A 44-year-old male patient with known Becker muscular dystrophy and concomitant non-ischemic dilated cardiomyopathy presented to our department because of worsening heart failure and presyncope. Upon admission, the patient was in New York Heart Association functional class III despite optimal pharmacological treatment; his ECG showed sinus rhythm with left bundle branch block and a wide QRS complex. Non-sustained ventricular tachycardia was recorded during 24-hour Holter monitoring. A complete three-dimensional echocardiographic study was performed and documented the dilatation and concomitant hypertrabeculation of the left ventricle (LV), with severely depressed systolic LV performance (ejection fraction 20%), as well as mechanical dyssynchrony--mainly in terms of intraventricular delay. A biventricular cardioverter-defibrillator (CRT-D) was implanted in this patient, with the LV lead in a lateral vein and the right ventricular defibrillating lead in the apical part of the interventricular septum. Echocardiography-guided device programming was performed in order to achieve the optimal atrio-, inter-, and intraventricular resynchronization. The patient's clinical condition was substantially improved within one month after the implantation.

BACKGROUND:

-Implantable cardioverter-defibrillators (ICDs), the first-line of therapy for preventing sudden cardiac death in high-risk patients, deliver "appropriate" shocks for termination of ventricular tachycardia/fibrillation (VT/VF). A common shortcoming of ICDs is imperfect rhythm discrimination, resulting in the delivery of "inappropriate" shocks for atrial fibrillation (AF). An underexplored area for rhythm discrimination is the difference in dynamic properties between AF and VT/VF. We hypothesized that the higher entropy of rapid cardiac rhythms preceding ICD shocks distinguishes AF from VT/VF.

METHODS AND RESULTS:

-In a multicenter, prospective, observational study of patients with primary prevention ICDs, 119 patients received shocks from ICDs with stored, retrievable intracardiac electrograms. Blinded adjudication revealed shocks were delivered for VT/VF (62%), AF (23%), and supraventricular tachycardia (15%). Entropy estimation of only 9 ventricular intervals prior to ICD shocks accurately distinguished AF (ROC curve area 0.98; 95% CI 0.93-1.0) and outperformed contemporary ICD rhythm discrimination algorithms.

CONCLUSIONS:

-This new strategy for AF discrimination based on entropy estimation expands on simpler concepts of variability, performs well at fast heart rates, and has potential for broad clinical application.

BACKGROUND:

-Conducting channels (CCs) are the target for ventricular tachycardia (VT) ablation. CCs could be identified with contrast enhanced-cardiac magnetic resonance (ce-CMR) as border zone (BZ) corridors. A three-dimensional (3D) reconstruction of the ce-CMR could allow visualization of the 3D structure of these BZ channels.

METHODS AND RESULTS:

-We included 21 patients with healed myocardial infarction and VT. A 3D high-resolution 3T ce-CMR was performed prior to CARTO-guided VT ablation. The left ventricular (LV) wall was segmented and characterized using a pixel signal intensity algorithm at 5 layers (endocardium, 25%, 50%, 75%, epicardium). A 3D color-coded shell map was obtained for each layer to depict the scar core and BZ distribution. The presence/characteristics of BZ channels were registered for each layer. Scar area decreased progressively from endocardium to epicardium (scar area/LV area: 34.0±17.4% at endocardium; 24.1±14.7% at 25%; 16.3±12.1% at 50%; 13.1±10.4 at 75%; 12.1±9.3% at epicardium, P <0.01). Forty-five BZ channels (2.1±1.0 per patient, 23.7±12.0 mm length, mean minimum-width 2.5±1.5 mm) were identified, 85% between the endocardium and 50% shell and 76% present in more than one layer. The ce-CMR-defined BZ channels identified 74% of the critical isthmus of clinical VTs and 50% of all the CCs identified in electroanatomical maps.

CONCLUSIONS:

-Scar area in ischemic patients decreases from the endocardium to the epicardium. BZ channels, more commonly seen in the endocardium, display a 3D structure within the myocardial wall that can be depicted with ce-CMR. The use of ce-CMR derived maps to guide VT ablation warrants further investigation.

