Repolarization Disturbances Research Articles

PVC induced QT prolongation for unmasking the LQTS

Abstract Background Long QT Syndrome (LQTS) is a congenital or acquired disorder of cardiac ion channels resulting in disturbances of myocardial repolarization, usually manifested by QT prolongation. Diagnostic criteria include the presence of the corrected QT interval (QTc) of at least 480ms (milliseconds) in repeated 12-lead ECGs or confirmed LQTS gene mutations. Patients with LQTS have an increased likelihood of developing life-threatening ventricular arrhythmias and sudden cardiac death. Hence, establishing an accurate diagnosis is crucial. Purpose About 50% of patients with LQTS presents with normal or borderline QTc interval. Such cases warrant additional work-up to confirm the diagnosis and can often get overlooked. Based on two separate patient cases we hypothesized that significant QTc interval prolongation occurring after premature ventricular contractions (PVCs) may be a valuable diagnostic clue for suspected LQTS or potentially life-threatening arrhythmia in cases with unclear diagnosis. Above mentioned patients displayed normal baseline QTc interval values that prolonged only after PVC. Later, one of them was diagnosed with congenital and another with drug-induced LQTS (see ECG 1). Methods We observed QT interval behavior after PVC in three prespecified groups:(I) Electrocardiographically affected LQTS subjects (QTc ≥480ms) – 10 patients, (II) Control group of unaffected, asymptomatic, otherwise healthy subjects (QTc<460ms) – 72 patients, (III) Index Group of 2 patients with baseline QTc interval of 360-460ms, prolonged only after PVC. 24-hour-ECG records were analyzed. We calculated means of QTc interval before and after PVC in abovementioned three groups and compared them to each other using ANCOVA analysis. Results The QT interval after PVC increased 488+23ms in the first and 390+10ms in the second group. In contrast to the index group, the QT interval was prolonged by 380+160ms after PVC. Post-PVC QTc interval mean difference adjusted to covariate, baseline QTc interval values, were statistically insignificant between I and II groups (P=0.o66), but significant between both I -III(P=0.000055) and II-III groups (P<.0001). Conclusion There are several studies indicating that PVCs affect QT interval, but the phenomena need more investigation. From the perspective of our study, we have also observed that QTc interval indeed increased after PVCs in both ECG-phenotype positive LQTS individuals and healthy subjects, but not in the extent of the index patients. Our study is limited by the small number of concealed LQTS cases. However, it gives us some basis to think, that this finding could be particularly useful to suspect and unmask concealed LQTS in the patients with non-diagnostic baseline ECG.ECG1

Cerebral Ischemia and Reperfusion-Induced Changes in Left Ventricular Function and Electrocardiogram in Mice

Background: Stroke may produce functional and electrical heart disturbances. The underlying characteristics and mechanisms have not been fully elucidated. Objectives: To evaluate whether acute cerebral ischemia (I) and reperfusion (R) may cause cardiac dysfunction and electrocardiographic alterations in an experimental mice model. Methods: Male mice that underwent cerebral ischemia and reperfusion (I/R) were evaluated by electrocardiography (ECG) and echocardiography. Heart rate, corrected QT (QTc) interval, T-wave peak to T-wave end (Tp-Te) interval, left ventricular ejection fraction (LVEF), shortening fraction (SF) and isovolumetric relaxation time (IVRT) were analyzed. Cerebral infarct size was calculated, and neurological deficit was assessed with the Longa scale. Results: Twenty-four hours after R, a statistically significant decrease in LVEF (I/R: 66.5±1.5% vs. sham: 74.3±0.9%; p=0.002) and in SF (I/R: 42.9±1.7% vs sham: 52.3±1.7%; p=0.004) was observed. QTc interval prolongation was observed during I/R (baseline: 125.1±4.3 ms; 60 min after I: 143.8±5.2 ms; 24 h after R: 170.3±5.8 ms; p=0.002). Tp-Te interval was not prolonged during I (baseline: 25.9±1.3 ms vs. 60 min after I: 23.8±1.4 ms; p=0.999) but it was prolonged during R (24 h after R: 32.0±2.3 ms; p=0.049). Cerebral infarct size was 34.9±2.5% and survival in the I/R group was 43.3%. Conclusion: Acute cerebral ischemia induces mild left ventricular dysfunction and disturbances in ventricular repolarization which intensify within the first 24 hours after reperfusion.

