Left main and three vessels spontaneous coronary artery dissection as an incidental finding in young man with history of Hodgkin's lymphoma-a case report.

BACKGROUND: Spontaneous coronary artery dissection is a rare and important cause of myocardial infarction, especially in young women without other coronary artery disease. This arterial dissection can occur within or between any of the 3 layers. Its predisposing factors include connective tissue diseases (Marfone syndrome, Ehlers-Danlos syndrome), vasculitis (polyarteritis nodosa, systemic lupus erythematosus, and Kawasaki disease), atherosclerosis and fibromuscular dysplasia. Clinical presentations of spontaneous coronary artery dissection are wide spectrum from asymptomatic to acute coronary disease, sustained ventricular arrhythmia and sudden cardiac death. CASE PRESENTATION: We describe A 33-year-old man with history of Hodgkin's lymphoma five years earlier that became a candidate for Patent foramen ovale closure due to recurrent embolic cerebrovascular accident. Before the intervention, coronary angiography incidentally showed dissection in the left main and all major coronary arteries. CONCLUSIONS: Based on our hypothesis, chemoradiotherapy-induced arteriopathies could be consider as a predisposing factor for spontaneous coronary artery dissection.

Whole-exome sequencing revealed a likely pathogenic variant in NF1 causing neurofibromatosis type I and Arrhythmogenic Cardiomyopathy.

BACKGROUND: Neurofibromatosis type I (NF1) is a genetic disorder characterized by the tumor's development in nerve tissue. Complications of NF1 can include pigmented lesions, skin neurofibromas, and heart problems such as cardiomyopathy. In this study, we performed whole-exome sequencing (WES) on an Iranian patient with NF1 to identify the genetic cause of the disease. METHODS: Following clinical assessment, WES was used to identify genetic variants in a family with a son suffering from NF1. No symptomatic manifestations were observed in other family members. In the studied family, in silico and segregation analysis were applied to survey candidate variants. RESULTS: Clinical manifestations were consistent with arrhythmogenic cardiomyopathy (ACM). WES detected a likely pathogenic heterozygous missense variant, c.3277G > A:p.Val1093Met, in the NF1 gene, confirmed by PCR and Sanger sequencing. The patient's parents and brother had a normal sequence at this locus. CONCLUSIONS: Although there is no cure for NF1, genetic tests, such as WES, can detect at-risk asymptomatic family members. Furthermore, cardiac evaluation could also help these patients before heart disease development.

A novel pathogenic variant in the carnitine transporter gene, SLC22A5, in association with metabolic carnitine deficiency and cardiomyopathy features.

BACKGROUND: Primary carnitine deficiency (PCD) denotes low carnitine levels with an autosomal recessive pattern of inheritance. Cardiomyopathy is the most common cardiac symptom in patients with PCD, and early diagnosis can prevent complications. Next-generation sequencing can identify genetic variants attributable to PCD efficiently. OBJECTIVE: We aimed to detect the genetic cause of the early manifestations of hypertrophic cardiomyopathy and metabolic abnormalities in an Iranian family. METHODS: We herein describe an 8-year-old boy with symptoms of weakness and lethargy diagnosed with PCD through clinical evaluations, lab tests, echocardiography, and cardiac magnetic resonance imaging. The candidate variant was confirmed through whole-exome sequencing, polymerase chain reaction, and direct Sanger sequencing. The binding efficacy of normal and mutant protein-ligand complexes were evaluated via structural modeling and docking studies. RESULTS: Clinical evaluations, echocardiography, and cardiac magnetic resonance imaging findings revealed hypertrophic cardiomyopathy as a clinical presentation of PCD. Whole-exome sequencing identified a new homozygous variant, SLC22A5 (NM_003060.4), c.821G > A: p.Trp274Ter, associated with carnitine transport. Docking analysis highlighted the impact of the variant on carnitine transport, further indicating its potential role in PCD development. CONCLUSIONS: The c.821G > A: p.Trp274Ter variant in SLC22A5 potentially acted as a pathogenic factor by reducing the binding affinity of organic carnitine transporter type 2 proteins for carnitine. So, the c.821G > A variant may be associated with carnitine deficiency, metabolic abnormalities, and cardiomyopathic characteristics.

