Phenotypes of Overdiagnosed Long QT Syndrome

BackgroundLong QT syndrome (LQTS) predisposes individuals to arrhythmic syncope or seizure, sudden cardiac arrest, or sudden cardiac death (SCD). Increased physician and public awareness of LQTS-associated warning signs and an increase in electrocardiographic screening programs may contribute to overdiagnosis of LQTS.ObjectivesThis study sought to identify the diagnostic miscues underlying the continued overdiagnosis of LQTS.MethodsElectronic medical records were reviewed for patients who arrived with an outside diagnosis of LQTS but were dismissed as having normal findings subsequently. Data were abstracted for details on referral, clinical history, and both cardiologic and genetic test results.ResultsOverall, 290 of 1,841 (16%) patients with original diagnosis of LQTS (174 [60%] female; mean age at first Mayo Clinic evaluation, 22 ± 14 years; mean QTc interval, 427 ± 25 milliseconds) were dismissed as having normal findings. The main cause of LQTS misdiagnosis or overdiagnosis was a prolonged QTc interval secondary to vasovagal syncope (n = 87; 30%), followed by a seemingly positive genetic test result for a variant in 1 of the main LQTS genes (n = 68; 23%) that was ultimately deemed not to be of clinical significance. Furthermore, patients received misdiagnoses because of a positive family history of SCD that was deemed unrelated to LQTS (n = 46; 16%), isolated/transient QT prolongation (n = 44; 15%), or misinterpretation of the QTc interval as a result of inclusion of the U-wave (n = 40, 14%).ConclusionsKnowing the 5 main determinants of discordance between a previously rendered diagnosis of LQTS and full diagnostic reversal or removal (vasovagal syncope, “pseudo”-positive genetic test result in LQTS-causative genes, family history of SCD, transient QT prolongation, and misinterpretation of the QTc interval) increases awareness and provides critical guidance to reduce this burden of overdiagnosed LQTS.     

Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair

BackgroundHeart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic strategy is to stimulate endogenous mechanisms of myocardial regeneration.ObjectivesThis study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI.MethodsAnxA1 knockout (AnxA1^−/−) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1.ResultsAnxA1^−/− mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1^−/− mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)–A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cx₃cr1cre^ERT2Vegf^flox/flox or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus.ConclusionsAnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.     

Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway

BackgroundPatients with chronic kidney disease (CKD) and coincident heart failure with preserved ejection fraction (HFpEF) may constitute a distinct HFpEF phenotype. Osteopontin (OPN) is a biomarker of HFpEF and predictive of disease outcome. We recently reported that OPN blockade reversed hypertension, mitochondrial dysfunction, and kidney failure in Col4a3^−/− mice, a model of human Alport syndrome.ObjectivesThe purpose of this study was to identify potential OPN targets in biopsies of HF patients, healthy control subjects, and human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs), and to characterize the cardiac phenotype of Col4a3^−/− mice, relate this to HFpEF, and investigate possible causative roles for OPN in driving the cardiomyopathy.MethodsOGDHL mRNA and protein were quantified in myocardial samples from patients with HFpEF, heart failure with reduced ejection fraction, and donor control subjects. OGDHL expression was quantified in hiPS-CMs treated with or without anti-OPN antibody. Cardiac parameters were evaluated in Col4a3^−/− mice with and without global OPN knockout or AAV9-mediated delivery of 2-oxoglutarate dehydrogenase-like (Ogdhl) to the heart.ResultsOGDHL mRNA and protein displayed abnormal abundances in cardiac biopsies of HFpEF (n = 17) compared with donor control subjects (n = 12; p < 0.01) or heart failure with reduced ejection fraction patients (n = 12; p < 0.05). Blockade of OPN in hiPS-CMs conferred increased OGDHL expression. Col4a3^−/− mice demonstrated cardiomyopathy with similarities to HFpEF, including diastolic dysfunction, cardiac hypertrophy and fibrosis, pulmonary edema, and impaired mitochondrial function. The cardiomyopathy was ameliorated by Opn^−/− coincident with improved renal function and increased expression of Ogdhl. Heart-specific overexpression of Ogdhl in Col4a3^−/− mice also improved cardiac function and cardiomyocyte energy state.ConclusionsCol4a3^−/− mice present a model of HFpEF secondary to CKD wherein OPN and OGDHL are intermediates, and possibly therapeutic targets.     