New recellularizable cardio-matrix scaffold as a base for alternative in vitro models for the cardiotoxicity risk prediction

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): SID 227944/22 DOR 2331157/23 Background Cardiotoxicity is the occurrence of cardiac dysfunction induced by pathophysiological stimuli as a result of toxic effects. A considerable number of drugs, including chemotherapics, antibiotics antidepressants but also antiarrhythmics, could cause an alteration of cardiac physiology, and then cardiac damage. These include disturbances in ventricular repolarization and QT interval, arrhythmias, bradycardia, tachycardia, decreases in left ventricular ejection fraction, and congestive heart failure. Precinical evaluation of drug cardiotoxicity has used animal models, which tend to be expensive, have lo throughput, and have limitations as not ever faithfully reflect the human pathophysiology, while current two-dimensional cellular models revealed to be not sufficient and specific. Purpose The aim of this study is to develop a myocardial tissue-like scaffold, in order to realize an efficient and easy-replicable in vitro model for drug cardiotoxicity prediction. This must be able to mimic the morphological, cellular, and electrophysiological complexity of the intact adult human myocardium. Material and Methods Starting from fresh porcine hearts, cardiac specimens were isolated from left ventricles using a scalpel, sectioned with a vibratome and punched with a biopsy puncher obtaining myocardial patches. Thus, samples were decellularized through a novel serial decellularization treatment based on osmotic shock and detergents. The decellularization procedure exploited a new automated, dynamic perfusion device for a standardized and optimized removal of cardiac cells and non-ECM proteins. These samples were analysed for decellularization effectiveness by DNA quantification, histology and immunofluorescence staining to evaluate cell removal and extracellular matrix integrity. Moreover, they were tested for cytocompatibility using human mesenchymal stem cells and cardiac progenitors, also derived from induced pluripotent stem cells. Cellular adhesion, behaviour, vitality, proliferation, and possible apoptotic effects were tested, too. Results In order to advance a robust bioelectronics model, an automated platform was developed to generate a three-dimensional, bioengineered replica of human myocardial tissue. With respect to the common decellularization protocol characterized by mild agitation, results based on the automated, dynamic treatments have shown a superior ability to obtain acellular, biocompatible scaffolds in terms of cell elements’ removal and extracellular matrix preservation, as well as time- and cost-effectiveness. Indeed, these decellularized scaffolds allow cell penetration, adhesion and survival. Conclusions Further experiments will be focused on evaluating functional bioengineered myocardial tissues with electrophysiological and molecular analysis to evaluate this new model's throughput capacity. Finally, the validation of these bioelectronic platforms will be performed with drugs with known cardiotoxic effects.

Cardiac Damage After SARS-CoV2 Infection.

COVID-19 is a viral disease that can manifest acutely in the respiratory tract and other organs. In this study, we aimed to investigate potential long-term damage to the heart from COVID-19. For this study, we divided 97 consecutive unselected COVID-19 patients aged 18-80 years at a cardiology practice in Cologne, Germany, into two groups based on the severity of their infection. We performed a resting ECG and a resting transthoracic echocardiography three and six months after SARS-CoV2 infection. The key discriminator determining disease severity was bed confinement or hospital admission. Group 1 included patients with less severe COVID-19, whereas group 2 contained more severe cases. Heart rate as the primary ECG endpoint was lower by a statistically significant amount for the entire study population (p=0.024), subdivided by gender (pwomen <0.001, pmen <0.001) and in group 1 p =0.003compared to three months. QTc time and repolarization disturbances as primary ECG endpoints and the echocardiographic primary endpoints, left ventricular ejection fraction, and left ventricular end-diastolic diameter (LVEDD), showed no relevant difference between the subgroups at three and six months or between the measurements taken at each point. In contrast, LVEDD normalized to body surface area was statistically significantly lower at six months in women in group 1 compared to group 2 (p=0.048) and in the overall study population at six months compared with the data after three months (p=0.034). E/E' was statistically lower at six months than at three months in the whole population (p=0.004) and in women (p=0.031). All measured echocardiographic and electrocardiographic mean values were within the normal range in all groups and follow-up controls. Overall, the prospective study conducted showed no significant evidence of long-term cardiac damage from COVID-19 disease, as evidenced by electrocardiographic and echocardiographic examinations at three and six months after infection.