A novel homozygous variant (c.5876T > C: p. Leu1959Pro) in DYSF segregates with limb-girdle muscular dystrophy: a case report.

BACKGROUND: Limb girdle muscular dystrophies (LGMDs) constitute a heterogeneous group of neuromuscular disorders with a very variable clinical presentation and overlapping traits. The clinical symptoms of LGMD typically appear in adolescence or early adulthood. Genetic variation in the dysferlin gene (DYSF) has been associated with LGMD. METHODS: We characterized a recessive LGMD in a young adult from consanguineous Irani families using whole-exome sequencing (WES) technology. Sanger sequencing was performed to verify the identified variant. Computational modeling and protein-protein docking were used to investigate the impact of the variant on the structure and function of the DYSF protein. RESULTS: By WES, we identified a novel homozygous missense variant in DYSF (NM_003494.4: c.5876T > C: p. Leu1959Pro) previously been associated with LGMD phenotypes. CONCLUSIONS: The identification and validation of new pathogenic DYSF variant in the present study further highlight the importance of this gene in LGMD.

Role of non-coding variants in cardiovascular disease.

Cardiovascular diseases (CVDs) constitute one of the significant causes of death worldwide. Different pathological states are linked to CVDs, which despite interventions and treatments, still have poor prognoses. The genetic component, as a beneficial tool in the risk stratification of CVD development, plays a role in the pathogenesis of this group of diseases. The emergence of genome-wide association studies (GWAS) have led to the identification of non-coding parts associated with cardiovascular traits and disorders. Variants located in functional non-coding regions, including promoters/enhancers, introns, miRNAs and 5'/3' UTRs, account for 90% of all identified single-nucleotide polymorphisms associated with CVDs. Here, for the first time, we conducted a comprehensive review on the reported non-coding variants for different CVDs, including hypercholesterolemia, cardiomyopathies, congenital heart diseases, thoracic aortic aneurysms/dissections and coronary artery diseases. Additionally, we present the most commonly reported genes involved in each CVD. In total, 1469 non-coding variants constitute most reports on familial hypercholesterolemia, hypertrophic cardiomyopathy and dilated cardiomyopathy. The application and identification of non-coding variants are beneficial for the genetic diagnosis and better therapeutic management of CVDs.

Genetic Variations in the Human Angiotensin-ConvertingEnzyme 2 and Susceptibility to Coronavirus Disease-19.

Background: Health and economies are both affected by the coronavirus disease-19 (COVID-19) global pandemic. Angiotensin-converting enzyme 2 (ACE2) is a polymorphic enzyme that is a part of the renin-angiotensin system, and it plays a crucial role in viral entry. Previous investigations and studies revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ACE2 have a considerable association. Recently, ACE2 variants have been described in human populations in association with cardiovascular and pulmonary conditions. In this study, genetic susceptibility to COVID-19 in different populations was investigated. Methods and Results: We evaluated the identified variants based on the predictive performance of 5 deleteriousness-scoring methods and the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. The results indicated 299 variants within the ACE2 gene. The variants were analyzed by different in-silico analysis tools to assess their functional effects. Ultimately, 5 more deleterious variants were found in the ACE2 gene. Conclusions: Collecting more information about the variations in binding affinity between SARS-CoV-2 and host-cell receptors due to ACE2 variants leads to progress in treatment strategies for COVID-19. The evidence accumulated in this study showed that ACE2 variants in different populations may be associated with the genetic susceptibility, symptoms, and outcome of SARS-CoV-2 infection.

Increased prevalence of thyroid dysfunction in Tehran - HAMRAH study.

