Improvement in Cardiac Morphology Demonstrated by Cardiac Magnetic Resonance Imaging and Echocardiography after Haploidentical Hematopoietic Cell Transplantation in Adults with Sickle Cell Disease.

Cardiopulmonary complications account for approximately 40% of deaths in patients with sickle cell disease (SCD). Diffuse myocardial fibrosis, elevated tricuspid regurgitant jet velocity (TRV) and iron overload are all associated with early mortality. Although HLA-matched sibling hematopoietic cell transplantation (HCT) offers a potential cure, less than 20% of patients have a suitable donor. Haploidentical HCT allows for an increased donor pool and has recently demonstrated improved safety and efficacy. Our group has reported improved cardiac morphology via echocardiography at 1 year after HCT. Here we describe the first use of cardiac magnetic resonance imaging (CMR), the gold standard for measuring volume, mass, and ventricular function, to evaluate changes in cardiac morphology post-HCT in adults with SCD. We analyzed baseline and 1-year data from 12 adults with SCD who underwent nonmyeloablative haploidentical peripheral blood HCT at the National Institutes of Health. Patients underwent noncontrast CMR at 3 T, echocardiography, and laboratory studies. At 1 year after HCT, patients showed marked improvement in cardiac chamber morphology by CMR, including left ventricular (LV) mass (70.2 to 60.1 g/m2; P = .02) and volume (114.5 to 90.6 mL/m2; P = .001). Furthermore, mean TRV normalized by 1 year, suggesting that HCT may offer a survival benefit. Fewer patients had pathologically prolonged native myocardial T1 times, an indirect marker of myocardial fibrosis at 1 year; these data showed a trend toward significance. In this small sample, CMR was very sensitive in detecting cardiac mass and volume changes after HCT and provided complementary information to echocardiography. Notably, post-HCT improvement in cardiac parameters can be attributed only in part to the resolution of anemia; further studies are needed to determine the roles of myocardial fibrosis reversal, improved blood flow, and survival impact after HCT for SCD.

Systemic primary carnitine deficiency induces severe arrhythmia due to shortening of QT interval.

BACKGROUND: Systemic primary carnitine deficiency (PCD) is characterized by cardiomyopathy and arrhythmia. Without carnitine supplementation, progression is usually towards fatal cardiac decompensation. While the cardiomyopathy is most likely secondary to energy deficiency, the mechanism of arrhythmia is unclear, and may be related to a short QT interval. OBJECTIVE: We aim to describe rhythmic manifestations at diagnosis and with carnitine supplementation. METHODS: French patients diagnosed for PCD were retrospectively included. Clinical and para clinical data at diagnosis and during follow-up were collected. Electrocardiograms with QT interval measurements were blinded reviewed by two paediatric cardiologists. RESULTS: Nineteen patients (median age at diagnosis 2.3 years (extremes 0.3-28.9)) followed in 8 French centres were included. At diagnosis, 21% of patients (4/19) had arrhythmia (2 ventricular fibrillations, 1 ventricular tachycardia and 1 sudden death), and 84% (16/19) had cardiomyopathy. Six electrocardiograms before treatment out of 11 available displayed a short QT (QTc < 340 ms). Median corrected QTc after carnitine supplementation was 404 ms (extremes 341-447) versus 350 ms (extremes 282-421) before treatment (p < 0.001). The whole QTc was prolonged, and no patient reached the criterion of short QT syndrome with carnitine supplementation. Three patients died, probably from rhythmic cause without carnitine supplementation (two extra-hospital sudden deaths and one non-recoverable rhythmic storm before carnitine supplementation), whereas no rhythmic complication occurred in patients with carnitine supplementation. CONCLUSION: PCD is associated with shortening of the QT interval inducing severe arrhythmia. A potential explanation would be a toxic effect of accumulated fatty acid and metabolites on ionic channels embedded in the cell membrane. Carnitine supplementation normalizes the QTc and prevents arrhythmia. Newborn screening of primary carnitine deficiency would prevent avoidable deaths.

