Impact of New-Onset Conduction Disturbances following Transcatheter Aortic Valve Replacement on Outcomes: A Single-Center Study.

Background: Transcatheter aortic valve replacement (TAVR) is known to increase the incidence of conduction disturbances compared to surgical aortic valve replacement; however, there are limited data on the impact and duration of these conduction disturbances on longer term outcomes. Objective: To determine the differential impact of persistent versus nonpersistent new-onset conduction disturbances on TAVR-related complications and outcomes. Methods: This is a single-center retrospective analysis of 927 consecutive patients with aortic stenosis who underwent TAVR at Yale New Haven Hospital from July 2012 to August 2019. Patients with new-onset conduction disturbances within 7 days following TAVR were selected for this study. Persistent and nonpersistent disturbances were, respectively, defined as persisting or not persisting on all patient ECGs for up to 1.5 years after TAVR or until death. Results: Within 7 days after TAVR, conduction disturbances occurred in 42.3% (392/927) of the patients. Conduction disturbances persisted in 150 (38%) patients and did not persist in 187 (48%) patients, and 55 (14%) patients were excluded for having mixed (both persistent and nonpersistent) disturbances. Compared with nonpersistent disturbances, patients with persistent disturbances were more likely to receive a PPM within 7 days after the TAVR procedure (46.0% versus 4.3%, p < 0.001) and had a greater unadjusted 1-year cardiac-related and all-cause mortality risk (HR 2.54, p=0.044 and HR 1.90, p=0.046, respectively). Conclusion: Persistent conduction disturbances were associated with a greater cardiac and all-cause mortality rate at one year following TAVR. Future research should investigate periprocedural factors to reduce persistent conduction disturbances and outcomes beyond one year follow-up.

Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Mutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series. METHODS: Clinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. RESULTS: DSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant). CONCLUSIONS: DSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.

Participation in thrill-seeking activities by patients with hypertrophic cardiomyopathy: Individual preferences, adverse events and physician attitude.

BACKGROUND: Thrill-seeking activities are a favorite pastime for people of all ages. Patients with hypertrophic cardiomyopathy (HCM) are often barred from participation on the basis of danger for arrhythmias. Our aim was to collect information regarding the safety of thrill-seeking activities for HCM patients. METHODS: An anonymous online survey invited adult HCM patients to report participation in 11 activities (rollercoaster riding, jet skiing, rafting, bungee jumping, rappelling, paragliding, kayaking/canoeing, motor racing, snowboarding, BASE jumping and skydiving) before and after HCM diagnosis, along with major (ICD shock, syncope) or minor (nausea, dizziness, palpitations, chest pain) adverse events related to participation, and relevant physician advice. RESULTS: Six hundred forty-seven HCM patients completed the survey, with 571 (88.2%) reporting participation in ≥1 TSAs (participant age 50.85 ±â€¯14.21, 56.6% female, 8143 post-diagnosis participations). At time of survey, 457 participants (70.6%) were ICD-carriers or had ≥1 risk factor for sudden cardiac death. Nine (1.5%) participants reported a major event during or immediately after (60 minutes) of surveyed activity. Minor adverse events were reported by 181 participants (31.6%). In addition, 8 participants reported a major adverse event >60 minutes later but within the same day. Regarding physician advice, of the 213 responders (32.9%) receiving specific advice, 56 (26.2%) were told safety data is absent with no definitive recommendation, while 24 (11.2%) and 93 (43.6%) were told TSAs were respectively safe or dangerous. CONCLUSIONS: In this cohort, participation in thrill-seeking activities rarely caused major adverse events. This information can be used for shared-decision making between providers and patients.

Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study.

BACKGROUND: Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST-segment-elevation myocardial infarction. Colchicine is a substance with potent anti-inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. METHODS AND RESULTS: Patients presenting with ST-segment-elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase-myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST-segment-elevation myocardial infarction. One hundred fifty-one patients were included (60 in the MRI substudy). The area under the creatine kinase-myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754-6940) ng·h(-1)·mL(-1) in the colchicine group in comparison with 6184 (IQR, 4456-6980) ng·h(-1)·mL(-1) in controls (P<0.001). Indexed MRI-late gadolinium enhancement-defined infarct size was 18.3 (IQR, 7.6-29.9) mL/1.73 m(2) in the colchicine group versus 23.2 (18.5-33.4) mL/1.73 m(2) in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0-25.3) % and 19.8 (IQR, 13.7-29.8) %, respectively (P=0.034). CONCLUSIONS: These results suggest a potential benefit of colchicine in ST-segment-elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285.