Transthyretin amyloid cardiomyopathy

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure and arrhythmia. This differential diagnosis should particularly be considered in older patients with left ventricular hypertrophy (LVH) who are also suffering from heart failure with preserved ejection fraction (HFpEF) or aortic valve stenosis. ATTR-CM is caused either by agenetic variation or by aging processes. The extracellular accumulation of amyloid fibrils in the heart causes arestrictive cardiomyopathy, which leads to typical heart failure symptoms as well as cardiac conduction and repolarization disturbances. Extracardiac problems such as acarpal tunnel syndrome can also be indicative for ATTR-CM. The disease can be diagnosed either by amyocardial biopsy or alternatively by apositive bone scintigraphy with the simultaneous exclusion of monoclonal proteins in blood and urine. Besides asymptomatic treatment, the transthyretin (TTR) stabilizer tafamidis is now available, which can significantly delay the disease progress. In the coming years, the approval of further drugs for the treatment of ATTR-CM is to be expected.

Patients with Achilles Tendon Rupture Are Prone to Develop Ventricular Arrhythmia.

This study aimed to examine the ventricular repolarization (VR) disturbances of patients operated on for acute spontaneous Achilles tendon ruptures (ATRs), by comparing them with a healthy individual control group. Between June 2014 and July 2020, a total of 29 patients (28 males, 1 female; mean age: 40 ± 9.78 years; range, 21-66 years) who presented to the emergency department within the first three weeks of injury, and were diagnosed with acute spontaneous ATRs and treated with an open Krackow suture technique, were retrospectively analyzed. Fifty-two healthy individuals (47 males, 5 females; mean age: 39 ± 11.45 years; range, 21-66 years) were recruited as a control group from the cardiology outpatient clinic. Clinical data (demographic features and laboratory parameters (serum glucose, creatinine, hemoglobin, white blood cell count, and lipid profile)) and electrocardiograms (ECGs) were collected from medical records. ECGs were evaluated for heart rate and VR parameters of QRS width, QTc interval, cQTd interval, Tp-e interval, and Tp-e/QT ratio. The clinical data and these ECG parameters were compared between groups. There was no statistically significant difference between groups, regarding clinical data (all p < 0.05). Among ECG parameters, heart rate, QRS width, QTc interval, and cQTd interval were similar between groups (all p < 0.05). There were two important statistically significant findings of this research: The mean Tp-e interval was longer (ATR group: 72.4 ± 24.7, control group: 58.8 ± 14.5, p: 0.01), and the Tp-e/QT ratio was higher (ATR group: 0.2 ± 0.1, control group: 0.16 ± 0.4, p: 0.027) in the ATR group. According to the ventricular repolarization disturbances found in this study, patients with ATR may be at a higher risk of ventricular arrhythmia than healthy people. As a result, ATR patients should be assessed for ventricular arrhythmia risk by an expert cardiologist.

P221 ASSOCIATION BETWEEN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND A SEVERE DILATED CARDIOMYOPATHY: A CASE REPORT

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 genes, encoding polycystin 1 and 2. We report the case of a 51–year–old woman with arterial hypertension and stage V chronic kidney disease from polycystic kidney disease, without a significant family health history. She was admitted to our Cardiology Ward for worsening dyspnea, dependent oedemas and a 3/6 systolic heart murmur detected. Blood tests showed mild anemia and hyperkalemia, severe renal failure (creatinine 6 mg/dl) and normal both liver and thyroid function. The ECG showed sinus rhythm with normal atrioventricular conduction, low voltage in precordial leads and non–specific repolarization disturbances. Hemodialysis and intravenous decongestion therapy were started. A transthoracic two–dimensional echocardiography was performed and a dilated left ventricle with severe global systolic dysfunction (EF 25%) was documented, with severe secondary mitral regurgitation (MR) with a central jet (EROA 0,5 cm2). A possible bicuspid aortic valve was suggested with moderate aortic regurgitation. CT scans showed small pleural and pericardial effusions, polycystosis affecting both kidneys and liver. Coronary CT showed a subcritical interventricular artery stenosis and confirmed a bicuspid aortic valve. Magnetic resonance angiography was negative for intracranial aneurysms. Finally, genetic testing revealed a heterozygous pathogenic mutation of PKD1 gene (c.9622del G p.Ala3208Hisfs*108 exone 28). Maximum tolerated heart failure therapy was prescribed after discharge, resulting in symptoms reduction but only mild echocardiographic improvement (EF 30% with severe MR). An edge–to–edge transcatheter mitral valve repair was proposed. In literature we learn that PKD1 mutations are linked to various cardiomyopathies: hypertrophic, dilated, left ventricular non compaction. We report the association of ADPKD with a complex dilated cardiomyopathy with severe secondary MR, an aortic congenital defect and an associated subcritical coronary artery stenosis. Further investigations are needed to study the genetic aspect of the ADPKD when associated with different cardiac anomalies.