Left ventricular noncompaction cardiomyopathy and short QT syndrome due to primary carnitine deficiency.

We report the case of a 13-year-old female patient presenting with presyncope and palpitations. Her electrocardiogram revealed an abbreviation of the rate-corrected QT interval with imaging showing significant left ventricular dysfunction. Carnitine levels were measured as part of her diagnostic workup, discovering a rare, reversible cause of short QT syndrome (SQTS) and associated cardiomyopathy-primary carnitine deficiency (PCD) caused by a homozygous mutation in the SLC22A5 gene, leading to an in-frame deletion mutation (NP_003051.1:p.Phe23del) affecting the organic cation transporter 2 (OCTN2) protein. Following the treatment with oral carnitine supplementation, her QT interval returned to within the normal range with significant improvement in left ventricular function.

Impact of early ventricular tachycardia ablation in patients with an implantable cardioverter-defibrillator: An updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There is limited information on whether early catheter ablation (CA) for ventricular tachycardia (VT) is associated with better outcomes compared with alternative strategies in patients with implantable cardioverter-defibrillator (ICD). OBJECTIVE: The purpose of this article was to assess the efficacy of early VT CA in patients with ICD. METHODS: EMBASE, PubMed, and Cochrane were searched from inception to April 2022. Randomized controlled trials comparing the efficacy of early VT CA with control groups, both in patients with ICD, were included in the analysis. Data on effect estimates in individual studies were extracted and combined via random effects meta-analysis using the DerSimonian and Laird method, a generic inverse variance strategy. RESULTS: Nine randomized controlled trials with 1106 patients (n = 1018, 92.1% with ischemic cardiomyopathy and n = 88, 7.9% with nonischemic cardiomyopathy) were evaluated. VT CA was associated with reduced VT recurrences (odds ratio [OR] 0.64; P = .007), appropriate ICD shocks (OR 0.53; P = .002), ICD therapies (OR 0.54; P = .002), and cardiovascular hospitalization (OR 0.67; P = .004). However, no significant differences were observed in terms of mortality rate, heart failure hospitalization, and quality of life between the early VT CA and control groups. CONCLUSION: Early CA was beneficial in reducing VT burden and ICD therapies. However, it did not affect mortality rate and quality of life. Since most patients in the included studies presented with ischemic cardiomyopathy, further studies on nonischemic cardiomyopathy should be conducted to validate if early CA has similar outcomes.

Kickboxing a cardiomyopathy: mitochondrial sequencing provides answer for young athlete and her family.

Mitochondrial diseases are rare, often go undiagnosed and can lead to devastating cascades of multisystem organ dysfunction. This report of a young woman with hearing loss and gestational diabetes illustrates a novel presentation of a cardiomyopathy caused by a previously described mutation in a mitochondrial gene, MT-TL1. She initially had biventricular heart dysfunction and ventricular arrhythmia that ultimately recovered with beta blockade and time. She continues to participate in sport without decline. It is important to keep mitochondrial diseases in the differential diagnosis and understand the testing and management strategies in order to provide the best patient care.

The Importance of the Fatty Acid Transporter L-Carnitine in Non-Alcoholic Fatty Liver Disease (NAFLD).

L-carnitine transports fatty acids into the mitochondria for oxidation and also buffers excess acetyl-CoA away from the mitochondria. Thus, L-carnitine may play a key role in maintaining liver function, by its effect on lipid metabolism. The importance of L-carnitine in liver health is supported by the observation that patients with primary carnitine deficiency (PCD) can present with fatty liver disease, which could be due to low levels of intrahepatic and serum levels of L-carnitine. Furthermore, studies suggest that supplementation with L-carnitine may reduce liver fat and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). L-carnitine has also been shown to improve insulin sensitivity and elevate pyruvate dehydrogenase (PDH) flux. Studies that show reduced intrahepatic fat and reduced liver enzymes after L-carnitine supplementation suggest that L-carnitine might be a promising supplement to improve or delay the progression of NAFLD.