BACKGROUND: The aim of the current study is to assess the prevalence of different categories of thyroid dysfunction and their associated risk factors among the modern urban population of Tehran, the capital of Iran. METHODS: The present investigation is a sub-study of the HAMRAH study, a population-based prospective study designed to assess the prevalence of traditional cardiovascular risk factors and their changes through a 10-year follow-up. 2228 (61% female) adults aged between 30 and 75 years old and with no overt cardiovascular diseases were selected through a multistage cluster randomized sampling. Blood levels of thyroid-stimulating hormone (TSH), thyroxin (T4), and triiodothyronine (T3) were measured with the aim of assessing the prevalence of abnormal thyroid function status among the modern urban Iranian population, and in order to report the total prevalence of participants with clinical hypo- or hyperthyroidism, the number of individuals taking thyroid-related drugs were added to the ones with overt thyroid dysfunction. A subgroup analysis was also performed to determine the associated risk factors of thyroid dysfunction. RESULTS: The prevalence of thyroid dysfunction among the total population was 7% (95%CI: 5.9 - 8%) and 0.4% (95% CI: 0.1 - 0.6%) for subclinical and overt hypothyroidism, and 1.6% (95% CI: 1 - 2%) and 0.2% (95% CI: 0 - 0.3%) for subclinical and overt hyperthyroidism, respectively. Clinical thyroid dysfunction was detected in 10.3% of the study population (9.4% had clinical hypo- and 0.9% had clinical hyperthyroidism). In the subgroup analysis, thyroid dysfunction was significantly more prevalent among the female participants (P-value = 0.029). CONCLUSIONS: In the current study, the prevalence of different categories of abnormal thyroid status, and also the rate of clinical hypo- and hyperthyroidism was assessed using the data collected from the first phase of the HAMRAH Study. In this study, we detected a higher prevalence of clinical and subclinical hypothyroidism among the Iranian population compared to the previous studies.

A novel heterozygous missense MYH7 mutation potentially causes an autosomal dominant form of myosin storage myopathy with dilated cardiomyopathy.

BACKGROUND: The MYH7 gene, which encodes the slow/ß-cardiac myosin heavy chain, is mutated in myosin storage myopathy (MSM). The clinical spectrum of MSM is quite heterogeneous in that it ranges from cardiomyopathies to skeletal myopathies or a combination of both, depending on the affected region. In this study, we performed clinical and molecular examinations of the proband of an Iranian family with MSM in an autosomal dominant condition exhibiting proximal muscle weakness and dilated cardiomyopathy. METHODS: Following thorough clinical and paraclinical examinations, whole-exome sequencing `was performed on the proband (II-5). Pathogenicity prediction of the candidate variant was performed through in-silico analysis. Co-segregation analysis of the WES data among the family members was carried out by PCR-based Sanger sequencing. RESULTS: A novel heterozygous missense variant, MYH7 (NM_000257): c.C1888A: p.Pro630Thr, was found in the DNA of the proband and his children and confirmed by Sanger sequencing. The in-silico analysis revealed that p.Pro630Thr substitution was deleterious. The novel sequence variant fell within a highly conserved region of the head domain. Our findings expand the spectrum of MYH7 mutations. CONCLUSIONS: This finding could improve genetic counseling and prenatal diagnosis in families with clinical manifestations associated with MYH7-related myopathy.

Development of a patients' satisfaction analysis system using machine learning and lexicon-based methods.