Too Little of a Good Thing: Strong Associations Between Cardiac Size and Fitness Among Women

BackgroundCardiorespiratory fitness (CRF) is associated with functional impairment and cardiac events, particularly heart failure (HF). However, the factors predisposing women to low CRF and HF remain unclear.ObjectivesThis study sought to evaluate the association between CRF and measures of ventricular size and function and to examine the potential mechanism linking these factors.MethodsA total of 185 healthy women aged >30 years (51 ± 9 years) underwent assessment of CRF (peak volume of oxygen uptake [Vo₂peak]) and biventricular volumes at rest and during exercise by using cardiac magnetic resonance (CMR). The relationships among Vo₂peak, cardiac volumes, and echocardiographic measures of systolic and diastolic function were assessed using linear regression. The effect of cardiac size on cardiac reserve (change in cardiac function during exercise) was assessed by comparing quartiles of resting left ventricular end-diastolic volume (LVEDV).ResultsVo₂peak was strongly associated with resting measures of LVEDV and right ventricular end-diastolic volume (R² = 0.58-0.63; P < 0.0001), but weakly associated with measures of resting left ventricular (LV) systolic and diastolic function (R² = 0.01-0.06; P < 0.05). Increasing LVEDV quartiles were positively associated with cardiac reserve, with the smallest quartile showing the smallest reduction in LV end-systolic volume (quartile [Q]1: −4 mL vs Q4: −12 mL), smallest augmentation in LV stroke volume (Q1: +11 mL vs Q4: +20 mL) and cardiac output (Q1: +6.6 L/min vs Q4: +10.3 L/min) during exercise (interaction P < 0.001 for all).ConclusionsA small ventricle is strongly associated with low CRF because of the combined effect of a smaller resting stroke volume and an attenuated capacity to increase with exercise. The prognostic implications of low CRF in midlife highlight the need for further longitudinal studies to determine whether women with small ventricles are predisposed to functional impairment, exertional intolerance, and HF later in life.     

KCNQ1 G219E and TRPM4 T160M polymorphisms are involved in the pathogenesis of long QT syndrome: A case report

Rationale:Long QT syndrome (LQTS) is an inheritable disease characterized by prolonged QT interval on the electrocardiogram. The pathogenesis of LQTS is related to mutations in LQTS-susceptible genes encoding cardiac ion channel proteins or subunits.Patient concerns:Here, we reported a 37-year-old female Uygur patient with palpitation and loss of consciousness.Diagnoses:At the time of admission, a 12-lead electrocardiogram showed a QTc interval of 514 ms. Genetic analysis revealed KCNQ1 G219E and TRPM4 T160M mutations.Interventions:Although beta-blockers remain the mainstay in treating LQTS, the patient underwent implantation of an automatic cardioverter defibrillator due to life-threatening arrhythmias.Outcomes:To explore the effect of the calcium ion antagonist verapamil on ion channels, we generated human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from the peripheral blood mononuclear cells of the patient. The changes of action potential duration in response to verapamil were observed.Lessons:Our results showed that patient-derived hiPSC-CMs could recapitulate the electrophysiological features of LQTS and display pharmaceutical responses to verapamil.     

A Population-Based Registry of Patients With Inherited Cardiac Conditions and Resuscitated Cardiac Arrest

