coronary artery disease (CAD) had higher plasma OPN (79.8 ± 44.0 ng/mL vs. 66.0 ± 31.8 ng/mL; P = 0.04). Both Gal-3 (r = -0.38; P = 0.01) and OPN (r = -0.27; p = 0.01) were negatively related to estimated glomerular filtration rate. After 29 ± 17 months, 20 patients (27%) reached the primary endpoint. Patients with VT/VF had higher plasma OPN and Gal-3 (97.4 ± 51.7 ng/mL vs. 65.9 ± 31.3 ng/mL; P = 0.002 and 19.7 ± 8.5 ng/mL vs. 16.2 ± 6.2 ng/mL; P = 0.05). In univariate analysis, OPN (log-OPN, HR: 32.4; 95%CI: 3.9-264.7; P = 0.001) and Gal-3 (HR: 1.05; 95%CI: 1.00-1.11; P = 0.04) predicted sustained VT/VF. In multivariable analysis, both OPN (HR: 41.4; 95%CI: 3.8-441.9; P = 0.002) and Gal-3 (HR: 1.06; 95%CI: 1.00-1.12; P = 0.03) retained their prognostic power after correction for age, sex, history of MI, EF, NYHA class, eGFR, use of ACE-I, and amiodarone. CONCLUSIONS: Plasma OPN and Gal-3 predict sustained VT/VF in HF patients at high risk for SCD. Larger prospective studies should outline the role of these biomarkers in predicting SCD on top of conventional risk stratification.

Determinants of peak oxygen uptake in patients with hypertrophic cardiomyopathy: a single-center study.

Most patients with hypertrophic cardiomyopathy (HCM) usually complain of a reduced exercise capacity, and several factors have been advocated as possible causes of this clinical feature. The present single-center study was designed to investigate exercise capacity and its main clinical determinants in HCM patients. One hundred ninety seven patients of 223 evaluated underwent a complete clinical assessment, including Doppler echocardiography, cardiopulmonary exercise test (CPET) and, in most cases, cardiac magnetic resonance. The HCM population (male 75 %; age 47 ± 16 years; NYHA class I or II 95 %; left ventricular ejection fraction 61 ± 3 %; resting left ventricular outflow tract gradient ≥30 mmHg 22 %; late gadolinium enhancement presence 58 %) showed slightly reduced mean peak oxygen uptake values (pVO2 75 ± 15 %, 23.2 ± 6.7 ml/kg/min) with a significant reduction of the achieved percentage of peak heart rate reserve (%pHRR 65 ± 20 %). Adopting a pVO2 <80 % cut-off value, 59 % of HCM patients showed a reduced exercise capacity. Age, male gender, left atrial size, chronotropic and systolic blood pressure response, ventilatory efficiency, late gadolinium enhancement presence and ß-blocker therapy were independently associated with pVO2 (R (2)-adjusted index 0.738). A %pHRR cut-off value of 74 % appeared to most accurately predict an impaired exercise capacity (area under curve 0.90). A great prevalence of reduced exercise capacity is present in NYHA class I-II HCM patients. Notwithstanding its multifactorial genesis, few parameters might be adopted in identifying this feature. In this context, %pHRR value might represent a reliable and easy-to-obtain tool for the clinical evaluation of HCM patients.

New oral anticoagulants in non-valvular atrial fibrillation.

Atrial fibrillation (AF) is associated with an increased risk of embolic stroke. Dose-adjusted vitamin K antagonists (VKAs) to a target international normalized ratio (INR) range of 2.0-3.0 reduce the risk of ischemic stroke and are currently recommended in all patients with AF at moderate-high risk for stroke or systemic embolism. However, VKAs have several drawbacks, including unpredictable anticoagulant response, food and drug interactions, need for regular laboratory monitoring and dose adjustment. These limitations prompted the introduction of new oral anticoagulants (NOA) that target thrombin and factor Xa, key-enzymes in the coagulation pathway. NOA have predictable pharmacodynamics, allowing fixed dosing without the need of laboratory monitoring, and have few drug and food interactions. The present review focuses on pharmacological properties, safety, and appropriate clinical use of dabigatran, rivaroxaban and apixaban.