Impact of sex on Transcatheter aortic valve replacement outcomes: Results of a single-center study.

BACKGROUND: Early studies on transcatheter aortic valve replacement (TAVR) outcomes showed that female sex was associated with better survival. With increased use of new-generation valves, the impact of sex on contemporary TAVR outcomes is less well known. METHODS: Retrospective analysis using institutional National Cardiovascular Data Registry STS/ACC TVT data was performed on all patients undergoing TAVR at Yale New Haven Hospital from July 2012 to August 2019. New-generation valves were Evolut PRO, Evolut R, and SAPIEN 3. Old-generation valves were CoreValve, SAPIEN, and SAPIEN XT. Log-rank test and Kaplan-Meier curves were used to compare sex differences in survival up to 1 year after TAVR. Cox modeling was used to adjust for baseline and procedural characteristic differences. RESULTS: 927 consecutive patients (41.4% women) underwent TAVR. Women were older (82.8 vs 80.6 years old; p < 0.001) with higher STS mortality scores compared with men (7.6% vs 6.4%; p < 0.001) despite lower prevalence of cardiovascular comorbidities including coronary artery disease, peripheral artery disease, and smoking. Most cases used transfemoral access (90.5%) and new-generation devices (72.3%). Women received smaller valves compared with men (20-26 mm: 78.0% vs 32.9%; 29-34 mm: 22.1% vs 67.1%; overall p < 0.0001). There were no statistically significant differences between sexes in both unadjusted and adjusted 1-year mortality. CONCLUSION: Our data show no significant difference in 1-year survival between sexes using primarily new generation valves. Further studies should reassess the impact of sex on TAVR outcomes and whether newer technologies like new valve design and sizes, and CT imaging may have eliminated sex-based disparities.

Rationale and Design of Heart Failure Prevalence and Evolution of Heart Failure in Diabetes Mellitus Type II Patients at High Risk (HF-LanDMark Study).

(1) Background: Patients with diabetes mellitus (DM) are at increased risk for heart failure (HF). Accurate data regarding the prevalence of HF stages among diabetics in Greece are scarce. (2) Aim: The present study will examine the prevalence and evolution of HF stages among patients with type II DM (T2DM) diagnosed in the past 10 years, with no previous history of HF and at high CV risk, in Greece, as well as will explore the potential determinants of the development of symptomatic HF in these patients. (3) Methods: Through a non-interventional, epidemiological, single-country, multi-center, prospective cohort study design, a sample of 300 consecutive patients will be enrolled in 11 cardiology departments that are HF centers of excellence. Patients will be either self-referred or referred by primary or secondary care physicians and will be followed for up to 24 months. Demographic, clinical, echocardiography, electrocardiography, cardiac biomarkers (troponin, NT-proBNP) and health-related quality of life questionnaire data will be recorded as well as clinical events, including mortality, HF hospitalizations and HF-related healthcare resource utilization. The primary outcomes are the proportion of patients diagnosed with symptomatic HF (ACC/AHA Stage C) at enrolment in the overall study population and the proportions of patients with HF stages A, B and C, as well as by NYHA functional classification in the overall study population. (4) Conclusions: The HF-LanDMark study is the first epidemiological study that will assess the prevalence of HF among T2DM patients in Greece that could potentially enhance prompt therapeutic interventions shown to delay the development of HF in the T2DM patient population (HF-LanDMark, Clinical Trials.gov number, NCT04482283).

Pancreatic injury after major hepatectomy: a study in a porcine model.