BackgroundThe relative proportion of each cardiac inherited disease (CID) causing resuscitated sudden cardiac arrest (RSCA) on a population basis is unknown.ObjectivesThis study describes the profile of patients with CIDs presenting with RSCA; their data were collected by the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ).MethodsData were collated from CIDRNZ probands presenting with RSCA (2002 to 2018).ResultsCID was identified in 115 (51%) of 225 RSCA cases: long QT syndrome (LQTS) (n = 48 [42%]), hypertrophic cardiomyopathy (HCM) (n = 28 [24%]), Brugada syndrome (BrS) (n = 16 [14%]), catecholaminergic polymorphic ventricular tachycardia (CPVT) (n = 9 [8%]), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 9 [8%]), and dilated cardiomyopathy (n = 5 [4%]). Seventy-one (62%) of 115 were male. Of 725 probands from the CIDRNZ with CID, the proportion presenting with RSCA was: CPVT, 9 (53%) of 17; BrS, 16 (33%) of 49; ARVC, 9 (25%) of 36; LQTS, 48 (20%) of 238; dilated cardiomyopathy, 5 (9%) of 58; and HCM, 28 (8%) of 354. Incident activity was: normal everyday activities, 44 (40%); exercising, 33 (30%); concurrent illness, 13 (12%); sleeping, 10 (9%); drugs/medication, 9 (8%); and emotion, 2 (2%). LQTS and CPVT predominated in those <24 years of age, 30 (77%) of 39; cardiomyopathies and BrS predominated in those >24 years of age, 49 (64%) of 76. For those >40 years of age, HCM was the most common (33%) CID. A genetic diagnosis in patients with CID was made in 48 (49%) of 98 tested. Diagnosis by age range was as follows: age 1 to 14 years, 78%; age 15 to 24 years, 53%; age 25 to 39 years, 54%; and age >40 years, 26%.ConclusionsThe commonest CID identified after RSCA was LQTS; the most common CID cause of RSCA for those >40 years of age was HCM. CPVT was the CID most likely to present with RSCA and HCM the least. Genetic yield decreases with age. Only one-third of RSCA cases due to CID occurred while exercising.     

Mitochondria-Rich Extracellular Vesicles From Autologous Stem Cell–Derived Cardiomyocytes Restore Energetics of Ischemic Myocardium

BackgroundMitochondrial dysfunction results in an imbalance between energy supply and demand in a failing heart. An innovative therapy that targets the intracellular bioenergetics directly through mitochondria transfer may be necessary.ObjectivesThe purpose of this study was to establish a preclinical proof-of-concept that extracellular vesicle (EV)-mediated transfer of autologous mitochondria and their related energy source enhance cardiac function through restoration of myocardial bioenergetics.MethodsHuman-induced pluripotent stem cell–derived cardiomyocytes (iCMs) were employed. iCM-conditioned medium was ultracentrifuged to collect mitochondria-rich EVs (M-EVs). Therapeutic effects of M-EVs were investigated using in vivo murine myocardial infarction (MI) model.ResultsElectron microscopy revealed healthy-shaped mitochondria inside M-EVs. Confocal microscopy showed that M-EV–derived mitochondria were transferred into the recipient iCMs and fused with their endogenous mitochondrial networks. Treatment with 1.0 × 10⁸/ml M-EVs significantly restored the intracellular adenosine triphosphate production and improved contractile profiles of hypoxia-injured iCMs as early as 3 h after treatment. In contrast, isolated mitochondria that contained 300× more mitochondrial proteins than 1.0 × 10⁸/ml M-EVs showed no effect after 24 h. M-EVs contained mitochondrial biogenesis-related messenger ribonucleic acids, including proliferator-activated receptor γ coactivator-1α, which on transfer activated mitochondrial biogenesis in the recipient iCMs at 24 h after treatment. Finally, intramyocardial injection of 1.0 × 10⁸ M-EVs demonstrated significantly improved post-MI cardiac function through restoration of bioenergetics and mitochondrial biogenesis.ConclusionsM-EVs facilitated immediate transfer of their mitochondrial and nonmitochondrial cargos, contributing to improved intracellular energetics in vitro. Intramyocardial injection of M-EVs enhanced post-MI cardiac function in vivo. This therapy can be developed as a novel, precision therapeutic for mitochondria-related diseases including heart failure.     