Increased temporal dispersion of myocardial repolarization in myotonic dystrophy type 1: beyond the cardiac conduction system.

BACKGROUND AND OBJECTIVES: The most frequently mechanism underlying sudden cardiac death in myotonic dystrophy type 1 (DM1) is bradyarrhythmias due to cardiac conduction abnormalities. However the risk of ventricular tachyarrhythmias remains a concern in clinical management as well as in its determinant. We therefore assessed autonomic nervous system activity aiming to disclose differences in the QT variability index (QTVI)-a marker of temporal myocardial repolarization lability-between DM1 patients and healthy controls. We also investigated the possible differences within DM1 patients by subdividing them according either to the presence of first degree atrioventricular block (1st AVB) or to the cytosine-thymine-guanine (CTG) repeat expansion size. METHODS: Sixty-two DM1 patients and 20 healthy subjects underwent neurological and cardiological examinations, the latter including ECG, echocardiography and 24-hour Holter monitoring. All underwent a 5-minute ECG recording to assess heart rate variability power spectral components, and the QTVI values. RESULTS: Power spectral data, namely total power, low frequency power and high frequency power, were lower, whereas QTVI values were higher in DM1 patients than in controls (p<.0001). Higher QTVI values were found in DM1 subgroups with 1st AVB (p=.009) and more than 500 CTG repeat (p=.014) with respect to DM1 patients without 1st AVB and CTG<500. Spectral data did not significantly differ. At multivariable analysis, QTVI and age were independently associated with PR interval and CTG repeat. CONCLUSIONS: The increased values of QTVI argue in favour of an important heart involvement extending beyond the conduction system. Whether QTVI could be useful in predicting clinical course of DM1 clearly requires larger prospective studies.

Three-dimensional echocardiographic characterization of patients with left ventricular noncompaction.

BACKGROUND: Despite several efforts using two-dimensional echocardiography and cardiac magnetic resonance in the diagnosis of left ventricular noncompaction (LVNC), there are no universally accepted diagnostic criteria. The aim of this study was to describe the extent of noncompacted myocardium using a new three-dimensional echocardiographic parameter. METHODS: Seventeen patients with diagnoses of LVNC on the basis of two-dimensional echocardiographic and clinical criteria, 26 Olympic rowing athletes, and 49 healthy volunteers underwent three-dimensional echocardiography. By offline analysis, left ventricular volumes, mass, ejection fraction, and sphericity index were calculated. Trabeculated left ventricular volume (TLV) was calculated as the difference between left ventricular end-diastolic volume obtained including and excluding the trabeculae in the cavity contour. TLV was also normalized by left ventricular end-diastolic volume (TLV%). RESULTS: TLV and TLV% were significantly higher in patients with LVNC (33.7 ± 10.9 mL and 24 ± 7%) as opposed to controls (7.1 ± 2.2 mL, P < .001, and 6 ± 2%, P < .001, respectively) and athletes (8.0 ± 3.0 mL, P < .001, and 5 ± 2%, P < .001, respectively). In detail, on receiver operating characteristic curve analysis, optimal cutoff values of 15.8 mL for TLV and 12.8% for TLV% were determined for the identification of LVNC (area under the curve, 1.00; P < .001). Mild positive correlations of TLV and TLV% were found with sphericity index (r = 0.294, P = .004, and r = 0.301, P = .004, respectively), and mild negative correlations were found with ejection fraction (r = -0.454, P < .001, and r = -0.217, P = .038, respectively). CONCLUSIONS: Because of high spatial resolution and accuracy in volumetric quantification, three-dimensional echocardiography allows accurate measurement of the extent of noncompacted myocardium and identification of patients with LVNC.