There are few areas in cardiology where the impact of genetics and of genetic testing on clinical management has been as great as in cardiac channelopathies, arrhythmic disorders of genetic origin related to the ionic control of the cardiac action potential. Among the growing number of diseases identified as channelopathies, three are sufficiently prevalent to represent significant clinical and societal problems and to warrant adequate understanding by practicing cardiologists: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. This review will focus selectively on the impact of genetic discoveries on clinical management of these three diseases. For each disorder, we will discuss to what extent genetic knowledge and clinical genetic test results modify the way cardiologists should approach and manage affected patients. We will also address the optimal use of genetic testing including its potential limitations and the potential medico-legal implications when such testing is not performed. We will highlight how important can be to understand the ways by which genotype can impact clinical manifestations, risk stratification, and responses to the therapy. We will also illustrate the close bridge between molecular biology and clinical medicine, and will emphasize that consideration of the genetic basis for these hereditable arrhythmia syndromes, as well as the proper use and interpretation of clinical genetic testing, should remain the standard-of-care.

Derivation of cardiomyocytes from induced pluripotent stem cells (iPS-CMs) allowed us to probe the Ca(2+)-signaling parameters of human iPS-CMs from healthy- and catecholaminergic polymorphic ventricular tachycardia (CPVT1)-afflicted individuals carrying a novel point mutation p.F2483I in ryanodine receptors (RyR2). iPS-CMs were dissociated on day 30-40 of differentiation and patch-clamped within 3-6 days. Calcium currents (ICa) averaged ~8pA/pF in control and mutant iPS-CMs. ICa-induced Ca(2+)-transients in control and mutant cells had bell-shaped voltage-dependence similar to that of ICa, consistent with Ca(2+)-induced Ca(2+)-release (CICR) mechanism. The ratio of ICa-activated to caffeine-triggered Ca(2+)-transients was ~0.3 in both cell types. Caffeine-induced Ca(2+)-transients generated significantly smaller Na(+)-Ca(2+) exchanger current (INCX) in mutant cells, reflecting their smaller Ca(2+)-stores. The gain of CICR was voltage-dependent as in adult cardiomyocytes. Adrenergic agonists enhanced ICa, but differentially altered the CICR gain, diastolic Ca(2+), and Ca(2+)-sparks in mutant cells. The mutant cells, when Ca(2+)-overloaded, showed longer and wandering Ca(2+)-sparks that activated adjoining release sites, had larger CICR gain at -30mV yet smaller Ca(2+)-stores. We conclude that control and mutant iPS-CMs express the adult cardiomyocyte Ca(2+)-signaling phenotype. RyR2 F2483I mutant myocytes have aberrant unitary Ca(2+)-signaling, smaller Ca(2+)-stores, higher CICR gains, and sensitized adrenergic regulation, consistent with functionally altered Ca(2+)-release profile of CPVT syndrome.

Each year infants, children and young adults die suddenly and unexpectedly. In many cases the cause of death can be elucidated by medico-legal autopsy, however, a significant number of these cases remain unexplained despite a detailed postmortem investigation and are labeled as sudden unexplained death (SUD). Post-mortem genetic testing, so called molecular autopsy, revealed that primary arrhythmogenic disorders including long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) may account for a certain number of these cases. Because of the inheritance of these diseases, close relatives of the deceased may also at potential risk of carrying fatal cardiac disorders. Therefore, advanced diagnostic analyses, genetic counseling and interdisciplinary collaboration should be integral parts of clinical and forensic practice. In the present study, we performed mutation analyses of the major genes causing cardiac channelopathies in 15 SUD cases. In four cases we found putative pathogenic mutations in cardiac ion channel genes. Clinical and genetic examination of family members of SUD victims was also performed and affected family members were identified. This study demonstrates that molecular genetic screening needs to become an inherent part of the postmortem examination. This will enhance the ability of screening family members of SUD victims who may be at risk. The present data also illustrate that detection and follow up of familial cases of sudden death is challenging and requires a close multidisciplinary collaboration between different medical disciplines, with great responsibility for the forensic pathologist.