PURPOSE: The aim of this study was to investigate the pathophysiology of pancreatitis after major hepatectomy. METHODS: The study used ten female pigs. Three served as sham animals (sham group) and were killed after laparotomy to obtain normal tissue samples. Seven animals were subjected to major hepatectomy (70-75%), using the Pringle maneuver for 150 min, after constructing a portacaval side-to-side anastomosis (hepatectomy group). Duration of reperfusion was 24 h. RESULTS: Pancreatic tissue sampled 24 h after reperfusion had increased necrosis and edema in comparison to sham group and to tissue sampled at 12 h. Tissue malondialdehyde (MDA) did not differ significantly between samples at 12 and 24 h but was increased in the hepatectomy group in comparison to sham animals. Percentage increase in portal MDA content during reperfusion was greater at 12 h of reperfusion in comparison to the increase after 24 h. Portal pressure increased significantly after 12 h of reperfusion. Serum amylase and C-peptide increased during reperfusion in comparison to baseline levels. CONCLUSIONS: The findings suggest that intraoperative portal congestion is not the only cause of the development of pancreatitis after major hepatectomy. The oxidative markers suggest that reactive oxygen species produced during vascular control may be responsible as well.

Angiographic Lesion Discordance in Women Presenting With Ischemic Heart Disease: Comparison of Visual Assessment, Quantitative Coronary Angiography, and Quantitative Flow Ratio.

BACKGROUND: Although visual assessment of stenosis severity is routinely used to guide coronary revascularization, there are concerns about its accuracy, especially in women, who present a higher variability in coronary anatomy and ischemic heart disease (IHD). The aim of this study was to assess whether quantitative coronary angiography (QCA) and quantitative flow ratio (QFR) could provide better discrimination of coronary stenosis severity and functional significance than visual assessment alone in women with IHD. METHODS: Coronary angiography was performed in a cohort of women with ischemic symptoms and non-invasive stress perfusion imaging. Visual assessment was done by blinded operators in clinical practice, while QCA and QFR were analyzed in an independent core laboratory. RESULTS: Ninety-nine consecutive patients with 101 lesions were included in the registry, and QFR was successfully measured in 81 lesions (80.2%). Visual assessment provided higher readings of angiographic severity than QCA in 50.5% (n = 51) of lesions. Mean absolute difference between QCA and visual assessment was significantly higher in lesions with >70% diameter stenosis (DS) (25.3 ± 7.3%), compared with both the 40%-55% (9.3 ± 6.8%; P<.001) and the <40% groups (7.0 ± 6.0%; P<.001). QFR was >0.80 in 33.3% of lesions with visually defined >70% DS, while all lesions with QCA-defined >70% DS had QFR ≤0.80. CONCLUSIONS: Interventional cardiologists' visual assessment results in a higher degree of coronary stenosis than QCA. Among women with ischemic symptoms and non-invasive stress perfusion imaging, additional lesion assessment by QCA and QFR may improve operators' ability to determine which patients and lesions will benefit from coronary revascularization.

Development of a porcine model of post-hepatectomy liver failure.

BACKGROUND: The aim of this study was to develop a porcine model of post-operative liver failure (POLF) that could accurately reproduce all the neurological and metabolic parameters of the corresponding clinical syndrome that may develop after extensive liver resections. METHODS: In our model, we induced POLF by combining extended left hepatectomy and ischemia of the small liver remnant of 150 min duration. Subsequently, the remnant liver parenchyma was reperfused and the animals were closely monitored for 24 h. MATERIALS: Twelve Landrace pigs (weight 25-30 kg) were randomly assigned in two groups; eight of them constituted the experimental group, in which POLF was induced (POLF group, n = 8), whereas the rest of them (n = 4) were included in the control group (sham laparotomy without establishment of POLF). RESULTS (MEANS ± SD): All POLF animals gradually developed neurological and biochemical signs of liver failure including, among many other parameters, elevated intracranial pressure (24.00 ± 4.69 versus 10.17 ± 0.75, P = 0.004) and ammonia levels (633.00 ± 252.21 versus 51.50 ± 9.49, P = 0.004) compared with controls. Histopathologic evaluation of the liver at the end of the experiment demonstrated diffuse coagulative necrosis and severe architectural distortion of the hepatic parenchyma in all POLF animals. CONCLUSION: Our surgical technique creates a reproducible porcine model of POLF which can be used to study the pathophysiology and possible therapeutic interventions in this serious complication of extensive hepatectomies.

Reversal of experimental posthepatectomy liver failure in pigs: a new application of hepatocyte bioreactors.