P408 CERTIFICATION FOR COMPETITIVE SPORTS ACTIVITY IN A TEENAGER WITH WPW BY VIA INTRAHYSSIAN ACCESSORY PATHWAY

Abstract The case of a 12–year–old male, height 160 cm, weight 46 kg, who practices water polo at a competitive level is reported. Negative family history of cardiovascular pathologies, general and cardiovascular physical examination within the limits of normality. On the electrocardiographic trace (ECG) presence of delta wave from ventricular pre–excitation from intrahyssian accessory pathway (Fig. 1). Echocardiography + color Doppler was normal. The subject underwent a cardiopulmonary stress test with an incremental ramp protocol and steps of 20 watts / min. Shutdown at 190 watts for muscle exhaustion with peak oxygen consumption (VO2) = 43.9 mL / Kg / min, Heart rate = 197 beats / minute, BP = 210/70 mmHg, VE / VCO2 slope = 27.6. Normal course of the cronotropic and pressure curve. The ventricular pre–excitation delta wave persisted for the entire duration of the test and in recovery (Fig. 2, Fig. 3). Secondary disturbances of ventricular repolarization characterized by ST segment sub–leveling and negative T wave appeared at high load and persisted in the first minutes of recovery, delta VO2 / delta WR = 12. Given the non–disappearance of the delta wave from ventricular pre–excitation during the maximal stress test, the subject was sent to an electrophysiological study and subsequent ablation of the accessory pathway. The electrophysiological study was negative for inducibility of atrial fibrillation (AF) and ventricular arrhythmias. Safe ablation was impossible given the intrahyssian position of the accessory pathway. Considering the negativity of the electrophysiological study due to non inducibility of supraventricular and ventricular arrhythmias, eligibility for competitive sports was granted.

Chronically elevated branched chain amino acid levels are pro-arrhythmic.

AimsCardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach.Methods and resultsWe employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation.ConclusionsOur findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.

The frontal plane QRS-T angle may affect our perspective on prehypertension: A prospective study

ABSTRACT Backround The frontal plane QRS-T [f(QRS-T)] angle is an easy marker of myocardial repolarization and was associated with adverse cardiovascular outcomes like prehypertension (PHT). This study was aimed to investigate to evaluate the f(QRS-T) angle in patients with PHT. Methods We measured f(QRS-T) angle of 70 subjects with PHT, 109 patients with hypertension (HT), and 102 normotensive healthy volunteers. The f(QRS-T) angle was calculated from 12-lead electrocardiography. Results The f(QRS-T) angle was significantly higher in the HT and PHT groups as compared to the control group, but there was no significant difference in the f(QRS-T) angle between the HT and PHT groups. The f(QRS-T) angle was significantly and positively correlated with age, systolic blood pressure (BP) in 24 hours, average BP in 24 hours, pulse pressure in 24 hours, hemoglobin, QT dispersion, TpE distance while was negatively correlated with left ventricular ejection fraction. In multivariable analysis, we showed that systolic BP, average BP in 24 hours, pulse pressure in 24 hours, hemoglobin, QT dispersion, Tpe distance were independent predictors of higher f(QRS-T) angle. Conclusions The f(QRS-T) angle, a noninvasive measurement analyzing the dysfunction in cardiac conduction system, was increased in subjects with PHT as compared to normotensives, and the subjects with PHT had f(QRS-T) angle as higher as patients with HT did. Our findings are supportive for the hypothesis that disturbances in ventricular repolarization is present in an early stage of essential hypertension.