Rutin ameliorates metabolic acidosis and fibrosis in alloxan induced diabetic nephropathy and cardiomyopathy in experimental rats.

Diabetic nephropathy and cardiomyopathy are two major causes of mortality among patients with diabetes mellitus (DM). Since current diabetic medications are associated with various side effects, the naturally occurring plant-derived compounds are in demand. Bioflavonoids originating from vegetables and medicinal plants have beneficial effects on diabetes by improving glycemic control, lipid metabolism, and anti-oxidant status. The present study is focused on the effect of rutin against alloxan induced diabetic nephropathy and cardiomyopathy. Male albino Wistar rats were divided into four groups, each of six rats. Group I control rats received 0.9% saline as a single dose intraperitoneally. Group II rats were induced diabetes with a single dose of alloxan monohydrate (150 mg/kg body weight in 0.9% saline) intraperitoneally. Group III rats received 0.28 M of NH4Cl in drinking water for 3 days for the experimental induction of metabolic acidosis. Group IV rats were injected with a single dose of alloxan monohydrate (150 mg/kg bodyweight) and administered rutin hydrate (100 mg/kg) for a period of 4 weeks by oral gavage. Administration of rutin prevented urinary ketone body formation and decreased serum creatinine and urea levels in alloxan induced diabetic rats. Rutin supplementation reduced the levels of serum triglycerides and cholesterol in diabetic rats. Gene expression profiling of metabolic acidosis related genes (AQP2, AQP3 and V2R) and also histopathological results demonstrated the protective effect of rutin against diabetic ketoacidodis and fibrosis. The results of the present study revealed rutin administration prevents the progression of diabetic nephropathy and cardiomyopathy through amelioration of fibrosis and metabolic acidosis.

2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Position Statement on the Management of Ventricular Tachycardia and Fibrillation in Patients With Structural Heart Disease.

This Canadian Cardiovascular Society position statement is focused on the management of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) that occurs in patients with structural heart disease (SHD), including previous myocardial infarction, dilated cardiomyopathy, and other forms of nonischemic cardiomyopathy. This patient population is rapidly increasing because of advances in care and improved overall survival of patients with all forms of SHD. In this position statement, the acute and long-term management of VT/VF are outlined, and the many unique aspects of care in this population are emphasized. The initial evaluation, acute therapy, indications for chronic suppressive therapy, choices of chronic suppressive therapy, implantable cardioverter-defibrillator programming, alternative therapies, and psychosocial care are reviewed and recommendations for optimal care are provided. The target audience for this statement includes all health professionals involved in the continuum of care of patients with SHD and VT/VF.

Ventricular Fibrillation Caused by Primary Carnitine Deficiency.

BACKGROUND: Primary carnitine deficiency (PCD) is a rare but potentially life-threatening genetic disorder if left untreated. Although some patients remain asymptomatic lifelong, a few patients present with hepatic encephalopathy, hypoglycemia, cardiomyopathy, dysrhythmia, and even sudden death. CASE REPORT: A 25-year-old woman with PCD collapsed suddenly while eating lunch. Bystander cardiopulmonary resuscitation (CPR) was performed for 8 min, with automated external defibrillation once before admission. Upon arrival at our emergency department (ED), she was unresponsive without a pulse or spontaneous breathing. The initial heart rhythm on the electrocardiogram monitor was ventricular fibrillation (VF). The medical staff continued CPR with defibrillation for sustained VF. Return of spontaneous circulation (ROSC) was achieved after a total resuscitation time of 14 min, with defibrillation twice after cardiac arrest. The heart rhythm after ROSC was atrial fibrillation, with a rapid ventricular rate initially and subsequent progression to sinus tachycardia with diffuse ST segment depression and a prolonged QT interval. Her low carnitine level was consistent with her underlying disease. Cardiac magnetic resonance imaging and sonography for detection of cardiomyopathy showed no significant findings. With carnitine supplementation for a few days, her plasma carnitine level returned to 30 µM, with no recurrence of ventricular dysrhythmia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: PCD is rare but could be life-threatening, and compiling detailed histories may help emergency physicians to determine the cause of sudden cardiac death after resuscitation. This information may be used to correct potential underlying problems and prevent recurrence of the condition after treatment.

Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma.

BACKGROUND: Fatigue is a common adverse event during lenvatinib treatment in patients with hepatocellular carcinoma. One mechanism contributing to development of fatigue might involve abnormal adenosine triphosphate synthesis that is caused by carnitine deficiency. To address this possibility, we examined the relationship between carnitine levels and fatigue during lenvatinib treatment. METHODS: This prospective study evaluated 20 patients with hepatocellular carcinoma who underwent lenvatinib treatment. Both blood and urine samples were collected from the patients before starting lenvatinib therapy (day 0), and on days 3, 7, 14, and 28 thereafter. Plasma and urine concentrations of free and acyl carnitine (AC) were assessed at each time point. The changes in daily fatigue were evaluated using the Brief Fatigue Inventory (BFI). RESULTS: Plasma levels of free carnitine (FC) at days 3 and 7 were significantly higher compared with baseline (p = 0.005, p = 0.005, respectively). The urine FC level at day 3 was significantly higher compared with baseline (p = 0.030) and that of day 7 tended to be higher compared with baseline (p = 0.057). The plasma AC concentration at days 14 and 28 was significantly higher compared with that of baseline (p = 0.002, p = 0.005, respectively). The plasma AC-to-FC (AC/FC) ratio on days 14 and 28 was significantly higher compared with baseline (p = 0.001, p = 0.003, respectively). There were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28 (r = 0.461, p = 0.041; r = 0.770, p = 0.002, respectively). CONCLUSIONS: Longitudinal assessments of carnitine and fatigue in patients with hepatocellular carcinoma suggest that lenvatinib affects the carnitine system in patients undergoing lenvatinib therapy and that carnitine insufficiency increases fatigue. The occurrence of carnitine insufficiency may be a common cause of fatigue during the treatment.

Secondary mitral regurgitation: pathophysiology, proportionality and prognosis.

Secondary mitral regurgitation (SMR) occurs as a result of multifactorial left atrioventricular dysfunction and maleficent remodelling. It is the most common and undertreated form of mitral regurgitation (MR) and is associated with a very poor prognosis. Whether SMR is a bystander reflecting the severity of the cardiomyopathy disease process has long been the subject of debate. Studies suggest that SMR is an independent driver of prognosis in patients with an intermediate heart failure (HF) phenotype and not those with advanced HF. There is also no universal agreement regarding the quantitative thresholds defining severe SMR and indeed there are challenges with echocardiographic quantification. Until recently, no surgical or transcatheter intervention for SMR had demonstrated prognostic benefit, in contrast with HF medical therapy and cardiac resynchronisation therapy. In 2018, the first two randomised controlled trials (RCTs) of edge-to-edge transcatheter mitral valve repair versus guideline-directed medical therapy in HF (Percutaneous Repair with the MitraClip Device for Severe (MITRA-FR), Transcather mitral valve repair in patients with heart failure (COAPT)) reported contrasting yet complimentary results. Unlike in MITRA-FR, COAPT demonstrated significant prognostic benefit, largely attributed to the selection of patients with disproportionately severe MR relative to their HF phenotype. Consequently, quantifying the degree of SMR in relation to left ventricular volume may be a useful discriminator in predicting the success of transcatheter intervention. The challenge going forward is the identification and validation of such parameters while in parallel maintaining a heart-team guided holistic approach.

Myocardial edema in paroxysmal permeability disorders: The paradigm of Clarkson's disease.

