Epidemiology and clinical characteristics of COVID- 19 patients requiring critical care in a Tertiary care teaching hospital.

BACKGROUND AND AIMS: We describe the epidemiological and clinical characteristics, and 28 day outcome of critically ill COVID-19 patients admitted to a tertiary care centre in India. MATERIAL AND METHODS: We included 60 adult critically ill COVID-19 patients in this prospective observational study, admitted to the intensive care unit (ICU) after obtaining ethics committee approval and informed consent. Demographics, clinical data, and treatment outcome at 28 days were assessed. RESULTS: Demographic characteristics of the COVID-19 patients reveal that compared to the survivors, the non-survivors were significantly older [57.5 vs. 47.5 years], had more comorbid disease [Charlson's comorbidity index 4 vs. 2], higher Apache II scores [19 vs. 8.5], and had significantly higher percentage of smokers. Diabetes mellitus and hypertension were the most common comorbidities. Dyspnea, fever, and cough were the most common presenting symptoms. Total leucocyte count as well as blood lactate level were significantly higher in non-survivors. Around 47% patients had severe ARDS, and 60% patients required invasive mechanical ventilation. 28 day ICU mortality was 50%, with a mortality of 75% in patients receiving invasive mechanical ventilation. Mortality was higher in males than females (57% vs. 33%). Acute kidney injury and septic shock were the most common non-pulmonary complications during ICU stay. Incidence of liver dysfunction, septic shock, and vasopressor use was significantly higher in the non-survivors. CONCLUSION: This study demonstrates a high 28 day mortality in severe COVID-19 patients. Further well designed prospective studies with larger sample size are needed to identify the risk factors associated with poor outcome in such patients.

Reconstructing the demographic history of the Himalayan and adjoining populations.

The rugged topography of the Himalayan region has hindered large-scale human migrations, population admixture and assimilation. Such complexity in geographical structure might have facilitated the existence of several small isolated communities in this region. We have genotyped about 850,000 autosomal markers among 35 individuals belonging to the four major populations inhabiting the Himalaya and adjoining regions. In addition, we have genotyped 794 individuals belonging to 16 ethnic groups from the same region, for uniparental (mitochondrial and Y chromosomal DNA) markers. Our results in the light of various statistical analyses suggest a closer link of the Himalayan and adjoining populations to East Asia than their immediate geographical neighbours in South Asia. Allele frequency-based analyses likely support the existence of a specific ancestry component in the Himalayan and adjoining populations. The admixture time estimate suggests a recent westward migration of populations living to the East of the Himalaya. Furthermore, the uniparental marker analysis among the Himalayan and adjoining populations reveal the presence of East, Southeast and South Asian genetic signatures. Interestingly, we observed an antagonistic association of Y chromosomal haplogroups O3 and D clines with the longitudinal distance. Thus, we summarise that studying the Himalayan and adjoining populations is essential for a comprehensive reconstruction of the human evolutionary and ethnolinguistic history of eastern Eurasia.

A Complete Absence of Missense Mutation in Myosin Regulatory and Essential Light Chain Genes of South Indian Hypertrophic and Dilated Cardiomyopathies.

BACKGROUND: Myosin is a hexameric contractile protein composed of 2 heavy chains associated with 4 light chains of 2 distinct classes - 2 regulatory light chains (MYL2) and 2 essential light chains (MYL3). The myosin light chains stabilize the long alpha helical neck of the myosin head and regulate the myosin ATPase activities. OBJECTIVES: Mutations in MYL2 and MYL3 are reported to be associated with cardiomyopathies. However, there is no study available on these genes in Indian cardiomyopathies, and therefore we planned to study them. METHOD: For the first time we sequenced MYL2 and MYL3 genes in a total of 248 clinically well-characterized cardiomyopathies consisting of 101 hypertrophic and 147 dilated cases along with 207 healthy controls from south India. RESULTS: Our study revealed a total of 10 variations - 7 in MYL2 and 3 in MYL3, of which 3 are novel variations observed exclusively in cases. However, the 15 causative missense mutations previously reported are totally absent in our study, which showed that the sequences of MYL2 and MYL3 are highly conserved in Indian cases/controls. CONCLUSIONS: MYL2 and MYL3 mutations are rare and the least cause of cardiomyopathies in Indians.

Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies.