BACKGROUND: Patients' rights are integral to medical ethics. This study aimed to perform sentiment analysis and opinion mining on patients' messages by a combination of lexicon-based and machine learning methods to identify positive or negative comments and to determine the different ward and staff names mentioned in patients' messages. METHODS: The level of satisfaction and observance of the rights of 250 service recipients of the hospital was evaluated through the related checklists by the evaluator. In total, 822 Persian messages, composed of 540 negative and 282 positive comments, were collected and labeled by the evaluator. Pre-processing was performed on the messages and followed by 2 feature vectors which were extracted from the messages, including the term frequency-inverse document frequency (TFIDF) vector and a combination of the multifeature (MF) (a lexicon-based method) and TFIDF (MF + TFIDF) vectors. Six feature selectors and 5 classifiers were used in this study. For the evaluations, 5-fold cross-validation with different metrics including area under the receiver operating characteristic curve (AUC), accuracy (ACC), F1 score, sensitivity (SEN), specificity (SPE) and Precision-Recall Curves (PRC) were reported. Message tag detection, which featured different hospital wards and identified staff names mentioned in the study patients' messages, was implemented by the lexicon-based method. RESULTS: The best classifier was Multinomial Naïve Bayes in combination with MF + TFIDF feature vector and SelectFromModel (SFM) feature selection (ACC = 0.89 ± 0.03, AUC = 0.87 ± 0.03, F1 = 0.92 ± 0.03, SEN = 0.93 ± 0.04, and SPE = 0.82 ± 0.02, PRC-AUC = 0.97). Two methods of assessment by the evaluator and artificial intelligence as well as survey systems were compared. CONCLUSION: Our results demonstrated that the lexicon-based method, in combination with machine learning classifiers, could extract sentiments in patients' comments and classify them into positive and negative categories. We also developed an online survey system to analyze patients' satisfaction in different wards and to remove conventional assessments by the evaluator.

Effect of resistance exercise on cardiac perturbations and systolic performance: A cross-over randomized trial comparing volumes and techniques.

This study investigated the magnitude and time-course of resistance exercise (RE) technique induced transient cardiac perturbations. Twenty-four participants were assigned to one of four arms: sets to failure or non-failure with 8-10 repetition maximum (RM), and sets to failure or non-failure with 15RM. Echocardiographic and blood pressure (BP) data were recorded at baseline and 30 min, 6 h and 24 h post-exercise. In all groups end-systolic circumferential wall stress (cESS), and ratio of transmitral inflow velocities (E/A) were significantly decreased while posterior wall thickness (PWT), global circumferential strain (GCS), GCS strain rate (GCSR), global longitudinal strain rate (GLSR), and stroke volume (SV) were significantly increased for up to 6 h of follow-up. In the 15RM groups, left ventricular (LV) mass and interventricular septal thickness (IVST) were significantly increased, and left atrial (LA) area was significantly decreased (p < 0.05) compared to the 8-10 RM groups. In the 15RM groups, RE decreased global longitudinal strain (GLS) and increased ejection fraction (EF) (p<0.01). After RE, transient cardiac perturbations, the reduction in LA compliance, and the improvement in LV myofibril geometry were volume dependent and influenced more by sets to failure technique. RE increased GCS and reduced the afterload, thus helping to preserve SV and EF.

Tenascin-C as a noninvasive biomarker of coronary artery disease.

BACKGROUND: Coronary artery disease (CAD), is the leading cause of mortality and morbidity worldwide. Tenascin-C (TNC) with high expression levels in inflammatory and cardiovascular diseases, leads to the rupture of atherosclerotic plaques. The origin of plaque destabilization can be associated to endothelial dysfunction. Given the high prevalence of CAD, finding valuable biomarkers for its early detection is of great interest. Using serum samples from patients with CAD and individuals without CAD, we assessed the efficacy of TNC expression levels in serum exosomes and during endothelial cell differentiation as a noninvasive biomarker of CAD. METHODS: TNC expression was analyzed using the RNA-sequencing data sets of 6 CAD and 6 normal samples of blood exosomes and endothelial differentiation transitions. Additionally, TNC expression was investigated in the serum samples of patients with CAD and individuals without CAD via qRT-PCR. ROC curve analysis was employed to test the suitability of TNC expression alterations as a CAD biomarker. RESULTS: TNC exhibited higher expression in the exosomes of the CAD samples than in those of the non-CAD samples. During endothelial differentiation, TNC expression was upregulated and then consistently downregulated in mature endothelial cells. Moreover, TNC was significantly upregulated in the serum of the CAD group (P = 0.02), with an AUC of 0.744 for the expression level (95% confidence interval, 0.582 to 0.907; P = 0.011). Hence its expression level can be discriminated CAD from non-CAD samples. DISCUSSION: Our study is the first to confirm that altered TNC expression is associated with pathological CAD conditions in Iranian patients. The expression of TNC is involved in endothelial differentiation and CAD development. Accordingly, TNC can serve as a valuable noninvasive biomarker with potential application in CAD diagnosis.

