Emilio Vanoli

Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population

Background— In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately ad 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results— The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking β-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (≤440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7±4 versus 13±9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions— KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome.

OBJECTIVESnThe purpose of this study was to test the hypothesis that differences in autonomic responses might modify clinical severity in long QT syndrome type 1 (LQT1) patients, those with KCNQ1 mutations and reduced I(Ks), in whom the main arrhythmia trigger is sympathetic activation.nnnBACKGROUNDnSome long QT syndrome (LQTS) patients experience life-threatening cardiac arrhythmias, whereas others remain asymptomatic throughout life. This clinical heterogeneity is currently unexplained.nnnMETHODSnIn a South African LQT1 founder population segregating KCNQ1-A341V, we correlated major cardiac events to resting heart rate (HR) and to baroreflex sensitivity (BRS) on and off beta-adrenergic blockers (BB).nnnRESULTSnIn 56 mutation carriers (MCs), mean HR was lower among asymptomatic patients (p < 0.05). Among MCs with a QT interval corrected for heart rate <or=500 ms, those in the lower HR tertile were less likely to have suffered prior cardiac events (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.04 to 0.79, p < 0.02). The BRS was lower among asymptomatic than symptomatic MCs (11.8 +/- 3.5 ms/mm Hg vs. 20.1 +/- 10.9 ms/mm Hg, p < 0.05). A BRS in the lower tertile was associated with a lower probability of being symptomatic (OR 0.13, 95% CI 0.02 to 0.96, p < 0.05). A similar trend was observed during BB. The MCs in the lower tertile for both HR and BRS were less frequently symptomatic than MCs with different patterns (20% vs. 76%, p < 0.05). Subjects with either ADRA2C-Del322-325 or homozygous for ADRB1-R389, 2 polymorphisms predicting enhanced adrenergic response, were more likely to have BRS values above the upper tertile (45% vs. 8%, p < 0.05).nnnCONCLUSIONSnLower resting HR and relatively low BRS are protective factors in KCNQ1-A341V carriers. A plausible underlying mechanism is that blunted autonomic responses prevent rapid HR changes, arrhythmogenic when I(Ks) is reduced. These findings help understanding phenotypic heterogeneity in LQTS and identify a physiological risk modifier, which is probably genetically determined.

Early autonomic and repolarization abnormalities contribute to lethal arrhythmias in chronic ischemic heart failure: characteristics of a novel heart failure model in dogs with postmyocardial infarction left ventricular dysfunction.

OBJECTIVESnUsing a model of arrhythmias associated with ischemic left ventricular (LV) dysfunction, this study investigated autonomic and electrophysiologic mechanisms associated with sudden cardiac death (SCD) in chronic heart failure (HF).nnnBACKGROUNDnLeft ventricular dysfunction from ischemic heart disease is associated with many instances of SCD. Electrophysiologic and autonomic derangements occur in HF, but their contribution to SCD risk is poorly understood.nnnMETHODSnSudden death risk was assessed in 15 dogs with a healed anterior myocardial infarction (MI) during submaximal exercise and brief acute circumflex ischemia. Left ventricular dysfunction was then induced by repetitive circumflex microembolization until LV ejection fraction reached 35%. Before embolization, six dogs were susceptible to SCD, and nine were resistant.nnnRESULTSnBaroreflex sensitivity was lower in susceptible dogs (10 ms/mm Hg +/- 4 ms/mm Hg vs. 20 ms/mm Hg +/- 11 ms/mm Hg, p = 0.04). QT intervals from susceptible dogs were longer after MI (246 ms +/- 26 ms susceptible vs. 231 ms +/- 20 ms resistant, p < 0.001) and prolonged within eight weeks after LV dysfunction was established (from 246 ms +/- 26 ms to 274 ms +/- 56 ms, +11%, p < 0.01). Heart rate in susceptible dogs increased during transient ischemia (+20%) and with progressive LV dysfunction (102 beats/min +/- 28 beats/min baseline to 154 beats/min +/- 7 beats/min LV dysfunction, p = 0.003). All susceptible dogs had spontaneous sustained ventricular tachycardia culminating in SCD. In contrast, QT intervals in resistant dogs prolonged after 24 +/- 6 weeks (from 231 ms +/- 20 ms to 238 ms +/- 15 ms, p < 0.05), and heart rates were unchanged. Only one resistant dog died suddenly with LV dysfunction.nnnCONCLUSIONSnDepressed vagal and elevated sympathetic control of heart rate coupled with abnormal repolarization are associated with high SCD risk when post-MI LV dysfunction develops.