Cardiac Tamponade: Epidemioclinical, Therapeutic and Evolutionary Aspects at the University Hospital of Brazzaville

Objectives: Contribute to improving the management of cardiac tamponade in Congo. Background: Cardiac tamponade is an acute or subacute compression of the heart chambers by pericardial effusion responsible for uncertain prognosis for patients. The objective of this study is to help improve the management of patients with cardiac tamponade. Patients and Methods: We conducted a retrospective and descriptive study at the University Hospital of Brazzaville, from January 2015 to December 31, 2019. Included were all patients hospitalized for cardiac tamponade. Epidemioclinical, therapeutic and evolutionary data were analyzed. Results: An overall of 14 patients were divided into 9 men (64.2%) and 5 women (35.7%), i.e. a sex ratio of 1.8. The mean age of patients was 34.2 ± 15.1 years old (18 years to 64). The most represented comorbidity was hypertension (n = 2; 14.3%). The most frequent clinical sign was dyspnea (n = 14; 100%). The ECG showed diffuse and concordant repolarization disturbances (n = 14; 100%), sinus tachycardia (n = 13; 92.8%), microvoltage (n = 12; 85.7%). Cardiomegaly was constant (n = 14; 100%). In terms of transthoracic ultrasound, we found: diastolic compression of the right ventricle (RV) (n = 12; 85.7%), dilation of the inferior vena cava (IVC) (n = 12; 85.7%). Treatment consisted of crystalloid vascular filling in all patients, pericardial puncture (n = 7; 50%), surgical drainage (n = 12; 85.7%), anti-tuberculosis drugs (n = 11; 78, 6%), antimitotics could be administered in one case (n = 1; 7.2%). Two cases of death were recorded, i.e. 14.3%. Conclusion: Cardiac tamponade, although it is a rare condition, remains a serious pathology and difficult to manage in our context.

Detection of myocardial injury in perinatal asphyxia by echocardiography and cardiac biomarkers

Perinatal hypoxia can induces cardiac (Cd) injury in the newborn and requires an early diagnosis. Cd troponin I (cTnI) is correlated to hypoxic myocardial lesion-may be a useful marker of it Objectives: to evaluate the utility of echocardiography(echo) and research of cTnI values for diagnosis of myocardial injury. Patients: 98 newborns (0–14 days), with perinatal hypoxia, without major Cd anomalies, to wich were performed: clinical exam, ECG, Rx.CT, echo, research of cTnT values. The patients had mainly signs of neurological post hypoxic suffering without signs of Cd distress. The Cd exam: tachycardia, systolic murmur (64 pts); RxCT: cardiomegaly (35); ECG: LV repolarization disturbances (37);. Echo at 2–7 days of life: the absence of severe Cd malformations; myocardial LV hypertrophy (42 pts); normal LV systolic function(all); LV diastolic dysfunction (45 pts).The importance of Cd involvement were correlated with signs of hypoxic ischemic encephalopathy. The pts received spironolactone 1 mg/kg/day for 1 month, then 1 mg/Kg at 2 days (the alternating pattern) for 2–3 months. Evolution: absence of new myocardial suffering signs, is maintains systolic murmur (2/3 pts); reevaluation of echo at 6 months: the reduction of the myocardial hypertrophy, normal LV diastolic function; elevated cTnT values (> 0.12 μg/l): 56% pts with perinatal hypoxic suffering. The perinatal hypoxia can induce the apparition of post hypoxic hypertrophic cardiomyopathy(HCMP)(69% pts), LV diastolic function disturbancies and normal systolic LV function, even if the signs of Cd suffering missing often; echo is the main method for diagnosis and follow up of perinatal hypoxic HCMP and is necessary from the first week of life; increased values of cTnT(> 0.12 μg/l) in perinatal asphyxia prove hypoxi c myocardial damage; traitement with spironolactone for 2–3 months induced improving of HCMP and normalising of LV diastolic disfunction and cTnI values.