Postoperative liver failure remains a major cause of morbidity and mortality after extensive hepatectomies. This study aims to evaluate the effectiveness of a hepatocyte bioreactor in the treatment of experimental post-hepatectomy liver failure. Our experimental model included a combination of a side-to-side portacaval shunt, occlusion of the hepatoduodenal ligament for 150 min, 70% hepatectomy, and reperfusion. Following the development of liver failure, 12 pigs were randomized into a control group (n = 6) and a treatment group (n = 6). Both groups underwent extracorporeal perfusion through a plasma separation device, a membrane oxygenator, and two parallel bioreactors. In the latter group, the bioreactors were loaded with 10 billion fresh hepatocytes, isolated from a donor pig. Following hepatocyte treatment, all animals were maintained for 24 h under mechanical ventilation, with intravenous fluid and glucose supplementation. Hemodynamic parameters, intracranial pressure, and biochemical parameters were measured. Liver biopsies were obtained during the 24-h autopsy. The extracorporeal circuit was well-tolerated hemodynamically. Treated animals had lower intracranial pressure compared with controls (at 24 h, 15 ± 3.1 vs. 22 ± 3.5 mm Hg, P = 0.006). Plasma ammonia in treated animals was lower compared with controls at 12 h (100 ± 29 vs. 244 ± 131 µmol, P = 0.026). Liver histological study showed decreased necrosis and increased regeneration activity in treated animals compared with controls. Treatment through an extracorporeal hepatocyte bioreactor attenuates brain edema and improves histological and functional parameters of the liver remnant of pigs with posthepatectomy liver failure.

Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.

Hypertrophic cardiomyopathy (HCM) is an inherited disorder caused primarily by mutations to thick and thinfilament proteins. Although thin filament mutations are less prevalent than their oft-studied thick filament counterparts, they are frequently associated with severe patient phenotypes and can offer important insight into fundamental disease mechanisms. We have performed a detailed study of tropomyosin (TPM1) E192K, a variant of uncertain significance associated with HCM. Molecular dynamics revealed that E192K results in a more flexible TPM1 molecule, which could affect its ability to regulate crossbridges. In vitro motility assays of regulated actin filaments containing TPM1 E192K showed an overall loss of Ca2+ sensitivity. To understand these effects, we used multiscale computational models that suggested a subtle phenotype in which E192K leads to an inability to completely inhibit actin-myosin crossbridge activity at low Ca2+. To assess the physiological impact of the mutation, we generated patient-derived engineered heart tissues expressing E192K. These tissues showed disease features similar to those of the patients, including cellular hypertrophy, hypercontractility, and diastolic dysfunction. We hypothesized that excess residual crossbridge activity could be triggering cellular hypertrophy, even if the overall Ca2+ sensitivity was reduced by E192K. To test this hypothesis, the cardiac myosin-specific inhibitor mavacamten was applied to patient-derived engineered heart tissues for 4 d followed by 24 h of washout. Chronic mavacamten treatment abolished contractile differences between control and TPM1 E192K engineered heart tissues and reversed hypertrophy in cardiomyocytes. These results suggest that the TPM1 E192K mutation triggers cardiomyocyte hypertrophy by permitting excess residual crossbridge activity. These studies also provide direct evidence that myosin inhibition by mavacamten can counteract the hypertrophic effects of mutant tropomyosin.

Treatment with bioartificial liver improves lung injury in a swine model of partial hepatectomy and ischemia/reperfusion.

PURPOSE: Hepatic ischemia/reperfusion injury can lead to remote lung injury by inducing oxidative stress and inflammation. this study aims to investigate whether support of liver function with a bioartificial liver can attenuate remote lung injury after extended hepatectomy. METHODS: Fourteen domestic pigs were subjected to liver ischemia for 150 minutes and 70-75% hepatectomy. Six hours after initiation of hepatic reperfusion the animals were randomly allocated to a 6-hour treatment with a bioartificial liver (group b, n=7) or observation (group C, n=7). Hemodynamic and metabolic parameters were monitored for 24 hours following reperfusion. Lung biopsies were used for histological, nitrotyrosine and mrNA analysis. RESULTS: Oxygenation gradually deteriorated in group C, but was not significantly impaired in group b. Histological evaluation revealed improvements in alveolar collapse, necrotized pneumonocytes and lymphocyte infiltration in group b. Nitrotyrosine content of the lung was lower in group b compared to group C (55+/-12 vs. 132+/-22 nM/mg protein, p<0.01). Lung mrNA expression of interleukin-6, Stat-3 and E-selectin also decreased in group b. Expression of transforming growth factor-alpha mrNA did not differ between groups. CONCLUSIONS: Application of a bioartificial liver was associated with improvement in several parameters of post-hepatectomy lung injury. the mechanisms appear to involve reduced nitrosative stress and attenuation of the native inflammatory process in the lung.