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Voltage-gated KCNQ1 (Kv7.1) potassium channels are expressed abundantly in heart but they are also found in multiple other tissues. Differential coassembly with single transmembrane KCNE beta subunits in different cell types gives rise to a variety of biophysical properties, hence endowing distinct physiological roles for KCNQ1–KCNEx complexes. Mutations in either KCNQ1 or KCNE1 genes result in diseases in brain, heart, and the respiratory system. In addition to complexities arising from existence of five KCNE subunits, KCNE1 to KCNE5, recent studies in heterologous systems suggest unorthodox stoichiometric dynamics in subunit assembly is dependent on KCNE expression levels. The resultant KCNQ1–KCNE channel complexes may have a range of zero to two or even up to four KCNE subunits coassembling per KCNQ1 tetramer. These findings underscore the need to assess the selectivity of small-molecule KCNQ1 modulators on these different assemblies. Here we report a unique small-molecule gating modulator, ML277, that potentiates both homomultimeric KCNQ1 channels and unsaturated heteromultimeric (KCNQ1)₄(KCNE1)_n (n < 4) channels. Progressive increase of KCNE1 or KCNE3 expression reduces efficacy of ML277 and eventually abolishes ML277-mediated augmentation. In cardiomyocytes, the slowly activating delayed rectifier potassium current, or I_Ks, is believed to be a heteromultimeric combination of KCNQ1 and KCNE1, but it is not entirely clear whether I_Ks is mediated by KCNE-saturated KCNQ1 channels or by channels with intermediate stoichiometries. We found ML277 effectively augments I_Ks current of cultured human cardiomyocytes and shortens action potential duration. These data indicate that unsaturated heteromultimeric (KCNQ1)₄(KCNE1)_n channels are present as components of I_Ks and are pharmacologically distinct from KCNE-saturated KCNQ1–KCNE1 channels.     

Myocardial Composition in Light-Chain Cardiac Amyloidosis More Than 1 Year After Successful Therapy

ObjectivesThe goals of this study were to characterize myocardial composition during the active and remission phases of light-chain (AL) cardiac amyloidosis.BackgroundCardiac dysfunction in AL amyloidosis is characterized by dual insults to the myocardium from infiltration and toxicity from light chains during the active phase and by infiltration alone in the remission phase.MethodsProspectively enrolled subjects with cardiac AL amyloidosis (21 remission AL amyloidosis; age: 63.4 ± 7.3 years; 47.6% male; and 48 active AL amyloidosis; age: 62.5 ± 7.4 years; 60.4% male) underwent contrast-enhanced cardiac magnetic resonance with T₁ and T₂ mapping and measurement of extracellular volume (ECV). By definition, serum free light-chain levels were normal for at least 1 year following successful AL therapy in the remission group and abnormal in the active group.ResultsMyocardial ECV was similarly expanded in the remission and active AL amyloidosis groups (0.488 ± 0.082 vs 0.519 ± 0.083, respectively; P = 0.15). However, myocardial T₂ relaxation times (47.7 ± 3.2 ms vs 45.5 ± 3.0 ms; P = 0.008) as well as native T₁ times (1,368 ms [IQR: 1,290-1,422 ms] vs 1,264 ms [IQR: 1,203-1,380 ms]; P = 0.024) were significantly higher in the remission compared to the active AL amyloidosis group.ConclusionsMyocardial ECV is substantially expanded in the active AL and remission AL cardiac amyloidosis groups, but native T₁ values were higher, suggesting a different myocardial composition. There is no evidence of myocardial edema in active AL cardiac amyloidosis. Future phenotyping studies of AL cardiac amyloidosis need to consider complementary myocardial markers that define the interstitial milieu in addition to changes in extracellular volume. (Molecular Imaging of Primary Amyloid Cardiomyopathy; NCT02641145)     

Cardiac Phenotypes and Markers of Adverse Outcome in Elite Athletes With Ventricular Arrhythmias