The repolarization pattern of ARVC patients, healthy gene carriers and controls as analyzed with a 252-leads Body Surface Mapping Vest

Abstract Background Repolarization abnormalities have a central role on the diagnosis of ARVC according to recent HRS consensus document from 2019 stating that T wave inversion in the right precordial leads is a major criteria if it appears in V1-V3 or a minor criteria if it appears in only V1-V2. Purpose The aim of our study was to investigate whether repolarization patterns as recorded by a Body Surface Mapping (BSM) system consisting of a vest with 252 ECG leads, could differentiate ARVC patients and even gene carriers from normal individuals. Our hypothesis is that the method can potentially identify repolarization disturbances earlier or better than conventional 12-lead ECG. Method 12 definite ARVC patients, 20 healthy gene carriers and 8 family members who tested negative for the family mutation (controls) were included. All patients underwent 12-lead ECG, including right precordial leads (V4R) and BSM recordings. Repolarization (T-wave polarity and concordance with QRS complex vector) was analyzed qualitatively in all BSM recordings, the results of which were displayed on a color code map (fig.1). Results The mean age was 49.6, 43.6 and 38.8 years in ARVC patients, healthy gene carriers and controls, respectively. The number of males in the three groups were 8/12, 8/20 and 5/8, respectively. All 8 controls had similar repolarization patterns with negative and concordant T waves on the right back panel, and T waves that successively changed from negative concordant (green) to positive disconcordant (red) and finally positive concordant (blue) on the left front panel (pattern 1). All 12 ARVC patients had different repolarization patterns as compared to the controls. Two of these patients had no apparent repolarization changes on conventional 12 lead ECG. The pattern type 2 repolarization, as defined by same pattern as the controls at the right back panel but different pattern at the front left panel was seen in 3/12 ARVC patients. The remaining 9 ARVC patients had different repolarization patterns both on the front and on the back panel (pattern 3). Among gene carriers, 15 had a normal repolarization pattern (pattern 1) and 5 demonstrated an abnormal repolarization pattern (4 had pattern type 2 and one pattern 3) despite normal surface ECG. Conclusions Using BSM recordings, abnormal repolarization patterns can be detected in all ARVC patients, even in those without repolarization changes on conventional surface ECG. The observation that 25% of gene carriers had divergent repolarization patterns, may indicate an early stage of the disease, and be used as an early diagnostic marker of the disease. Further and larger studies are warranted to confirm these observations. Repolarisation patterns recorded by BSM Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Selanders Stiftelse

Transgenic LQT2, LQT5, and LQT2-5 rabbit models with decreased repolarisation reserve for prediction of drug-induced ventricular arrhythmias.

Background and PurposeReliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss‐of‐function mutations of human HERG (HERG‐G628S, loss of IKr; LQT2), KCNE1 (KCNE1‐G52R, decreased IKs; LQT5), or both transgenes (LQT2‐5) in the heart.Experimental ApproachEffects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild‐type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff‐perfused hearts.Key ResultsLQTS models reflect patients with clinically “silent” (LQT5) or “manifest” (LQT2 and LQT2‐5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr‐blocking (LQT5) or IK1/IKs‐blocking (LQT2 and LQT2‐5) properties of drugs compared to healthy WT animals. Impaired QT‐shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2‐5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT.Conclusion and ImplicationsLQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2‐5), their combined use could provide more reliable and more thorough prediction of (multichannel‐based) pro‐arrhythmic potential of novel drug candidates.

Combined effects of exercise training and high doses of anabolic steroids on cardiac autonomic modulation and ventricular repolarization properties in rats.

Several studies have reported that high doses of synthetic anabolic androgenic steroids (AAS) can have serious negative effects on health, including the cardiovascular system. The aim of this study was to evaluate the combined effects of AAS and exercise training on ventricular repolarization and cardiac autonomic modulation in rats. Male Wistar rats were allocated into 4 groups: sedentary rats treated with vehicle, sedentary rats treated with nandrolone decanoate, swimming-trained rats treated with vehicle, and swimming-trained rats treated with nandrolone decanoate. Ventricular repolarization was evaluated by electrocardiographic analysis of QT interval and QT dispersion. Cardiac autonomic modulation was assessed by heart rate variability. Our results show that AAS increased QT interval and QT dispersion in sedentary rats treated with nandrolone decanoate as compared to sedentary rats treated with vehicle, indicating AAS-induced ventricular repolarization abnormalities. When rats treated with nandrolone decanoate were subjected to concomitant exercise training, ventricular repolarization was normalized. On the other hand, AAS-induced reduction in cardiac parasympathetic modulation was not prevented by exercise training. In conclusion, AAS produced cardiac autonomic dysfunction and ventricular repolarization disturbances in rats. Combining an exercise training protocol during the AAS treatment attenuated the ventricular repolarization abnormalities and did not prevent cardiac autonomic dysfunction.