The differential impact of volatile and intravenous anaesthetics on stress response in the swine.

OBJECTIVE: To compare the effects of various anaesthetics on stress response in the presence and absence of surgical stimulation. DESIGN: Twenty-nine pigs scheduled to undergo surgical central vein catheter placement were randomly allocated to receive only sedation with ketamine-midazolam (group SHAM, n=5) or general anaesthesia with either propofol 8 mg/kg/h (group PROP, n=8), sevoflurane 1.0 MAC (group SEVO, n=8) or desflurane 1.0 MAC (group DESF, n=8). Following surgery, anaesthesia was maintained for a total period of 4 hours. Thyroid hormones, noradrenaline, cortisol, corticotrophin (ACTH), beta-endorphin, interleukin-1beta and -6 and tumor necrosis factor-alpha were determined by appropriate methodology after premedication (t0), after surgical procedure (t1) and at the end of 4h (t2). RESULTS: At t1 ACTH and beta-endorphin increased in all groups, thyroxin in groups SEVO, DESF and PROP, noradrenaline in group SEVO and cortisol in the SHAM and PROP groups. At t2 cortisol and ACTH levels were lower in the PROP compared to SEVO group. Serum cytokines were not significantly altered in either group. CONCLUSIONS: The choice of the general anaesthetic did not affect thyroid hormones levels in either the presence or absence of surgical stimulus. In the presence of surgical stimulation, sevoflurane resulted in higher noradrenaline levels and in higher activity of the ACTH-cortisol axis compared to propofol.

Access and Outcomes Among Hypertrophic Cardiomyopathy Patients in a Large Integrated Health System.

Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. Current guidelines endorse management in expert centers, but patient socioeconomic status can affect access to specialty care. The effect of socioeconomic status and specialty care access on HCM outcomes has not been examined. Methods and Results We conducted a retrospective cohort study that examined outcomes among HCM patients receiving care in the Yale New Haven Health System between June 2011 and December 2017. Patients were assigned to lower or higher socioeconomic status groups (LSES/HSES) based on medical insurance provider and to receivers of specialty care (SC) at Yale's Inherited Cardiomyopathy clinic or general cardiology care (GC). The primary outcome was all-cause death, and the secondary outcome was all-cause hospitalization. We identified 953 HCM patients; 820 (86%) were HSES and 133 (14%) were LSES. Forty-three (4.5%) patients died from cardiac and noncardiac causes. LSES patients within the general cardiology care cohort had significantly higher all-cause mortality compared with HSES patients (adjusted hazard ratio, [95% CI]=10.06 [4.38-23.09]; P<0.001). This was not noted in the specialty care cohort (adjusted hazard ratio, [95% CI]=2.87 [0.56-14.73]; P=0.21). The moderator effect of specialty care on mortality difference between LSES versus HSES, however, did not reach statistical significance (hazard ratio, 0.29 [0.05-1.77]; P=0.18). Specialist care was associated with increased hospitalization (adjusted hazard ratio, [95% CI]=3.28 [1.11-9.73]; P=0.03 for LSES; 2.19 [1.40-3.40]; P=0.001 for HSES). Conclusions Socioeconomically vulnerable HCM patients had higher mortality when not referred to specialty care. Further study is needed to understand the underlying causes.