Pathophysiology of dynamic left ventricular outflow tract obstruction in a critically ill patient.

Left ventricular outflow tract obstruction is not a rare problem in the intensive care units and can precipitate hemodynamic shock unresponsive to catecholamine therapy. The use of echocardiographic examination is extremely important in recognizing this phenomenon and its underlying conditions, finally identifying the most appropriate therapeutic strategy. The simple correction of one or more of these factors can dramatically change patients clinical outcome. We report the clinical case of a 72-year-old man who developed hemodynamic shock in the intensive care unit. Hypovolemia, catecholamine infusion, and mechanical ventilation induced geometric modification of the left ventricle causing a systolic anterior motion of the mitral anterior leaflet and a severe subaortic gradient. Simple restoration of fluids and discontinuation of medical therapy dramatically changed the outcome of the patient. A review of the medical literature has been carried out to deeply investigate pathophysiology of left ventricular outflow tract obstruction in critically ill patients.

Long-term prognostic significance of three-dimensional echocardiographic parameters of the left ventricle and left atrium.

AIMS: We sought to investigate the long-term prognostic significance of two- and three-dimensional echocardiography. METHODS AND RESULTS: One hundred and seventy-eight consecutive outpatients underwent two-dimensional echocardiography and three-dimensional echocardiography for the assessment of LV volumes, mass, ejection fraction, and LA maximum and minimum volumes. After 45 months of follow-up, 31 patients (17%) had major cardiovascular events (death, myocardial infarctions, or stroke). From the two-dimensional echocardiography data, a significant time relationship to cardiovascular events was achieved only by LV end-systolic volume [hazard ratio (HR): 1.047; 95% confidence interval (CI): 0.994-1.083; P = 0.031] and mass (HR: 1.038; CI: 0.993-1.082; P = 0.019), whereas from three-dimensional echocardiography, all the examined variables: LV end-diastolic (HR: 1.014; CI: 1.003-1.025; P = 0.014) and end-systolic volume (HR:1.018; CI: 1.006-1.029; P = 0.003), ejection fraction (HR: 0.032; CI: 0.002-0.565; P = 0.019), mass (HR: 1.030; CI: 1.016-1.045; P < 0.001), LA maximum (HR: 1.055; CI: 1.031-1.080; P < 0.001) and minimum (HR: 1.049; CI: 1.028-1.070; P < 0.001) volumes, were found to bear a significant relationship to cardiovascular events. By multivariate analysis, three-dimensional echocardiography derived LA minimum volume was identified as the best independent predictor of adverse cardiovascular events (HR: 1.217; CI: 1.075-1.378; P = 0.002). CONCLUSION: Owing to a superior accuracy, three-dimensional echocardiography derived parameters and most notably LA minimum volume provide more relevant information on outpatient prognosis.

Differentiation of hypertrophic cardiomyopathy from other forms of left ventricular hypertrophy by means of three-dimensional echocardiography.