The most frequent known causes of primary cardiomyopathies are mutations in the genes encoding sarcomeric proteins. Among those are 30 single-residue mutations in TPM1, the gene encoding α-tropomyosin. We examined seven mutant tropomyosins, E62Q, D84N, I172T, L185R, S215L, D230N, and M281T, that were chosen based on their clinical severity and locations along the molecule. The goal of our study was to determine how the biochemical characteristics of each of these mutant proteins are altered, which in turn could provide a structural rationale for treatment of the cardiomyopathies they produce. Measurements of Ca(2+) sensitivity of human ß-cardiac myosin ATPase activity are consistent with the hypothesis that hypertrophic cardiomyopathies are hypersensitive to Ca(2+) activation, and dilated cardiomyopathies are hyposensitive. We also report correlations between ATPase activity at maximum Ca(2+) concentrations and conformational changes in TnC measured using a fluorescent probe, which provide evidence that different substitutions perturb the structure of the regulatory complex in different ways. Moreover, we observed changes in protein stability and protein-protein interactions in these mutants. Our results suggest multiple mechanistic pathways to hypertrophic and dilated cardiomyopathies. Finally, we examined a computationally designed mutant, E181K, that is hypersensitive, confirming predictions derived from in silico structural analysis.

Indian Siddis: African descendants with Indian admixture.

The Siddis (Afro-Indians) are a tribal population whose members live in coastal Karnataka, Gujarat, and in some parts of Andhra Pradesh. Historical records indicate that the Portuguese brought the Siddis to India from Africa about 300-500 years ago; however, there is little information about their more precise ancestral origins. Here, we perform a genome-wide survey to understand the population history of the Siddis. Using hundreds of thousands of autosomal markers, we show that they have inherited ancestry from Africans, Indians, and possibly Europeans (Portuguese). Additionally, analyses of the uniparental (Y-chromosomal and mitochondrial DNA) markers indicate that the Siddis trace their ancestry to Bantu speakers from sub-Saharan Africa. We estimate that the admixture between the African ancestors of the Siddis and neighboring South Asian groups probably occurred in the past eight generations (∼200 years ago), consistent with historical records.

Examining recombinant human TSH primed ¹³¹I therapy protocol in patients with metastatic differentiated thyroid carcinoma: comparison with the traditional thyroid hormone withdrawal protocol.

PURPOSE: Recombinant human thyroid-stimulating hormone (rhTSH)-based protocol is a promising recent development in the management of differentiated thyroid carcinoma (DTC). The objectives of this prospective study were: (1) to assess the feasibility and efficacy of the rhTSH primed (131)I therapy protocol in patients with DTC with distant metastatic disease, (2) to perform lesional dosimetry in this group of patients compared to the traditional protocol, (3) to document the practical advantages (patient symptoms and hospital stay) of the rhTSH protocol compared to the traditional thyroid hormone withdrawal protocol, (4) to document and record any adverse effect of this strategy, (5) to compare the renal function parameters, and (6) to compare the serum TSH values achieved in either of the protocols in this group of patients. METHODS: The study included 37 patients with metastatic DTC having lung or skeletal metastases or both. A comparison of lesional radiation absorbed dose, hospital stay, renal function tests, and symptom profile was undertaken between the traditional thyroid hormone withdrawal protocol and rhTSH-based therapy protocol. Dosimetric calculations of metastatic lesions were performed using lesion uptake and survey meter readings for calculation of effective half-life. Non-contrast-enhanced CT was used for assessment of tumor volume. Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) QOL forms. A comparison of pretreatment withdrawal thyroglobulin (TG) was done with the withdrawal TG level 3 months after treatment. RESULTS: The mean effective half-life of (131)I in metastatic lesions was less during the rhTSH protocol (29.49 h) compared to the thyroid hormone withdrawal protocol (35.48 h), but the difference was not statistically significant (p = 0.056). The mean 24-h % uptake of the lesions during the traditional protocol (4.84 %) was slightly higher than the 24-h % uptake during the rhTSH protocol (3.56 %), but the difference was not found to be statistically significant (p = 0.301). The mean tumor radiation absorbed dose per mCi was less during the rhTSH protocol (6.04 rad/mCi) than during the thyroid hormone withdrawal protocol (8.68 rad/mCi), and the difference was statistically significant (p = 0.049), though visual analysis of the rhTSH posttherapy scans showed avid concentration of (131)I in the metastatic sites and revealed more lesions in 30 % of the patients compared to the traditional large dose scan and equal number of lesions in 65 % of the patients. Visual analysis of the traditional large dose scan, rhTSH pretreatment scan, and rhTSH posttherapy scans showed that the traditional large dose scan is better compared to the rhTSH 1 mCi scan as it showed more lesions in 19 of 37 patients (51.35 %). rhTSH posttherapy scans were better compared to the traditional large dose scans and rhTSH pretreatment scans. More lesions were seen on rhTSH posttherapy scans in 11 of 37 patients (29.7 %) compared to the traditional large dose scans and in 24 of 37 (64.86 %) patients compared to the rhTSH 1 mCi scans. Our findings demonstrate that the rhTSH primed pretreatment scan undertaken at 24 h after diagnostic dose is suboptimal to evaluate whether a metastatic lesion concentrates (131)I. The majority of these lesions demonstrated radioiodine accumulation in the posttreatment scan. Quality of life as assessed using EORTC QOL-3 forms clearly showed that rhTSH improved the quality of life of patients compared to the thyroid hormone withdrawal protocol. Functional scale and global health status were significantly better in the rhTSH protocol compared to the thyroid hormone withdrawal protocol (p < 0.001). The mean symptom scale score was significantly higher in the thyroid hormone withdrawal protocol (45.25) compared to the rhTSH protocol (13.59) (p < 0.001). Of the 20 patients, 4 (20 %) had more than 25 % increase in the TG value on follow-up. The median hospital stay of patients receiving (131)I therapy with the rhTSH protocol was shorter (2 days, range 2-8 days) compared to the thyroid hormone withdrawal protocol (3 days, range 1-8 days) and the difference was found to be statistically significant (p = 0.007). The mean serum creatinine level was significantly lower in the rhTSH protocol (0.826 mg/dl) than the thyroid hormone withdrawal protocol (0.95 mg/dl) (p = 0.013), though the mean blood urea level of patients during the rhTSH therapy protocol was slightly higher (22.81 mg/dl) than during the thyroid hormone withdrawal protocol (21.91 mg/dl) without statistical significance (p = 0.55). The mean serum TSH on day 2 of the rhTSH protocol was 140.99 µIU/ml (range 71-176 µIU/ml) compared to 72.62 µIU/ml (range 2.05-154 µIU/ml) in the traditional protocol after around 4-6 weeks of thyroid hormone withdrawal (p < 0.05). CONCLUSION: Overall, the rhTSH primed (131)I therapy protocol was found to be feasible and a good alternative to the thyroid hormone withdrawal protocol in patients with metastatic DTC. The lesional dosimetry findings need to be further examined in subsequent studies. The rhTSH primed pretreatment scan at 24 h after diagnostic dose is suboptimal to determine whether a metastatic lesion concentrates (131)I and the posttreatment scan is important for the correct impression.

