AimsSudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure (CHF). To investigate determinants of the increased arrhythmogenic susceptibility, we studied cardiac remodelling and arrhythmogenicity in CHF patients and in a mouse model of chronic pressure overload. Methods and resultsClinical and (immuno)histological data of myocardial biopsies from CHF patients with (VT+) and without (VT2) documented ventricular arrhythmia were compared with controls. In CHF patients, ejection fraction was decreased and QRS duration was increased. Cell size and interstitial fibrosis were increased, but Connexin43 (Cx43) levels, the most abundant gap junction in ventricular myocardium, were unchanged. No differences were found between VT+ and VT2 patients, except for the distribution pattern of Cx43, which was significantly more heterogeneous in VT+. Mice were subjected to transverse aortic constriction (TAC) or sham operated. At 16 weeks, cardiac function was determined by echocardiography and epicardial ventricular activation mapping was performed. Transverse aortic constriction mice had decreased fractional shortening and prolonged QRS duration. Right ventricular conduction velocity was reduced, and polymorphic VTs were induced in 44% TAC and 0% sham mice. Interstitial fibrosis was increased and Cx43 quantity was unchanged in TAC mice with and without arrhythmias. Similar to CHF patients, heterogeneous Cx43 distribution was significantly associated with arrhythmias in TAC mice and with spatial heterogeneity of impulse conduction. ConclusionHeterogeneous Cx43 expression during CHF is associated with dispersed impulse conduction and may underlie enhanced susceptibility to ventricular tachyarrhythmias.--

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Myocardial fibrosis increases arrhythmia vulnerability of the diseased heart. The renin-angiotensin-aldosterone system (RAAS) governs myocardial collagen synthesis. We hypothesized that reducing cardiac fibrosis by chronic RAAS inhibition would result in reduced arrhythmia vulnerability of the senescent mouse heart. Wild-type mice (52 wk old) were treated for 36 wk: 1) untreated control (C); 2) eplerenone (E); 3) losartan (L); and 4) cotreatment with eplerenone and losartan (EL). Ventricular epicardial activation mapping was performed on Langendorff-perfused hearts. Arrhythmia inducibility was tested by one to three premature stimuli and burst pacing. Longitudinal and transverse conduction velocity and dispersion of conduction were determined during pacing at a basic cycle length of 150 ms. Sirius red staining (collagen) was performed. As a result, in the RV of mice in the E, L, and EL groups, transverse conduction velocity was significantly increased and anisotropic ratio was significantly decreased compared with those values of mice in the C group. Anisotropic reentrant arrhythmias were induced in 52% of untreated mice and significantly reduced to 22%, 26%, and 16% in the E, L, and EL groups, respectively. Interstitial fibrosis was significantly decreased in both the RV and LV of all treated groups. Scattered patches of replacement fibrosis were found in 90% of untreated hearts, which were significantly reduced in the E, L, and EL groups. A strong correlation between the abundance of patchy fibrosis and arrhythmia inducibility was found. In conclusion, chronic RAAS inhibition limited aging-related interstitial fibrosis. The lower arrhythmogeneity of treated mice was directly correlated to the reduced amount of patchy fibrosis.

Reduction of both electrical coupling and excitability results in normal conduction velocity parallel to fibre orientation but in pronounced conduction slowing transverse to fibre orientation in RV only, although this does not affect arrhythmogeneity.

Both acute and chronic CaM/CaMKII inhibition improves conduction characteristics and enhances localization of Cx43 in the intercalated disc. In the absence of fibrosis, this reduced the susceptibility for arrhythmias.