Novel homozygous stop-gain pathogenic variant of PPP1R13L gene leads to arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease with two main features: electric instability and myocardial fibro-fatty replacement. There is no defined treatment except for preventing arrhythmias and sudden death. Detecting causative mutations helps identify the disease pathogenesis and family members at risk. We used whole-exome sequencing to determine a genetic explanation for an ACM-positive patient from a consanguineous family. METHODS: After clinical analysis, cardiac magnetic resonance, and pathology, WES was performed on a two-year-old ACM proband. Variant confirmation and segregation of available pedigree members were performed by PCR and Sanger sequencing. The PPP1R13L gene was also analyzed for possible causative variants and their hitherto reported conditions. RESULTS: We found a novel homozygous stop-gain pathogenic variant, c.580C > T: p.Gln194Ter, in the PPP1R13L gene, which was confirmed and segregated by PCR and Sanger sequencing. This variant was not reported in any databases. CONCLUSIONS: WES is valuable for the identification of novel candidate genes. To our knowledge, this research is the first report of the PPP1R13L c.580C > T variant. The PPP1R13L variant was associated with ACM as confirmed by cardiac magnetic resonance and pathology. Our findings indicate that PPP1R13L should be included in ACM genetic testing to improve the identification of at-risk family members and the diagnostic yield.

The effects of preoperative supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine on inflammatory and hematological markers of patients with heart surgery: a randomized controlled trial.

BACKGROUND: Cardiac surgery is associated with a widespread inflammatory response, by an additional release of free radicals. Due to the importance of these patient's nutritional status, the present study was designed to evaluate the effectiveness of supplementation with a combination of glutamine, ß-hydroxy-ß-methylbutyrate (HMB) and arginine in patients undergoing to the heart surgery. METHODS: The experiment was performed in 1 month (30 days) before cardiac surgery. patients were asked to take 2 sachets of Heallagen® (a combination of 7 g L-arginine, 7 g L-glutamine, and 1.5 g daily HMB) or placebo with identical appearance and taste (maltodextrin) with 120 cc of water. Clinical and biochemical factors were evaluated in the baseline and end of the study. RESULTS: Totally, 60 preoperative patients (30 interventions and 30 placeboes) with a mean age of 53.13 ± 14.35 years participated in the study. Subjects in Heallagen® group had a lower serum levels of interleukin-6 (P = 0.023), erythrocyte sedimentation rate (P < 0.01), high sensitivity C-reactive protein (P < 0.01), and lymphocyte number (P = 0.007) compared to the placebo, at end of the study. CONCLUSION: In the patients undergoing heart surgery, Heallagen® significantly improved some of the inflammatory factors and hematological parameters. These results need to be confirmed in a larger trial. TRIAL REGISTRATION: The protocol of the study was registered in the IRCT.ir with registration no. IRCT20120913010826N31 at 13/10/2020.

Cost-effectiveness of a population-based AAA screening program for men over 65 years old in Iran.