In clinical practice, differential diagnosis among different forms of left ventricular (LV) hypertrophy is not always easy, and hypertrophic cardiomyopathy (HC) can be misdiagnosed. In this study, it was hypothesized that a 3-dimensional echocardiographically derived index of LV regional mass distribution could be useful in differentiating HC from other forms of LV hypertrophy. Sixty-eight subjects underwent 2- and 3-dimensional echocardiography; of these, 20 were healthy volunteers, 18 were top-level athletes, 15 had essential hypertension, and 15 had HC. In off-line analysis, a 12-segment model was generated for segmental mass measurement. A mass dispersion index (MDI) was calculated as the average of the SDs of segmental mass values at the basal, middle, and apical layers. The ratio of ventricular septal thickness to posterior wall thickness was also calculated using 2-dimensional echocardiography. Patients with HC had significantly higher MDI values (1.75 +/- 0.43) than healthy volunteers (0.39 +/- 0.13) (p <0.0001), athletes (0.49 +/- 0.12) (p <0.0001), and patients with hypertension (0.38 +/- 0.10) (p <0.0001). The ratio of ventricular septal thickness to posterior wall thickness was significantly higher in patients with HC (1.31 +/- 0.23) than normal subjects (1.04 +/- 0.05) (p <0.0001), highly trained athletes (1.03 +/- 0.06) (p = 0.001), and patients with hypertension (1.06 +/- 0.06) (p = 0.002). However, receiver-operating characteristic analysis showed a higher sensitivity for MDI (93.3% for the cut-off value of 1.13) than the ratio of ventricular septal thickness to posterior wall thickness (66.7% for the cut-off value of 1.20), with excellent specificity for both (100%) in identifying patients with HC. In conclusion, the 3-dimensional echocardiographically derived MDI could be considered a useful and reliable additional tool in differentiating HC from other forms of LV hypertrophy.

Relation of left atrial maximal volume measured by real-time 3D echocardiography to demographic, clinical, and Doppler variables.

Left atrial (LA) enlargement is a negative prognostic factor for survival in patients with stroke, congestive heart failure, and myocardial infarction. In the absence of mitral valvular disease it is also a marker of chronic elevated left ventricular filling pressures. The aim of our study was to examine whether the currently considered factors such as demographic, clinical, and Doppler parameters fully correspond to LA maximal volume measured by real time three-dimensional echocardiography (RT3DE). Two-hundred-twenty-four patients (age 58+/-12 years) were studied. Of these, 66 were healthy volunteers and 158 were patients with more than 2 cardiovascular risk factors (109), documented coronary heart disease (CHD) and normal LV function (33), and patients with (10) and without (6) IHD and LV systolic dysfunction. Two-dimensional Doppler and tissue Doppler (TDI) echocardiographic parameters and LA maximal volume, assessed by RT3DE were analyzed. LA maximal volume values were positively and highly significantly associated, after adjustment for age and sex, with LV mass, mitral flow peak E velocity and E/A ratio, TDI E'/A' ratio and E/e' ratio (P<0.001). There were highly significant inverse associations of LA maximal volume and ejection fraction and peak A' velocity detected by TDI (P<0.0001). LA maximal volume was significantly correlated with the progression of diastolic dysfunction from normal to grade III. In particular, there was a clear difference between the normal and pseudonormal filling patterns (p<0.001) in terms of LA maximal volume. In conclusion, progressive LA volume increase is directly correlated with age, LV mass, and LV diastolic dysfunction, and inversely correlated with LV systolic function.

2- and 3-dimensional echocardiographic analysis of an unusual transient apical ballooning.

We report the clinical case of a 60-year-old woman who referred to our hospital for the occurrence of typical chest pain during mild effort. At admission, the electrocardiogram showed S-T segment elevation from V(3) to V(6), and an increase in troponin I level (11.4 ng/mL). Echocardiogram showed midapical segment akinesia with depressed ejection fraction (30%). Basal segments were hypercontractile and there was evidence of dynamic obstruction of the left ventricle with an end-systolic peak gradient of 65 mm Hg. Results of emergency coronary arteriography were normal and left ventricular angiography confirmed the midapical akinesia and hypercontractility of the basal segments. Serial 2- and 3-dimensional Doppler echocardiographic examinations were performed. Regression of left ventricular outflow tract obstruction was soon detected (day 3). Fifteen days after admission, 2- and 3-dimensional echocardiography showed a complete regression of both apical ballooning and wall-motion abnormalities with an improvement in overall systolic function. Segmental volumetric analysis allowed accurate assessment of regional volumes and ejection fraction, which were indicative for a progressive reverse remodeling. Regression of wall-motion abnormalities was expressed by a normalization in regional ejection fraction curves at 15 days.