NGF and heart: Is there a role in heart disease?

The review emphasizes the role of NGF, the most representative member of the neurotrophins family, in cardiac physiopathology with a particular focus on healing and sprouting processes occurring after tissue damage. Cardiac and circulating NGF levels dramatically increase following myocardial injury (MI). A very early rise of this neurotrophin is indeed observed soon after MI (hours). Such a rise may lead to sympathetic nerve sprouting which may underlie the later genesis of arrhythmias but may also favor the healing process. At later times (months after), when heart failure develops, the opposite is detected and NGF tissue levels are below the normal range, an event that may in turn participate to defective innervation and cardiac failure. Through a careful analysis of preclinical and clinical studies, this review proposes that time is the key variable when studying these opposite changes in NGF expression observed following MI and attempting to interpret and correlate them with cardiac physiopathology. The examination of the results leads to the speculation that NGF modulation may be a pharmacological target for interventions in specific stages of heart dysfunction following MI.

Vagal reflexes following an exercise stress test: A simple clinical tool for gene-specific risk stratification in the long QT syndrome

OBJECTIVESnThe study assessed whether heart rate (HR) reduction following an exercise stress test (ExStrT), an easily quantifiable marker of vagal reflexes, might identify high- and low-risk long QT syndrome (LQTS) type 1 (LQT1) patients.nnnBACKGROUNDnIdentification of LQTS patients more likely to be symptomatic remains elusive. We have previously shown that depressed baroreflex sensitivity, an established marker of reduced vagal reflexes, predicts low probability of symptoms among LQT1.nnnMETHODSnWe studied 169 LQTS genotype-positive patients < 50 years of age who performed an ExStrT with the same protocol, on and off β-blockers including 47 South African LQT1 patients all harboring the KCNQ1-A341V mutation and 122 Italian LQTS patients with impaired (I(Ks)-, 66 LQT1) or normal (I(Ks)+, 50 LQT2 and 6 LQT3) I(Ks) current.nnnRESULTSnDespite similar maximal HR and workload, by the first minute after cessation of exercise the symptomatic patients in both I(Ks)- groups had a greater HR reduction compared with the asymptomatic (19 ± 7 beats/min vs. 13 ± 5 beats/min and 27 ± 10 beats/min vs. 20 ± 8 beats/min, both p = 0.009). By contrast, there was no difference between the I(Ks)+ symptomatic and asymptomatic patients (23 ± 9 beats/min vs. 26 ± 9 beats/min, p = 0.47). LQT1 patients in the upper tertile for HR reduction had a higher risk of being symptomatic (odds ratio: 3.28, 95% confidence interval: 1.3 to 8.3, p = 0.012).nnnCONCLUSIONSnHR reduction following exercise identifies LQT1 patients at high or low arrhythmic risk, independently of β-blocker therapy, and contributes to risk stratification. Intense exercise training, which potentiates vagal reflexes, should probably be avoided by LQT1 patients.

Multislice computed tomography for the evaluation of coronary bypass grafts and native coronary arteries: Comparison with traditional angiography

Background Multislice computed tomography (CT) is a promising new noninvasive technique for the detection of atherosclerotic disease within a vessels wall. The present study was designed to assess the diagnostic accuracy of 64-slice CT in detecting graft disease and in the evaluation of native vessels distally to the grafts. Methods Forty consecutive patients with previous coronary artery bypass underwent both invasive coronary angiography and 64-slice CT. The CT data were acquired over 7–12 s period during a single-breath hold using the Smartprep technique. Images were reconstructed using the retrospective modality on a synchronized ECG in a time frame of between 40 and 80% of the R-R interval. Results A total of 118 grafts were investigated (80 vein and 38 arterial conduits). At CT, 31/38 arterial grafts were classified as patent and free from significant lesions, whereas seven appeared diseased (five complete occlusion and two significant stenoses along the body of the graft). Out of 80 vein grafts, 52 appeared free of disease and 28 diseased (23 total occlusion and five critical stenosis). An absolute concordance between CT and angiographic findings was documented for all arterial and venous grafts (100% diagnostic concordance). The accuracy of 64-slice CT in the assessment of distal run-off arteries was 90%. Conclusion The 64-slice CT detected with very high accuracy the presence of diseased arterial and vein grafts. Moreover, an optimal diagnostic accuracy was also documented in the appraisal of native vessels distal to the graft anastomoses. On the basis of these results, 64-slice CT can be proposed for the study of patients after coronary artery bypass and may represent an effective screening technique to select those patients with indications of new revascularization.