Appropriate and inappropriate shocks in hypertrophic cardiomyopathy patients with subcutaneous implantable cardioverter-defibrillators: An international multicenter study.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillators (S-ICDs) are attractive for preventing sudden cardiac death in hypertrophic cardiomyopathy (HCM) as they mitigate risks of transvenous leads in young patients. However, S-ICDs may be associated with increased inappropriate shock (IAS) in HCM patients. OBJECTIVE: The purpose of this study was to assess the incidence and predictors of appropriate shock and IAS in a contemporary HCM S-ICD cohort. METHODS: We collected electrocardiographic and clinical data from HCM patients who underwent S-ICD implantation at 4 centers. Etiologies of all S-ICD shocks were adjudicated. We used Firth penalized logistic regression to derive adjusted odds ratios (aORs) for predictors of IAS. RESULTS: Eighty-eight HCM patients received S-ICDs (81 for primary and 7 for secondary prevention) with a mean follow-up of 2.7 years. Five patients (5.7%) had 9 IAS episodes (3.8 IAS per 100 patient-years) most often because of sinus tachycardia and/or T-wave oversensing. Independent predictors of IAS were higher 12-lead electrocardiographic R-wave amplitude (aOR 2.55 per 1 mV; 95% confidence interval 1.15-6.38) and abnormal T-wave inversions (aOR 0.16; 95% confidence interval 0.02-0.97). There were 2 appropriate shocks in 7 secondary prevention patients and none in 81 primary prevention patients, despite 96% meeting Enhanced American College of Cardiology/American Heart Association criteria and the mean European HCM Risk-SCD score predicting 5.7% 5-year risk. No patients had sudden death or untreated sustained ventricular arrhythmias. CONCLUSION: In this multicenter HCM S-ICD study, IAS were rare and appropriate shocks confined to secondary prevention patients. The R-wave amplitude increased IAS risk, whereas T-wave inversions were protective. HCM primary prevention implantable cardioverter-defibrillator guidelines overestimated the risk of appropriate shocks in our cohort.

Left atrial fibrosis correlates with extent of left ventricular myocardial delayed enhancement and left ventricular strain in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with increased left ventricular (LV) mass, decreased myocardial strain, and the presence of LV fibrosis and scar. The relationship between LV scar and fibrosis with left atrial (LA) fibrosis in the setting of HCM has not been examined. The purpose of this study is to demonstrate a correlation between the degree of LA fibrosis and LV parameters in subjects with HCM. Twenty-eight subjects with HCM were imaged on a 1.5T MRI scanner with cine, LV and LA late gadolinium enhancement (LGE) sequences. LA LGE and LA measurements were correlated with LV measurements of volumes, mass, strain, and LGE. Other clinical conditions and medication usage were also examined and evaluated for correlation with LA and LV parameters. LV LGE was identified in 24 (86%) of the cases and LA LGE was identified in all of the cases. Extent of LA fibrosis significantly correlated with percent LV LGE (r = 0.64, p = 0.001), but not with indexed LV mass or maximum wall thickness. Extent of LA fibrosis also moderately correlated with decreased LV global strain (radial, r = - 0.50, p = 0.013; circumferential, r = 0.47, p = 0.02; longitudinal, r = 0.52, p = 0.013). Increased LA systolic volume correlated moderately with LV end diastolic volume (r = 0.50, p = 0.006). Patients on therapy with Renin-Angiotensin-Aldosterone System (RAAS) Inhibition had significantly less LA LGE compared to those without (18.6% vs 10.8%, p = 0.023). LA fibrosis, as measured by LGE, is prevalent in HCM and is correlated with LV LGE. The correlation between LA and LV LGE might suggest either that LA fibrosis is a consequence of LV remodeling, or that LA and LV fibrosis are both manifestations of the same cardiomyopathic process. Further study is warranted to determine the causality of LA scar in this population.

Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder with variable genetic etiologies. Here we focused on understanding the precise molecular pathology of a single clinical variant in DSP, the gene encoding desmoplakin. We initially identified a novel missense desmoplakin variant (p.R451G) in a patient diagnosed with biventricular ACM. An extensive single-family ACM cohort was assembled, revealing a pattern of coinheritance for R451G desmoplakin and the ACM phenotype. An in vitro model system using patient-derived induced pluripotent stem cell lines showed depressed levels of desmoplakin in the absence of abnormal electrical propagation. Molecular dynamics simulations of desmoplakin R451G revealed no overt structural changes, but a significant loss of intramolecular interactions surrounding a putative calpain target site was observed. Protein degradation assays of recombinant desmoplakin R451G confirmed increased calpain vulnerability. In silico screening identified a subset of 3 additional ACM-linked desmoplakin missense mutations with apparent enhanced calpain susceptibility, predictions that were confirmed experimentally. Like R451G, these mutations are found in families with biventricular ACM. We conclude that augmented calpain-mediated degradation of desmoplakin represents a shared pathological mechanism for select ACM-linked missense variants. This approach for identifying variants with shared molecular pathologies may represent a powerful new strategy for understanding and treating inherited cardiomyopathies.