ObjectivesThis study describes the cardiac phenotypes and markers of adverse outcome in athletes with ventricular arrhythmias with no other discernable etiology than high exercise doses.BackgroundLittle is known about phenotypes and risk markers of life-threatening arrhythmic events in athletes with ventricular arrhythmia.MethodsWe compared high-performance athletes who have ventricular arrhythmia with healthy controls using clinical data and cardiac imaging. None of the patients had family history of arrhythmogenic cardiomyopathy or any other discernable etiology of ventricular arrhythmia. Right (RV) and left ventricular (LV) function was assessed by echocardiographic longitudinal strain (right ventricular free wall strain longitudinal [RVFWSL] and left ventricular global longitudinal strain [LVGLS]). Mechanical dispersion was defined as the standard deviation of time to peak strain in 16 LV segments. RV ejection fraction and presence of late gadolinium enhancement was assessed by cardiac magnetic resonance.ResultsWe included 43 athletes (45 ± 14 years of age, 16% female) with ventricular arrhythmias and 30 healthy athletes (41 ± 9 years of age, 7% female). Athletes with ventricular arrhythmias had worse RV function than healthy athletes by echocardiography (RVFWSL: ?22.9 ± 4.8% vs. ?26.6 ± 3.3%; p < 0.001) and by cardiac magnetic resonance (RV ejection fraction 48 ± 7% vs. 52 ± 6%; p = 0.04), and had more late gadolinium enhancement (24% vs. 3%; p = 0.03). Life-threatening arrhythmic events (aborted cardiac arrest, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator therapy) had occurred in 23 (53%) athletes with ventricular arrhythmias. These had impaired LV function compared to those with less severe ventricular arrhythmias (LVGLS: -17.1 ± 3.0% vs. -18.8 ± 2.0%; p = 0.04). LV mechanical dispersion was an independent marker of life-threatening events (adjusted odds ratio: 2.2 [1.1 to 4.8] by 10 ms increments; p = 0.03).ConclusionsAthletes with ventricular arrhythmias had impaired RV function and more myocardial fibrosis compared to healthy athletes. Athletes with life-threatening arrhythmic events had additional LV contraction abnormalities. These phenotypes mimic arrhythmogenic cardiomyopathy and may potentially be induced by high doses of exercise in susceptible individuals.     

Prognostic Value of Late Gadolinium Enhancement Detected on Cardiac Magnetic Resonance in Cardiac Sarcoidosis

BackgroundSarcoidosis is a complex multisystem inflammatory disorder, with approximately 5% of patients having overt cardiac involvement. Patients with cardiac sarcoidosis are at an increased risk of both ventricular arrhythmias and sudden cardiac death. Previous studies have shown that the presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is associated with an increased risk of mortality and ventricular arrhythmias and may be useful in predicting prognosis.ObjectivesThis systematic review and meta-analysis assessed the value of LGE on CMR imaging in predicting prognosis for patients with known or suspected cardiac sarcoidosis.MethodsThe authors searched the Embase and MEDLINE databases from inception to March 2022 for studies reporting individuals with known or suspected cardiac sarcoidosis referred for CMR with LGE. Outcomes were defined as all-cause mortality, ventricular arrhythmia, or a composite outcome of either death or ventricular arrhythmias. The primary analysis evaluated these outcomes according to the presence of LGE. A secondary analysis evaluated outcomes specifically according to the presence of biventricular LGE.ResultsThirteen studies were included (1,318 participants) in the analysis, with an average participant age of 52.0 years and LGE prevalence of 13% to 70% over a follow-up of 3.1 years. Patients with LGE on CMR vs those without had higher odds of ventricular arrhythmias (odds ratio [OR]: 20.3; 95% CI: 8.1-51.0), all-cause mortality (OR: 3.45; 95% CI: 1.6-7.3), and the composite of both (OR: 9.2; 95% CI: 5.1-16.7). Right ventricular LGE is invariably accompanied by left ventricular LGE. Biventricular LGE is also associated with markedly increased odds of ventricular arrhythmias (OR: 43.6; 95% CI: 16.2-117.2).ConclusionsPatients with known or suspected cardiac sarcoidosis with LGE on CMR have significantly increased odds of both ventricular arrhythmias and all-cause mortality. The presence of biventricular LGE may confer additional prognostic information regarding arrhythmogenic risk.     