Background-The electrically remodeled canine heart after chronic AV block (CAVB) has a high susceptibility for drug-induced torsade de pointes (TdP) arrhythmias. Although focal mechanisms have been considered for initiation, there is still controversy about whether reentry is the dominant mechanism for perpetuation of TdP. In this animal model with known nonuniform prolongation of repolarization, the mechanism of perpetuation of TdP arrhythmia was explored. Methods and Results-Seventeen TdP-sensitive CAVB and 10 sinus rhythm (SR) dogs were studied. In 6 animals, 66 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Activation times and activation recovery intervals were determined before and during ibutilide-induced TdP. In 12 CAVB and 9 SR dogs, left ventricular (LV) and right ventricular (RV) epicardial electrograms were recorded with a 208-point multiterminal grid electrode allowing conduction velocity (CV) and ventricular effective refractory period (VERP) measurements. Biopsy specimens were processed for connexin43 (Cx43) expression and collagen content. Ventricular myocytes were isolated to determine sodium current (I Na ) density and cell dimensions. Computer simulations were used to assess the effects of changes therein. In CAVB, VERP and ARI were increased, whereas CV was unaltered in LV. Transversal but not longitudinal CV was increased in RV. I Na was reduced by 37% in LV but unaltered in RV. LV and RV cell size were increased, but collagen and Cx43 content remained unchanged. Simulations showed increase in CV of RV as a consequence of increased cell size at normal I Na . Ibutilide increased ARI, ERP, and maximal transmural dispersion of ERP (45Ϯ25 to 120Ϯ65 ms; PϽ0.05). Twenty-eight of 47 episodes of selfterminating TdP (43Ϯ72 beats) were analyzed. The majority (Ͼ90%) of beats were focal; reentry was observed only occasionally. Conclusions-Focal activity is the dominant mechanism involved in perpetuation of ibutilide-induced TdP in CAVB dogs based on detailed 3D mapping. This conclusion is in line with unaltered conduction and documented increase in VERP. (Circ Arrhythm Electrophysiol. 2011;4:566-576.)Key Words: mechanisms of arrhythmia Ⅲ conduction Ⅲ ion channels Ⅲ long-QT syndrome Ⅲ torsade de pointes S ince Dessertenne 1 initially described the torsade de pointes (TdP) arrhythmia in 1966, identification of the arrhythmogenic mechanisms involved in this polymorphic ventricular tachycardia has been the subject of great interest. Especially, the etiology of the acquired, including druginduced, form of TdP has been the focus of attention. Both in vivo and in vitro studies have revealed that the initiation of TdP was based on early afterdepolarization (EAD)-dependent ectopic activity. [2][3][4][5][6][7][8][9] The mechanism underlying the continuation of TdP is, however, still under debate. Some investigators claim that reentry is the mechanism of perpetuation because spatial dispersion of repolarization forms the substrate for conduction blo...

A 23-year-old healthy male volunteer took part in a clinical trial in which the volunteer took chloroquine chemoprophylaxis and received three intradermal doses at four-week intervals of aseptic, purified Plasmodium falciparum sporozoites to induce protective immunity against malaria. Fifty-nine days after the last administration of sporozoites and 32 days after the last dose of chloroquine the volunteer underwent controlled human malaria infection (CHMI) by the bites of five P. falciparum-infected mosquitoes. Eleven days post-CHMI a thick blood smear was positive (6 P. falciparum/μL blood) and treatment was initiated with atovaquone/proguanil (Malarone®). On the second day of treatment, day 12 post-CHMI, troponin T, a marker for cardiac tissue damage, began to rise above normal, and reached a maximum of 1,115 ng/L (upper range of normal = 14 ng/L) on day 16 post-CHMI. The volunteer had one ~20 minute episode of retrosternal chest pain and heavy feeling in his left arm on day 14 post-CHMI. ECG at the time revealed minor repolarization disturbances, and cardiac MRI demonstrated focal areas of subepicardial and midwall delayed enhancement of the left ventricle with some oedema and hypokinesia. A diagnosis of myocarditis was made. Troponin T levels were normal within 16 days and the volunteer recovered without clinical sequelae. Follow-up cardiac MRI at almost five months showed normal function of both ventricles and disappearance of oedema. Delayed enhancement of subepicardial and midwall regions decreased, but was still present. With the exception of a throat swab that was positive for rhinovirus on day 14 post-CHMI, no other tests for potential aetiologies of the myocarditis were positive. A number of possible aetiological factors may explain or have contributed to this case of myocarditis including, i) P. falciparum infection, ii) rhinovirus infection, iii) unidentified pathogens, iv) hyper-immunization (the volunteer received six travel vaccines between the last immunization and the CHMI), v) atovaquone/proguanil treatment, or vi) a combination of these factors. Definitive aetiology and pathophysiological mechanism for the myocarditis have not been established.

Passive ventricular remodeling is defined by the process of molecular ventricular adaptation to different forms of cardiac pathophysiology. It includes changes in tissue architecture, such as hypertrophy, fiber disarray, alterations in cell size and fibrosis. Besides that, it also includes molecular remodeling of gap junctions, especially those composed by Connexin43 proteins (Cx43) in the ventricles that affect cell-to-cell propagation of the electrical impulse, and changes in the sodium channels that modify excitability. All those alterations appear mainly in a heterogeneous manner, creating irregular and inhomogeneous electrical and mechanical coupling throughout the heart. This can predispose to reentry arrhythmias and adds to a further deterioration into heart failure. In this review, passive ventricular remodeling is described in Hypertrophic Cardiomyopathy (HCM), Dilated Cardiomyopathy (DCM), Ischemic Cardiomyopathy (ICM), and Arrhythmogenic Cardiomyopathy (ACM), with a main focus on the heterogeneity of those alterations mentioned above.