BACKGROUND: Screening program tend to recognized patients in their early stage and consequently improve health outcomes. Cost-effectiveness of the abdominal aortic aneurysm (AAA) screening program has been scarcely studied in developing countries. We sought to evaluate the cost-effectiveness of a screening program for the abdominal aortic aneurysm (AAA) in men aged over 65 years in Iran. METHODS: A Markov cohort model with 11 mutually exclusive health statuses was used to evaluate the cost-effectiveness of a population-based AAA screening program compared with a no-screening strategy. Transitions between the health statuses were simulated by using 3-month cycles. Data for disease transition probabilities and quality of life outcomes were obtained from published literature, and costs were calculated based on the price of medical services in Iran and the examination of the patients' medical records. The outcomes were life-years gained, the quality-adjusted life-year (QALY), costs, and the incremental cost-effectiveness ratio (ICER). The analysis was conducted for a lifetime horizon from the payer's perspective. Costs and effects were discounted at an annual rate of 3%. Uncertainty surrounding the model inputs was tested with deterministic and probabilistic sensitivity analyses. RESULTS: The mean incremental cost of the AAA screening strategy compared with the no-screening strategy was $140 and the mean incremental QALY gain was 0.025 QALY, resulting in an ICER of $5566 ($14,656 PPP) per QALY gained. At a willingness-to-pay of 1 gross domestic product (GDP) per capita ($5628) per QALY gained, the probability of the cost-effectiveness of AAA screening was about 50%. However, at a willingness-to-pay of twice the GDP per capita per QALY gained, there was about a 95% probability for the AAA screening program to be cost-effective in Iran. CONCLUSIONS: The results of this study showed that at a willingness-to-pay of 1 GDP per capita per QALY gained, a 1-time AAA screening program for men aged over 65 years could not be cost-effective. Nevertheless, at a willingness-to-pay of twice the GDP per capita per QALY gained, the AAA screening program could be cost-effective in Iran. Further, AAA screening in high-risk groups could be cost-effective at a willingness-to-pay of 1 GDP per capita per QALY gained.

A prospective survey of atrial fibrillation management in Iran: Baseline results of the Iranian Registry of Atrial Fibrillation (IRAF).

BACKGROUND: Atrial fibrillation. (AF) is the most common sustained arrhythmia globally and its prevalence is likely to increase in the next decades as a result of increasing age and co-morbidities. There are no data on demographic features, clinical characteristics, associated comorbidities, and practice patterns of AF in Iran. METHODS: The Iranian Registry of Atrial Fibrillation (IRAF) is a hospital-based prospective survey of AF patients with a 12-month follow-up. Data were collected on a standardized case report form and entered into a web-based electronic database. This paper reports the baseline characteristics of the IRAF cohort. RESULTS: Between February 2018 and March 2020, a total of 1300 patients (57% Male, mean age, 60 ± 14 years) were enrolled. Palpitations were the most common presenting symptom (66%). The most common cardiac comorbidities were hypertension (52%), heart failure (23.7%), and valvular heart disease (21.8%). AF mainly presented as a paroxysmal pattern (44.6%). Seventy-eight percent of the patients with non-valvular AF had CHA2 DS2 -VASc score ≥1 and most (97%) were at low risk for bleeding (HAS-BLED score <3). Rhythm control was given to 55.1% of the patients. Anticoagulation for stroke prevention was provided to 69.5% of the eligible patients, while aspirin was used in 35%. CONCLUSION: The IRAF Registry has provided a systematic collection of contemporary data regarding the management and treatment of AF in Iran. Oral anticoagulant was used in 69.5%, but aspirin use was still common.

Preparation, escalation, de-escalation, and normal activities.

Iran is one of the earliest countries involved with coronavirus disease 2019 (COVID-19) pandemic. In the present short report, we have presented our experiences as a cardiovascular tertiary center during the COVID-19 outbreak. At the beginning, we have pursued our activities in four field of administrative, preventative, therapeutic, and research. Then by gaining new experiences, we have tailored our strategies. Finally, we have described our challenges and future strategies on returning to normal activities.

Effects of intravenous and transdermal photobiomodulation on the postoperative complications of coronary artery bypass grafting surgery: a randomized, controlled clinical trial.