PURPOSE: Paroxysmal Permeability Disorders (PPDs) comprise a variety of diseases characterized by recurrent and transitory increase of endothelial permeability. Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a rare PPD that leads to an abrupt massive shift of fluids and proteins from the intravascular to the interstitial compartment. In some cases, tissue edema may involve the myocardium, but its role in the development of shock has not been elucidated so far. MATERIALS AND METHODS: Assessment of cardiac involvement during ten life-threatening ISCLS episodes admitted to ICU. RESULTS: Transthoracic echocardiographic examination was performed in eight episodes, whereas a poor acoustic window prevented cardiac ultrasound assessment in two episodes. Myocardial edema was detected by echocardiography in eight episodes and marked pericardial effusion in one-episode. Cardiac magnetic resonance showed diffuse myocardial edema in another episode. In one case, myocardial edema caused fulminant left ventricular dysfunction, which required extracorporeal life support. The mean septum thickness was higher during the shock phase compared to the recovery phase [15.5 mm (13.1-21 mm) vs. 9.9 mm (9-11.3 mm), p = .0003]. Myocardial edema resolved within 72 h. CONCLUSIONS: During early phases of ISCLS, myocardial edema commonly occurs and can induce transient myocardial dysfunction, potentially contributing to the pathogenesis of shock.

Mapping and Ablation of Ventricular Arrhythmias in Cardiomyopathies.

Mapping and ablation of ventricular arrhythmias in patients with nonischemic cardiomyopathies remain a major challenge. The electroanatomic abnormalities are frequently inaccessible to conventional endocardial ablations. Diagnostic diligence with a thorough understanding of the potential mechanisms/substrate, coupled with detailed electroanatomic mapping, is essential. Careful procedural planning, advanced imaging, and unipolar recordings help to formulate ablation strategy, facilitate work flow, and improve outcomes. Inaccessibility of arrhythmogenic substrate and disease progression are important causes of ablation failure. Early intervention may help to improve outcome and minimize complications. Several novel adjunctive ablation techniques are capable of serving as alternative options in refractory cases.

Multisize Electrodes for Substrate Identification in Ischemic Cardiomyopathy: Validation by Integration of Whole Heart Histology.

OBJECTIVES: This study sought to evaluate the value of combined electrogram (EGM) information provided by simultaneous mapping using micro- and conventional electrodes in the identification of post-myocardial infarction ventricular tachycardia substrate. BACKGROUND: Ventricular tachycardias after myocardial infarction are related to scars with complex geometry. Scar delineation and ventricular tachycardia substrate identification relies on bipolar voltages (BV) and EGM characteristics. Early reperfusion therapy results in small, nontransmural scars, the details of which may not be delineated using 3.5 mm tip catheters. METHODS: Nine swine with early reperfusion myocardial infarction were mapped using Biosense Webster's QDOT Micro catheter, incorporating 3 microelectrodes at the tip of the standard 3.5 mm electrode. Analysis of EGM during sinus rhythm, right ventricular pacing, and short-coupled right ventricular extrastimuli was performed. The swine were sacrificed and mapping data were projected onto the heart. Transmural biopsies (n = 196) corresponding to mapping points were obtained, allowing a head-to-head comparison of EGM recorded by micro- and conventional electrodes with histology. RESULTS: To identify scar areas using standard electrodes, unique cutoff values of unipolar voltage <5.44 mV, BV <1.27 mV (conventional), and BV <2.84 mV (microelectrode) were identified. Combining the information provided by unipolar voltage and BV mapping, the sensitivity of scar identification was increased to 93%. Micro-EGM were better able to distinguish small near-fields corresponding to a layer of viable subendocardium than conventional EGM were. CONCLUSIONS: The combined information provided by multisize electrode mapping increases the sensitivity with which areas of scar are identified. EGM from microelectrodes, with narrower spacing, allow identification of near-fields arising from thin subendocardial layer and layers activated with short delay obscured in EGM from conventional mapping catheter.

Molecular Autopsy Implicates Primary Carnitine Deficiency in Sudden Unexplained Death and Reversible Short QT Syndrome.

We report a case of sudden unexplained death in a young asymptomatic woman in whom postmortem genetic testing after a negative autopsy identified a homozygous pathogenic mutation in SLC22A5 which leads clinically to primary carnitine deficiency (PCD). Her brother was subsequently diagnosed clinically with short QT syndrome, received an implantable defibrillator, and was then found to carry the same pathogenic homozygous mutation and critically low levels of carnitine. His QT interval improved with the use of carnitine supplementation, highlighting the close relationship between electrophysiology and biochemistry, and the importance of postmortem genetic testing in the clinical management of surviving relatives.