Hyperpolarized Metabolic and Parametric CMR Imaging of Longitudinal Metabolic-Structural Changes in Experimental Chronic Infarction

BackgroundProlonged ischemia and myocardial infarction are followed by a series of dynamic processes that determine the fate of the affected myocardium toward recovery or necrosis. Metabolic adaptions are considered to play a vital role in the recovery of salvageable myocardium in the context of stunned and hibernating myocardium.ObjectivesThe potential of hyperpolarized pyruvate cardiac magnetic resonance (CMR) alongside functional and parametric CMR as a tool to study the complex metabolic-structural interplay in a longitudinal study of chronic myocardial infarction in an experimental pig model is investigated.MethodsMetabolic imaging using hyperpolarized [1-¹³C] pyruvate and proton-based CMR including cine, T₁/T₂ relaxometry, dynamic contrast-enhanced, and late gadolinium enhanced imaging were performed on clinical 3.0-T and 1.5-T MR systems before infarction and at 6 days and 5 and 9 weeks postinfarction in a longitudinal study design. Chronic myocardial infarction in pigs was induced using catheter-based occlusion and compared with healthy controls.ResultsMetabolic image data revealed temporarily elevated lactate-to-bicarbonate ratios at day 6 in the infarcted relative to remote myocardium. The temporal changes of lactate-to-bicarbonate ratios were found to correlate with changes in T₂ and impaired local contractility. Assessment of pyruvate dehydrogenase flux via the hyperpolarized [¹³C] bicarbonate signal revealed recovery of aerobic cellular respiration in the hibernating myocardium, which correlated with recovery of local radial strain.ConclusionsThis study demonstrates the potential of hyperpolarized CMR to longitudinally detect metabolic changes after cardiac infarction over days to weeks. Viable myocardium in the area at risk was identified based on restored pyruvate dehydrogenase flux.     

T1 Mapping and Extracellular Volume Fraction in Dilated Cardiomyopathy: A Prognosis Study

ObjectivesThe aim of this study is to examine the prognostic value of T1 mapping and the extracellular volume (ECV) fraction in patients with dilated cardiomyopathy (DCM).BackgroundPatients with DCM with functional left ventricular remodeling have poorer prognoses. Noninvasive assessment of myocardial fibrosis using T1 mapping and the ECV fraction may improve risk stratification of patients with DCM; however, this has not yet been systematically evaluated.MethodsA total of 659 consecutive patients with DCM (498 men; 45 ± 15 years) who underwent cardiac magnetic resonance with T1 mapping and late gadolinium enhancement (LGE) imaging with a 1.5-T magnetic resonance scanner were enrolled in this study. Primary endpoints were cardiac-related death and heart transplantation. Secondary endpoints were hospitalization for heart failure, ventricular arrhythmias, and implantable cardioverter-defibrillator or cardiac resynchronization therapy implantation. Survival estimates were calculated by Kaplan-Meier curves with the log-rank test.ResultsDuring a mean follow-up of 66.3 ± 20.9 months, 122 and 205 patients with DCM reached the primary and secondary endpoints, respectively. The presence of LGE had an association with both of the primary and secondary endpoints observed in the patients with DCM (both P < 0.001). The maximum native T1 (HR: 1.04; 95% CI: 1.02-1.09) and maximum ECV fraction (HR: 1.14; 95% CI: 1.08-1.21) had associations with the primary endpoints in the patients with positive LGE (both P < 0.001), whereas the mean native T1 (HR: 1.13; 95% CI: 1.10-1.36) and mean ECV fraction (HR: 1.32; 95% CI: 1.12-1.53) had the best associations in the patients with negative LGE (all P < 0.001).ConclusionsT1 mapping and the ECV fraction had prognostic value in patients with DCM and were particularly important in patients with DCM without LGE. Using a combination of T1 mapping, ECV fraction, and LGE provided optimal risk stratification for patients with DCM.     

Effect of Immunosuppressive Therapy and Biopsy Status in Monitoring Therapy Response in Suspected Cardiac Sarcoidosis