Although coronary artery bypass graft (CABG) surgery is one of the most worldwide commonly performed cardiac surgeries to enhance myocardial perfusion in high-grade myocardial occlusion, it remains a high-risk procedure. Photobiomodulation (PBM) is one of the methods which have been shown to have positive effects on the healing process after CABG and postoperative complications. The aim of this study was to evaluate the efficacy of PBM in patients who underwent a coronary artery bypass graft (CABG). Ths study was conducted with 192 volunteers who electively submitted to CABG. The volunteers were randomly allocated into two groups: laser-treated (transdermal: 980 nm, 200 mW, continuous, average energy fluency of 6 J/cm2 and intravenous: 405 nm, 1.5 mW, continuous for 30 min) and standard treatment and control group (standard treatment only). Intravenous laser was illuminated the day before the surgery, immediately after transferring the patient to CCU post-operation and IV laser in addition to transdermal laser was applied every day after surgery for 6 days. A total of 170 out of 192 participants completed the study, 82 (48.2%) in the PBM group and 88 (51.8%) in the control group. Level of LDH and CPK was significantly lower in the PBM group (P < 0.05) in the 4th day postoperatively. The PBM group also showed significantly lower post-surgery complications, including pericardial effusion, ejection fraction, pathologic ST changes, pathologic Q, rehospitalization, heart failure, and mediastinitis (P < 0.05). Likewise, the VAS pain score after surgery was significantly lower in patients in the laser group (P < 0.05). PBM seems a promising, safe, cost-benefit therapeutic modality to reduce postoperative complications of CABG. Trial registration number: IRCT2016052926069N4 .

Whole-exome sequencing identified compound heterozygous variants in the TTN gene causing Salih myopathy with dilated cardiomyopathy in an Iranian family.

BACKGROUND: Salih myopathy, characterised by both congenital myopathy and fatal dilated cardiomyopathy, is an inherited muscle disorder that affects skeletal and cardiac muscles. TTN has been identified as the main cause of this myopathy, the enormous size of this gene poses a formidable challenge to molecular genetic diagnostics. METHOD: In the present study, whole-exome sequencing, cardiac MRI, and metabolic parameter assessment were performed to investigate the genetic causes of Salih myopathy in a consanguineous Iranian family who presented with titinopathy involving both skeletal and heart muscles in an autosomal recessive inheritance pattern. RESULTS: Two missense variants of TTN gene (NM_001267550.2), namely c.61280A>C (p. Gln20427Pro) and c.54970G>A (p. Gly18324Ser), were detected and segregations were confirmed by polymerase chain reaction-based Sanger sequencing. CONCLUSIONS: The compound heterozygous variants, c.61280A>C, (p. Gln20427Pro) and c.54970G>A, (p. Gly18324Ser) in the TTN gene appear to be the cause of Salih myopathy and dilated cardiomyopathy in the family presented. Whole-exome sequencing is an effective molecular diagnostic tool to identify the causative genetic variants of large genes such as TTN.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Rivaroxaban in patients undergoing surgical mitral valve repair.

In patients undergoing mitral valve repair (MVre), a 3-month course of anticoagulation is currently recommended. The role of the non-vitamin K antagonist oral anticoagulants has here been scarcely studied. In the present mixed cohort study, the safety and efficacy of rivaroxaban (prospective analysis) were compared with those of warfarin (retrospective analysis) in patients undergoing MVre. Anticoagulation therapy was continued for at least 3 months, and the patients were followed for 1 year following surgery. The present study recruited 736 patients undergoing MVre with or without concomitant coronary artery bypass or surgical repair on the other valves. Concomitant valvular replacement and severe chronic kidney diseases were the most important exclusion criteria. The final analysis was conducted on 153 patients treated with rivaroxaban and 144 patients treated with warfarin. Dissimilarities in baseline characteristics necessitated propensity score matching, in which 104 patients in each group were compared. No major bleeding or cerebrovascular accident occurred during the 1-year follow-up. Clinically relevant non-major bleeding was reported in 2 patients in the rivaroxaban group and 4 patients in the warfarin group, a difference non-statistically significant before and after propensity score matching (P = 0.371 and P = 0.407, respectively). The type of anticoagulation did not predict the 1-year outcome (HR 2.165, 95% CI 0.376 to 12.460; P = 0.387). In this mixed cohort study, rivaroxaban was both safe and efficient in patients with MVre. Such preliminary results should prompt larger randomized controlled trials.