Drug potency on inhibiting late Na+ current is sensitive to gating modifier and current region where drug effects were measured

IntroductionCardiac late Na+ current (INaL) contributes to ventricular action potential duration. Pathological increase in INaL is arrhythmogenic, and inhibition of INaL offers protection against ventricular repolarization disturbance. Recently, two INaL datasets generated by different laboratories that assessed current inhibition by a panel of clinical drugs as a part of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative were published. The results revealed a surprising degree of data variability despite of the use of a standardized voltage protocol. This study investigated whether remaining procedural differences related to experimental methods and data analysis associated with these datasets can produce differences in INaL pharmacology. MethodsWhole cell voltage clamp recordings were performed on cells expressing NaV1.5 α- and β1-subunits to study: 1) the impact of gating modifiers used to augment INaL (ATX-II vs. veratridine), internal solution composition (with vs. without ATP and GTP), and recording temperature (23 °C vs 37 °C) on stability of INaL measured across the duration of a patch clamp experiment; 2) mechanisms of each gating modifier on Na+ channels; and 3) effects of six drugs (lidocaine, mexiletine, chloroquine, ranolazine, ritonavir, and verapamil) on INaL induced by either gating modifier. ResultsStability of INaL is affected by the choice of gating modifier, presence of nucleotides in the internal solution, and recording temperature. ATX-II and veratridine produced different changes in Na+ channel gating, inducing mechanistically distinct INaL. Drug potencies on inhibiting INaL were dependent on the choice of gating modifier and current region where drug effects were measured. DiscussionINaL pharmacology can be impacted by all experimental factors examined in this study. The effect of gating modifier and current region used to quantify drug inhibition alone led to 30× difference in half inhibitory concentration (IC50) for ritonavir, demonstrating that substantial difference in drug inhibition can be produced. Drug potencies on inhibiting INaL derived from different patch clamp studies may thus not be generalizable. For INaL pharmacology to be useful for in silico modeling or interpreting drug-induced changes in cardiac action potentials or ECG, standardizing INaL experimental procedures including data analysis methods is necessary to minimize data variability.

Prolonged QTc Interval in Rat after Long-term High-Intensity Interval Training and Detraining

Long-term exercise induces cardiac remodelling known as exercise-induced ventricle hypertrophy and accompanied by electrical remodelling that can be recorded by ECG. This study aimed at recognizing electrocardiographic changes in rats undergoing long-term high-intensity interval exercise followed by a period of detraining. This study conducted at the Laboratory of the Biochemistry and Molecular Biology Department, FMUI from November 2014-January 2015. Four groups of young adults male wistar rats (100-200gBW) were randomly selected. Group 1 and 2 were assigned as control group for ECG recording on week (4 and 8) and (12 and 16) respectively. Group 3 was given 4 weeks of intensive training, followed by 4 weeks of detraining, while group 4 was given 12 weeks of intensive training followed by 4 weeks of detraining. ECG examination was performed at the end of each period of training or detraining and compared to control group of the same period of age. P wave in the exercising group was significantly increased (pl0.05), PR interval was decreased in group 4 after detraining (pl0.05). QRS amplitude was increased although not significantly different compared to control group. However, a significant persistent prolonged QTc interval was observed in the exercising group (62.76+4.03 ms and 64.24+3.78 ms) compared to control group (48.88+2.15 ms and 47.33+3.43 ms). Detraining did not restore QTc interval (57.81+1.96 ms and 61.16+5.02 ms) vs (48.93+2.40 ms and 48.13+1.66 ms). In conclusion, cardiac remodelling after long-term high intensity interval training causes ventricular hypertrophy with persistent repolarization disturbances after a period of detraining, indicated by an increase in QRS amplitude and a significant prolonged QTc interval.