Muscarinic Effects on Action Potential Duration and its Rate Dependence in Canine Purkinje Fibers

Studies of the autonomic influence on action potential duration (APD) in the ventricles show direct effects of muscarinic stimulation on epicardial, but not endocardial, APD and conflicting results regarding direct vagal effects on the conduction system. In canine Purkinje fibers, we analyzed the action of the M2 agonist oxotremorine (OXO, 0.1μM) on APD and on its cycle length (CL) dependence. Fibers were impaled with glass microalectrodes and superfused with Tyrode s solution. APD90 was measured after 3 minutes of drive at CL between 0.3 and 5 seconds. The best fit for the APD/CL relationship at steady state was a hyperbole: APD = APDmax*CL/(CL+CL50), where APDmax (APD at infinite CL) is a rate independent measure of APD, and CL50 (CL at which 50% APDmax is reached) is an index of the rate dependence of APD. In five fibers, OXO reduced APD at all CL (P < 0.05), APDmax was also reduced to 377 ± 41 ms from 447 ± 34 ms (P < 0.05), while CL50 was unchanged (405 ± 46 ms from 437 ± 28 ms). No effects of OXO on APD and APDmax were seen in two fibers obtained from dogs pretreated with pertussis toxin (PTX). In conclusion, stimulation of M2 receptors in intact, and not PTX treated, Purkinje fibers affects APD but not its CL dependence. This may reflect the activation of a rate independent, background current through a GTP binding protein‐linked pathway, such as, IK.ACH These data differ from those obtained in endocardial and epicardial muscle, stressing the regional differences in vagal modulation of ventricular electrophysiological properties.

The Baroreceptor as a Therapeutic Target for Heart Failure

Sympathoactivation is a prominent feature of heart failure (HF). Its role in cardiac remodeling and arrhythmogenesis is well-recognized today, although incomplete understanding of autonomic mechanisms was a barrier to development of contemporary medical therapies. Despite widespread availability of drugs and devices, mortality and morbidity in HF remain unacceptably high. Recognition of an additional phenotype, HF with preserved ejection fraction (EF), poses additional challenges. New treatment options are required. Electrical modulation of the central nervous system with baroreflex activation therapy offers a new approach. Activation of this afferent pathway induces the central nervous system to rebalance autonomic modulation of the cardiovascular system. Results in animal models of HF demonstrating increased survival and beneficial cardiac remodeling recently led to a clinical feasibility study in HF with reduced EF wherein the clinical course of patients dramatically improved. Results in resistant hypertension patients further suggest potential for benefit in HF with preserved EF.

Vagomimetic Effects of Fingolimod: Physiology and Clinical Implications

Fingolimod is a sphingosine 1‐phosphate (S1P) receptor modulator approved to treat relapsing‐remitting multiple sclerosis (MS). Initiation of treatment with fingolimod has been found to produce transient bradycardia and/or slowing of atrioventricular impulse conduction in a small proportion of patients. This effect is thought to be due to the interaction of fingolimod with S1P receptors on the surface membrane of atrial myocytes causing a vagomimetic effect, similar to the action of acetylcholine on muscarinic receptors. As a precaution, patients are under electrocardiogram (ECG) monitoring for 6 h after receiving their first dose. Fingolimod is contraindicated in patients with overt or concealed cardiac diseases. However, the Fingolimod Initiation and caRdiac Safety Trial (FIRST), which was designed specifically to investigate the cardiac profile of fingolimod, did not show an increased risk of clinically relevant cardiac events with fingolimod. This review examines the electrophysiology and pathophysiology of cardiac impulse formation in the context of fingolimod. It concludes that these vagomimetic effects should be considered benign and should not prevent the effective use of fingolimod in the treatment of patients with MS.

Novel approaches to the post-myocardial infarction/heart failure neural remodeling

The review aims to discuss the role of nerve growth factor (NGF) as a potential novel biomarker in post-myocardial infarction (MI) and in heart failure (HF), with a specific focus on neural remodeling and sprouting processes occurring after tissue damage. Many experimental data show that MI induces nerve sprouting, leading to increased sympathetic outflow and higher risk of ventricular arrhythmias and sudden cardiac death. In this framework, cardiac and circulating NGF might be an indicator of the innervation process and neural remodeling: it dramatically increases after MI, while it declines along with advanced HF and ventricular dysfunction. The bimodal behavior of NGF in acute and chronic settings leads to the speculation that NGF modulation may be a pharmacological target for intervention in different stages of the ischemic heart disease. Specifically, a fascinating possibility is to support or to inhibit NGF receptors, in order to prevent negative cardiac remodeling after MI and consequent ventricular dysfunction.