BackgroundPatients with suspected cardiac sarcoidosis frequently undergo fluorodeoxyglucose (FDG)–positron emission tomography (PET)/computed tomography (CT) imaging to assess disease activity at baseline and after treatment initiation.ObjectivesThis study investigated the effect of immunosuppressive therapy and biopsy status to achieve complete treatment response (CTR), partial treatment response (PTR), or no response (NR) on myocardial FDG-PET/CT.MethodsThis study analyzed 83 patients with suspected cardiac sarcoidosis (aged 53 ± 1.8 years, 71% were male, 69% were White, 61% had a history of biopsy-confirmed sarcoidosis) who were treatment naive, had evidence of myocardial FDG at baseline, and underwent repeat PET imaging after treatment initiation. CTR was graded visually, and PTR/NR were measured both visually and quantitatively using the total glycolytic activity. Patients were also evaluated for the occurrence of death, sustained ventricular arrhythmias, and heart failure admissions.ResultsOverall, 59 patients (71%) achieved CTR/PTR (30%/41%) at follow-up scan (P = 0.04). Total glycolytic activity and visual estimate of PTR/NR had excellent agreement (κ = 0.86 [95% CI: 0.72-0.99]; P < 0.0001). In patients receiving prednisone only, the highest rates of CTR/PTR were observed in patients initiated on moderate or high dose (P < 0.01). In a regression model, moderate prednisone start dose (P = 0.03) was more strongly associated with achieving CTR/PTR than was high prednisone start dose. However, the latter patients were tapered faster between start dose and follow-up scan (P < 0.01). After a median follow-up of 4.7 (IQR: 3.1-7.8) years, patients who were biopsy-proven (vs non-biopsy-proven; P = 0.029) and with preserved left ventricular function (P = 002) were less likely to experience major adverse cardiac events. Outcomes based on treatment response status (CTR vs PTR vs NR; P = 0.23) were not significantly different.ConclusionsAmong patients with suspected sarcoidosis and evidence of myocardial inflammation, treatment response by serial FDG-PET was variable, but a favorable response was more common when using moderate-to-high intensity prednisone dose. Biopsy-proven individuals and those with preserved systolic function were less likely to experience adverse outcomes during follow-up.     

Prognostic Value of Microvascular Resistance at Rest in Patients With Takotsubo Syndrome

BackgroundMicrovascular resistance (MR) is increased in takotsubo syndrome (TTS) and can be assessed by a validated pressure-wire-free tool called nonhyperemic angiography-derived index of microcirculatory resistance (NH-IMRangio).ObjectivesThe authors aimed to study whether the degree and extent of an altered MR in TTS patients were associated with 1-year prognosis.MethodsThe authors recruited 181 consecutive patients with TTS who underwent cardiac angiography. Impaired MR was defined as an NH-IMRangio ≥25. The degree and extent of impaired MR were assessed by the value of maximum NH-IMRangio in each major coronary artery and by the number of coronary arteries with an NH-IMRangio ≥25, respectively. Major adverse cardiac events (MACE) were a composite of cardiovascular death, heart failure event, acute myocardial infarction, and hospitalization for symptomatic arrhythmias.ResultsA total of 166 patients had NH-IMRangio available. The mean age was 74.8 years, and 83% were women. The rate of MACE at 1 year was 21.1%, mainly due to heart failure events that were generally mild. Kaplan-Meier curves showed higher rates of MACE in patients with higher NH-IMRangio (28.9% vs 13.3%; P = 0.019) and in those with 3 coronary arteries with increased MR compared to those with 2 or 1 affected arteries (33.3% vs 15.9% vs 9.5%; P = 0.040 and P = 0.040, respectively). After a multivariable Cox regression analysis, higher values of NH-IMRangio (HR: 3.41 [95% CI: 1.54-7.52]; P = 0.002) and the presence of 3 coronary arteries with increased MR (HR: 6.39 [95% CI: 1.46-27.87]; P = 0.014) were independent predictors of MACE in TTS patients.ConclusionsThe degree and extent of an impaired MR assessed by a validated pressure-wire-free tool were independent predictors of MACE at 1-year follow-up in TTS patients.     

Effect of pharmacological interventions and placebo on liver Histology in nonalcoholic steatohepatitis: A network meta-analysis

