Faculty Bibliography

Implementing clinical practice guidelines improves outcomes. This has been shown by several large scale registries. However, in spite of this, guidelines are poorly implemented in clinical practice for a wide variety of reasons. We examine the reasons behind the low uptake of guidelines into routine medical practice. Many physicians are simply not aware that guidelines exist; or they do not believe in them; or they simply do not care to implement them. Economic and social factors may also influence uptake of guidelines. It is the role of professional societies to disseminate best scientific knowledge, and ensure optimum implementation of guidelines. This can be achieved through educational activities and CME credit. Close collaboration between the profession, health authorities, and maybe even the industry could improve uptake of clinical practice guidelines, and thereby improve patient outcome

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death. The autosomal dominant form of CPVT is caused by mutations in the RyR2 gene encoding the cardiac isoform of the ryanodine receptor. In vitro functional characterization of mutant RyR2 channels showed altered behavior on adrenergic stimulation and caffeine administration with enhanced calcium release from the sarcoplasmic reticulum. As of today no experimental evidence is available to demonstrate that RyR2 mutations can reproduce the arrhythmias observed in CPVT patients. We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT families, to evaluate if the animals would develop a CPVT phenotype and if beta blockers would prevent arrhythmias. Twenty-six mice (12 wild-type (WT) and 14RyR(R4496C)) underwent exercise stress testing followed by epinephrine administration: none of the WT developed ventricular tachycardia (VT) versus 5/14 RyR(R4496C) mice (P=0.02). Twenty-one mice (8 WT, 8 RyR(R4496C), and 5 RyR(R4496C) pretreated with beta-blockers) received epinephrine and caffeine: 4/8 (50%) RyR(R4496C) mice but none of the WT developed VT (P=0.02); 4/5 RyR(R4496C) mice pretreated with propranolol developed VT (P=0.56 nonsignificant versus RyR(R4496C) mice). These data provide the first experimental demonstration that the R4496C RyR2 mutation predisposes the murine heart to VT and VF in response caffeine and/or adrenergic stimulation. Furthermore, the results show that analogous to what is observed in patients, beta adrenergic stimulation seems ineffective in preventing life-threatening arrhythmias

OBJECTIVE: Emotional stress is well established as a trigger of sudden death in the context of coronary heart disease (CHD), but its role in patients experiencing cardiac arrest with apparently normal hearts is unknown. This study sought to determine the role of psychosocial stress as a precipitant of cardiac arrest in patients with apparently normal hearts, so-called idiopathic ventricular fibrillation (IVF). METHODS: We interviewed 25 IVF survivors (12 men, 13 women) and 25 matched comparison patients regarding life events during the 6 months and 24 hours preceding the cardiac event. The comparison group consisted of patients with an acute myocardial infarction or angina pectoris requiring angioplasty but without cardiac arrest. Judges independently rated written summaries of these interviews for psychosocial stress at each time point on a three-point scale (low, moderate, severe). RESULTS: During the 6 months before the cardiac event, 20 patients sustaining IVF had severe/moderate stress and five had low stress, whereas 10 comparison patients had severe/moderate stress and 15 had low stress (Fisher exact p = .008). During the preceding 24 hours, nine patients with IVF had severe/moderate stress and 16 had low stress, whereas two comparison patients had severe/moderate stress and 22 had low stress (Fisher exact p = .04) (one silent myocardial infarction could not be precisely dated). CONCLUSION: These data suggest that psychosocial stress is playing a role in otherwise unexplained cardiac arrest

Catecholaminergic polymorphic ventricular tachycardia (VT) is a rare arrhythmogenic disease characterized by exercise- or stress-induced ventricular tachyarrhythmias, syncope, or sudden death, usually in the pediatric age group. Familial occurrence has been noted in about 30% of cases. Inheritance can be autosomal dominant or recessive, usually with high penetrance. The causative genes have been mapped to chromosome 1. Mutations of the cardiac ryanodine receptor gene (RyR2) have been identified in autosomal dominant pedigrees, while calsequestrin gene (CASQ2) mutations are seen in recessive cases. Ankyrin-B mutations may also be implicated in catecholaminergic polymorphic VT: mutations in this gene were previously linked to the long-QT 4 phenotype. Ventricular ectopy, bidirectional VT, and polymorphic VT occur in a predictable and progressive manner with increasing heart rate during exercise or isoproterenol infusion. Estimated mortality of untreated cases ranges from 30% to 50% before the age of 20-30 years according to family studies. Although beta-blocker therapy was considered to be effective in preventing clinical recurrence in the initial series, recent data show low efficacy. As there is a chance for sudden cardiac death if even a single dose of beta-blocker is missed, there is a trend toward implantation of defibrillators in more and more patients

Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG (I(Kr)) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (I(Ks)) channel. Here we identify a new variant, 'SQT3', which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I(K1) than the wild-type (P<0.05) at potentials between -75 mV and -45 mV, with the peak current being shifted in the former with respect to the latter (WT, -75 mV; D172N, -65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I(K1) greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients' consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias

The increasing interaction between molecular biology and clinical cardiology has allowed to demonstrate that mutations on the genes encoding cardiac ion channels or regulatory proteins can cause inherited arrhythmogenic disorders predisposing to sudden death in young individuals. These diseases are the long QT syndrome, the Brugada syndrome, the catecholaminergic polymorphic ventricular tachycardia, and the short QT syndrome. Since incomplete penetrance is present, genetic screening is pivotal to perform a correct diagnosis in mutation carriers who do not manifest phenotype, but are still at increased risk of cardiac events if left untreated. All these syndromes show genetic heterogeneity and it is becoming evident that each genetic variant of the disease presents distinguishing clinical characteristics suggesting that genetics may be used for targeting risk stratification and treatment of these diseases. In this chapter, the molecular bases, the clinical features and the current therapeutic approach of these syndromes are presented

The 1996 American Heart Association consensus panel recommendations stated that pre-participation cardiovascular screening for young competitive athletes is justifiable and compelling on ethical, legal, and medical grounds. The present article represents the consensus statement of the Study Group on Sports Cardiology of the Working Group on Cardiac Rehabilitation and Exercise Physiology and the Working Group on Myocardial and Pericardial diseases of the European Society of Cardiology, which comprises cardiovascular specialists and other physicians from different European countries with extensive clinical experience with young competitive athletes, as well as with pathological substrates of sudden death. The document takes note of the 25-year Italian experience on systematic pre-participation screening of competitive athletes and focuses on relevant issues, mostly regarding the relative risk, causes, and prevalence of sudden death in athletes; the efficacy, feasibility, and cost-effectiveness of population-based pre-participation cardiovascular screening; the key role of 12-lead ECG for identification of cardiovascular diseases such as cardiomyopathies and channelopathies at risk of sudden death during sports; and the potential of preventing fatal events. The main purpose of the consensus document is to reinforce the principle of the need for pre-participation medical clearance of all young athletes involved in organized sports programmes, on the basis of (i) the proven efficacy of systematic screening by 12-lead ECG (in addition to history and physical examination) to identify hypertrophic cardiomyopathy-the leading cause of sports-related sudden death-and to prevent athletic field fatalities; (ii) the potential screening ability in detecting other lethal cardiovascular diseases presenting with ECG abnormalities. The consensus document recommends the implementation of a common European screening protocol essentially based on 12-lead ECG