Predisposition of functional genetic variants of A-kinase anchoring protein 10 toward acquired repolarization disorders in high-risk vascular surgery patients

PurposeWe aimed at assessing the predisposition of A-kinase anchoring protein 10 (AKAP10) polymorphism toward acquired repolarization disorders in high-risk vascular surgery patients.Patients and methodsOne hundred adult patients (age =44–85 years), scheduled for an elective high-risk “open” vascular surgery procedure, were recruited. The electrocardiogram Holter monitor was used to assess repolarization stability from the beginning of the operation up to 24 hours afterward. The AKAP10 gene rs203462 polymorphism and cardiac complications were analyzed.ResultsRepolarization disturbances defined as QT interval duration corrected for heart rate (QTc) interval prolongation >500 ms and QTc interval dispersion >65 ms were recorded in 46 patients. A model of multivariate logistic regression showed that only the presence of allele G of the AKAP10 polymorphism was an independent risk factor for repolarization disturbances in the perioperative period (odds ratio =14.35; 95% CI =4.65–44.23; p<0.0001).ConclusionWhen the acquired QTc interval prolongation or QTc dispersion is associated with AKAP10 polymorphism, it may remain clinically silent.

Type 1 diabetes is associated with T-wave morphology changes. The Thousand & 1 Study

BackgroundRepolarization is impaired in patients with type 1 diabetes mellitus (T1DM), and repolarization disturbances are associated with an increased mortality. To study cardiac repolarization, we assessed T-wave morphology in patients with T1DM without known heart disease. Methods855 T1DM patients without known heart disease were matched 1:2 with 1710 people from a background population. Rate-corrected T-wave morphology markers were obtained. Patients were stratified by albuminuria. Results are mean ± standard deviation. ResultsT-waves were flatter (0.398 ± 0.059 vs. 0.382 ± 0.062, p < 0.001) and more asymmetric (0.082 ± 0.068 vs. 0.071 ± 0.084, p = 0.001) in T1DM. Patients with albuminuria had an increased heart rate (normoalbuminuria: 71 ± 13 bpm, microalbuminuria: 75 ± 12 bpm, p < 0.001, macroalbuminuria: 78 ± 12 bpm, p < 0.001) and more asymmetric T-waves (normoalbuminuria: 0.079 ± 0.060, microalbuminuria: 0.094 ± 0.085, p < 0.01, macroalbuminuria: 0.101 ± 0.080, p < 0.01), but the QTc interval remained unchanged. ConclusionsT1DM is associated with changes in T-wave morphology. T-wave asymmetry but not QTc interval is associated with albuminuria in T1DM and may be used for stratification.

Acute interruption of treatment with nandrolone decanoate is not sufficient to reverse cardiac autonomic dysfunction and ventricular repolarization disturbances in rats

Anabolic androgenic steroids are a class of synthetic compounds derived from testosterone, eventually used by athletes, to improve physical performance. However, anabolic steroids can also modify normal cardiovascular function. Thus, we investigated cardiac electrophysiological and autonomic abnormalities in rats, through a electrocardiographic variability protocol during and after interruption of administration of nandrolone decanoate (DECA) anabolic steroid. Twenty male Wistar rats (60–70 days old) received DECA (10 mg. kg−1i.m) once a week or vehicle, during eight weeks. Electrocardiogram was recorded in conscious rats by a noninvasive method, and time and domain analysis of heart rate variability as well as electrocardiogram intervals (QTc / QTd) were performed. Body mass was lower in treated rats compared to control after 4th and 8th weeks, but not at the end of 14th week. QTc and QTd were longer in DECA group compared to control on 4th, 8th, 11th, but equal on 14th week. Cardiac autonomic dysfunction (vagal attenuation) was present on DECA group after 4th week and did not normalize after interruption of treatment. The animals of DECA group showed a correlation between attenuated parasympathetic modulation and increased correct QT interval. Our data allow us to conclude that long-term treatment with DECA impairs autonomic cardiac physiology, predisposing to cardiovascular risk and sudden death, and interruption of administration does not recovery the normality immediately.