Bioartificial liver attenuates intestinal mucosa injury and gut barrier dysfunction after major hepatectomy: Study in a porcine model.

BACKGROUND: The aim of this study was to evaluate whether bioartificial liver support can attenuate gut mucosa injury in a porcine model of posthepatectomy liver dysfunction. METHODS: Posthepatectomy liver failure was induced in pigs combining major (70%) liver resection and ischemia/reperfusion injury. An ischemic period of 150 minutes was followed by reperfusion for 24 hours. Animals were divided randomly into 2 groups: a control group (n = 6) that received standard critical care and a bioartificial liver support group (Hepat, n = 6) that were subjected to extracorporeal liver support for 6 hours during reperfusion. Intestinal mucosal injury, bacterial translocation, and endotoxin translocation were evaluated in all animals. Intestinal mucosa was also evaluated with markers of oxidative injury and immunohistochemical staining for caspase 3. RESULTS: When compared with median values, the control group, animals in the Hepat group had a lesser intestinal mucosal injury score (4.0 [range:2.0-5.0] vs 1.0 [range:1.0-2.0]; P < .01), decreased bacterial translocation in the portal and the systemic circulation at 24 hours of reperfusion (P < .05), and decreased portal and systemic endotoxin levels at 24 hours (P < .05). At 24 hours after reperfusion, mucosal protein carbonyls and malondialdehyde levels were decreased in Hepat animals (0.57 nmol/mg [range:0.32-0.70] vs 0.33 nmol/mg [range:0.03-0.53] and 3.85 nmol/mg [range:3.01-6.43] vs 3.27 nmol/mg [range:1.46-3.55], respectively; P < .05). There was no difference in tissue caspase staining. CONCLUSION: Bioartificial liver support seems to attenuate intestinal mucosal injury and gut barrier dysfunction after major hepatectomy.

Molecular studies of the immunological effects of the sevoflurane preconditioning in the liver and lung in a rat model of liver ischemia/reperfusion injury.

Sevoflurane has been shown to improve ischemia/reperfusion injury (IRI) through several mechanisms, including amelioration of inflammatory response. However, there haven't been any studies considering the potential role of the complement system in sevoflurane-mediated amelioration of ischemia/reperfusion injury. Our purpose was to investigate the molecular mechanisms involved in sevoflurane preconditioning in liver and lung injury induced by liver ischemia-reperfusion (LIR), giving emphasis to the immunological mechanisms. In order to do that, fifty male Wistar rats were randomly allocated in five groups (n=10 each): Animals in group LIR received ketamine and xylazine and were then subjected to ischemia of the right and median hepatic lobe for 45 min and reperfusion for 6h. Group SEVO/LIR received sevoflurane and then LIR was induced, as in group LIR. Animals in group SHAM/LIR were anesthetized with ketamine and xylazine and then laparotomy followed. Group SHAM/SEVO received sevoflurane for 30 min and then laparotomy followed. Finally, in group VEN, animals only received ketamine and xylazine. Our results showed that sevoflurane preconditioning significantly improved liver-biochemical tests (decreased Alanine transaminase (ALT), Alkaline phosphatase (ALP), Aspartate transaminase (AST) and Alkaline phosphatase (ALP) levels) and limited inflammatory cell infiltration in BALF. Additionally, compared with the LIR group, the reduction in plasma C3 was significantly reduced in the SEVO/LIR group. No significant differences were observed in histological examination in the liver and lung. Immunostaining of the liver for Intracellular Adhesion Molecule 1 (ICAM1) however, showed a decrease in ICAM1 levels in the SEVO/LIR group. In the lung, sevoflurane seemed to exert no effect in ICAM1 levels. Caspase 3 (CASP3) levels in the liver and the lung also appeared unaffected by sevoflurane preconditioning. In the SEVO/LIR group, ICAM1 mRNA expression was significantly reduced in the liver. No statistical significantly differences were observed in Complement component 3 (C3), Complement component 5 (C5) and Clusterin (CLU) mRNA levels in the liver or the lung tissue. Summarizing, sevoflurane preconditioning seems to ameliorate LIR-induced injury in the rats, mediated by mechanisms that include ICAM1 and complement C3 down regulation.