BACKGROUND:

Boxer dogs are reported to be predisposed to arrhythmogenic right ventricular cardiomyopathy (ARVC), but the natural history has not been well characterized and inconsistent diagnostic criteria have been applied to identify affected dogs. Echocardiographic examination findings are unremarkable in many affected Boxer dogs, and in these dogs, 24-hour ambulatory ECG (Holter) monitoring often is used for diagnostic and prognostic purposes, despite limited information available relating Holter findings to outcome. HYPOTHESIS/

OBJECTIVES:

Boxers with complex ventricular arrhythmias at initial presentation will have shorter survival times. The objective was to investigate the prognostic value of Holter monitoring in Boxer dogs.

ANIMALS:

One hundred and twenty-two Boxer dogs seen at 3 university referral hospitals.

METHODS:

Retrospective study. Survival times were obtained for Boxer dogs evaluated by echocardiography and a 24-hour Holter ECG. Kaplan-Meier survival analysis was used to estimate the median survival time and Cox proportional hazards analysis was used to identify variables independently associated with cardiac mortality.

RESULTS:

Outcome data were obtained for 122/163 dogs meeting the inclusion criteria. Of the 70 dogs that had died, 45 were considered to have suffered cardiac-related deaths. Median survival was significantly longer in dogs with a left ventricular systolic diameter (LVIDs) ≤ 35 mm compared with those with LVIDs > 35 mm (P < .001). Multivariable analysis in dogs with LVIDs ≤ 35 mm showed that the presence of ventricular tachycardia, age >4.5 years, and male sex were independent predictors of cardiac mortality.

CONCLUSIONS

AND CLINICAL IMPORTANCE: Holter monitoring in Boxer dogs provides valuable prognostic information.

Timothy syndrome, long QT syndrome type 8, is highly malignant with ventricular tachyarrhythmia. A 30-month-old boy had sudden cardiac arrest during anesthesia induction before plastic surgery for bilateral cutaneous syndactyly. After successful resuscitation, prolonged QT interval (QTc, 0.58-0.60 sec) and T-wave alternans were found in his electrocardiogram. Starting β-blocker to prevent further tachycardia and collapse event, then there were no more arrhythmic events. The genes KCNQ1, KCNH2, KCNE1 and 2, and SCN5A were negative for long QT syndrome. The mutation p.Gly406Arg was confirmed in CACNA1C, which maintains L-type calcium channel depolarization in the heart and other systems.

Cardiac amyloidosis results in severely symptomatic heart failure that has a poor prognosis because of the development of a restrictive cardiomyopathy. The diagnosis of cardiac amyloidosis is often delayed because of nonspecific signs and symptoms. We report the case of a 66-year-old woman who had been diagnosed with sick sinus syndrome and presented 5 months later with a long QT interval and recurrent polymorphic ventricular tachycardia. The diagnosis of cardiac amyloidosis was confirmed upon analysis of endomyocardial biopsy results. The patient was subsequently diagnosed with and treated for underlying plasma cell myeloma and later died of cardiac arrest. This atypical presentation of cardiac amyloidosis underscores the need to consider it in the differential diagnosis of patients who have ventricular arrhythmias. To our knowledge, the combination of long QT interval and polymorphic ventricular tachycardia has not been previously reported in association with amyloid heart disease.

Coronary heart disease (CHD) is the most common cause of human mortality. Despite of recent advances in the management of CHD (drug treatment, coronary angioplasty and stenting, coronary artery bypass surgery) prognostic estimation of this kind of mortality threatens to increase to the year 2030. Major cause of adversity of CHD is decrease in myocardial contractility which leads to heart failure (HF). HF occurs as a result of myocardial cell ischemic injury or infarction.; There is general assumption that recovery of myocardial contractility after tissue injury is not available. This dogma has been changed for the last decade with the introduction of stem cell (SC) therapy in cardiology. Research in this detection (nowadays the phase I-II of research is going on) proved SC therapy safety for human body (no risk of oncogenesis, heart attack or ventricular tachycardia, there is no heart remodeling and no need of coronary revascularization) and efficacy in myocardial contractility improvement (increase of left ventricular ejection fraction). Such positive results were obtained with the use of high dose SC therapy (10 8 cell) and its application the first week of acute myocardial infarction.