BackgroundThe aims of this study were to quantify the histological improvement and its risk factors in patients with NASH enrolled in the placebo arms of randomized controlled trials (RCTs), and to indirectly compare the effect of several investigational drugs for NASH on validated histological outcomes.Data synthesisA comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administration (FDA) recommendations, primary outcomes included: 1) NASH resolution without worsening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta-analysis and meta-regressions were conducted on placebo arms, while network meta-analysis was performed on intervention arms.A total of 15 RCTs met the eligibility criteria. The meta-analysis on placebo arms showed a pooled estimate rate of 17% (95%C.I. 12%–23%;I² = 86%; p < 0.01) for NASH resolution without worsening of fibrosis and of 21% (95%C.I. 13%–31%;I² = 84%; p < 0.01) for ≥1stage improvement of fibrosis without worsening of NASH. Phase 3 (vs Phase 2)RCTs, older age and higher AST levels were significantly associated with progression of liver disease by univariate meta-regression. At network meta-analysis, Semaglutide (P-score 0.906), Pioglitazione alone (score 0.890) and plus Vitamin E (0.826) had the highest probability of being ranked the most effective intervention for NASH resolution without worsening of fibrosis, while Aldafermin (0.776), Lanifibranor (0.773) and Obeticholic acid (0.771) had the highest probability to achieve ≥1 stage of fibrosis improvement without worsening of NASH.ConclusionThis study confirms the heterogeneity of histological progression of untreated patients with NASH and provides evidence to stratify patients according to identified risk factors in future RCTs of combination therapies. PROSPERO CRD42021287205.     

Screen time and the risk of metabolic syndrome among children and adolescents: A systematic review and dose-response meta-analysis

AimsThe metabolic syndrome (MetS) and its consequences are one of the main public health challenges worldwide. We conducted a systematic review and dose-response meta-analysis of studies that examined the association between screen time and the MetS among children and adolescents.Data synthesisA systematic search was conducted using electronic databases, including PubMed, Scopus, ProQuest, and Cochrane Library, for studies published from 1963 up to 2 May 2022. In this systematic review and meta-analysis, observational studies with cross-sectional, case-control, and cohort design evaluating the association between screen time and MetS were included. Random effects models and linear and nonlinear dose-response meta-analyses were used to pool study results.ResultsSeven studies were included in the meta-analysis. The summary OR of MetS among children and adolescents for the highest vs. lowest time of screen time was 1.64 (95% CI: 1.32–2.03, with little evidence of heterogeneity, I² = 9.3%, P-_{heterogeneity} = 0.35, n = 7 studies) and 1.64 (95% CI: 1.27–2.12, I² = 27.7%, n = 6) for cross-sectional studies. Results persisted across several additional subgroup analyses. There was a linear positive association between screen time and the risk of MetS (P dose-response < 0.0001; P nonlinearity = 0.64) with an OR of 1.29 (95% CI: 1.12–1.46) per 2 h/day increment in screen time.ConclusionThe current dose-response meta-analysis suggested that increased screen time is associated with an increased risk of MetS among children and adolescents. Public health strategies may target unhealthy screen-based related behaviors to halt the development of MetS among children and adolescents.     

Impaired Adrenergic/Protein Kinase A Response of Slow Delayed Rectifier Potassium Channels as a Long QT Syndrome Motif: Importance and Unknowns

The slow delayed rectifier potassium current (I_Ks) significantly contributes to cardiac repolarization under specific conditions, particularly at stimulation by the protein kinase A (PKA) during increased sympathetic tone. Impaired PKA-mediated stimulation of I_Ks channels may considerably aggravate dysfunction of the channels induced by mutations in the KCNQ1 gene that encodes the structure of the α-subunit of I_Ks channels. These mutations are associated with several subtypes of inherited arrhythmias, mainly long QT syndrome type 1, less commonly short QT syndrome type 2, and atrial fibrillation. The impaired PKA reactivity of I_Ks channels may significantly increase the risk of arrhythmia in these patients. Unfortunately, only approximately 2.7% of the KCNQ1 variants identified as putatively clinically significant have been studied with respect to this problem. This review summarizes the current knowledge in the field to stress the importance of the PKA-mediated regulation of I_Ks channels, and to appeal for further analysis of this regulation in KCNQ1 mutations associated with inherited arrhythmogenic syndromes. On the basis of the facts summarized in our review, we suggest several new regions of the α-subunit of the I_Ks channels as potential contributors to PKA stimulation, namely the S4 and S5 segments, and the S2-S3 and S4-S5 linkers. Deeper knowledge of mechanisms of the impaired PKA response in mutated I_Ks channels may help to better understand this regulation, and may improve risk stratification and management of patients suffering from related pathologies.