Ventricular tachycardia in nonischemic cardiomyopathy: Anteroseptal vs inferolateral origin based on ICD ventricular electrogram timing.

INTRODUCTION: The majority of patients with nonischemic cardiomyopathy (NICM) present a perivalvular substrate that is either predominantly antero-septal (AS) or infero-lateral (IL), corresponding to specific ventricular tachycardia (VT) morphologies. The relative timing of far-field and near-field ventricular electrograms (EGMs) from stored implantable cardioverter-defibrillator (ICD) events of VT may be used to distinguish AS from IL VT in NICM. METHODS AND RESULTS: We analyzed 48 patients with NICM with either a primarily AS (54%) or IL (56%) VT source undergoing catheter ablation between 2003 and 2018. Only patients with retrievable ICD-EGMs of spontaneous VT events which could be matched with VTs induced during the ablation procedure were included. A total of 56 VT events (52% AS origin and 48% IL origin) were analyzed, yielding a mean far-field to near-field interval of 31 ± 13 milliseconds for AS VTs and 47 ± 19 milliseconds for IL VTs (P = .001). At receiver operating characteristic analysis (AUC = 0.734), a far-field to near-field interval of ≥ 60 milliseconds ruled out AS VTs in 29 (100%) cases and diagnosed IL VTs with a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 63%. An interval of ≤ 20 milliseconds ruled out IL VTs in 25 (93%) cases and diagnosed AS VTs with a PPV of 83% and NPV of 57%. Significant overlap between the two groups was observed among far-field to near-field intervals in between 20 milliseconds and 60 milliseconds. CONCLUSIONS: The relative timing of far-field and near-field EGMs from stored clinical ICD events of VT can be helpful to differentiate AS vs IL origin of VT in NICM.

Calcitriol and Punica Granatum Extract Concomitantly Attenuate Cardiomyopathy of Diabetic Mother Rats and Their Neonates via Activation of Raf/MEK/ERK Signalling and Mitigation of Apoptotic Pathways.

We investigated the detrimental effects of diabetes on myocardium of pregestational streptozotocin (STZ)-diabetic mother rats and their neonates via evaluations of oxidative redox, inflammatory and apoptotic pathways, also aiming to characterize whether calcitriol and/or pomegranate peel extract confer myocardial protection in hyperglycaemic dams and their foetuses via modulation of the Raf/MEK/ERK cascade. Sixty Sprague-Dawley female rats were randomized into five groups (N = 12): control, diabetic, diabetic treated with calcitriol and/or pomegranate peel extract (PPE), and mated with non-diabetic healthy males. After confirmation of pregnancy, treatments were kept until gestational day (E-18). Serum and cardiac tissues of mothers and foetuses were collected and processed for biochemical, histopathological, and molecular assessments. We observed that, compared to the control, diabetic mothers showed dramatically increased hyperglycaemia and hyperlipidaemia associated with decreased myocardial functions and disrupted maternal performance. Also, diabetic mothers and their neonates exhibited elevated levels of myocardial injury (troponin I, endothelin 1, creatine kinase-MB, lactate dehydrogenase), with increased pro-inflammatory cytokines (interleukin 1, interleukin 1ß, transforming growth factor ß) and oxidative redox. Concurrently, the MAPK pathway was significantly down-regulated with increased myocardial apoptotic activity. Furthermore, mRNA expression of angiogenic and fibrotic markers was significantly increased. Paradoxically, calcitriol and/or pomegranate peel extract alleviated these diabetic myocardial insults and normalized the aforementioned assayed parameters. Our findings hypothesized that calcitriol and/or pomegranate peel extract exerted cardioameliorative impacts due to their unique anti-oxidative and anti-inflammatory properties, and thus may be a promising treatment that directly targets the secondary myocardial complications of diabetes in dams and their offspring.