Outcomes of graft angiography with distal radial access: a retrospective cohort study.

Background: This retrospective cohort study aimed to compare the outcomes of graft angiography using these two approaches. Methods: Medical records and angiographic data of adult patients who underwent graft angiography between January 2020 and December 2022 were analyzed. Results: The study included 452 patients in the distal radial access (DRA) group and 960 patients in the femoral access group. Angiographic characteristics showed a higher prevalence of triple vessel disease in the femoral access group (29.8% vs. 20.8%; p = 0.012). The DRA group had a procedural success rate of 93.0%, while the femoral access group had a higher success rate of 95.8%. The odds ratio was 0.66 (95% CI: 0.46-0.94), indicating lower odds of procedural success in the DRA group. Conclusion: Our study suggests that both DRA and femoral access are effective and safe approaches for graft angiography after coronary artery bypass surgery.

This study compared graft angiography outcomes using wrist (distal radial) and groin (femoral) access in patients after coronary artery bypass surgery. Analyzing data from January 2020 to December 2022, 452 patients used wrist access, and 960 used groin access, with similar age and heart function across groups. Femoral access had more cases of triple vessel disease (29.8% vs. 20.8%) and a higher success rate (95.8% vs. 93.0%), with wrist access showing lower odds of procedural success. Despite this, both methods proved to be effective and safe.

Electrocardiographic changes in pneumothorax: an updated review.

ECG changes in pneumothorax have gained recognition as important indicators of cardiopulmonary interactions. This narrative review examines the existing literature to provide insights into the various ECG abnormalities observed in patients with pneumothorax, their underlying mechanisms, and clinical implications. The review highlights the commonly reported changes, including alterations in the electrical axis, ST segment deviations, T-wave abnormalities, and arrhythmias. The rightward shift of the electrical axis is attributed to cardiac displacement caused by increased intrathoracic pressure. ST segment deviations may reflect the influence of altered intrathoracic pressure on myocardial oxygen supply and demand. T-wave abnormalities may result from altered myocardial repolarization and hypoxemia. Arrhythmias, although varying in incidence and type, have been associated with pneumothorax. The clinical implications of these ECG changes are discussed, emphasizing their role in diagnosis, risk stratification, treatment optimization, and prognostication. Additionally, future research directions are outlined, including prospective studies, mechanistic investigations, and the integration of artificial intelligence. Enhancing our understanding of ECG changes in pneumothorax can lead to improved patient care, better management strategies, and the development of evidence-based guidelines. The objective of this review is to demonstrate the presence of various ECG abnormalities in patients with pneumothorax.

Clinicopathological profile of post-COVID-19 mucormycosis cases: A report from a tertiary care center.

Introduction: Mucormycosis is a fatal fungal infection, which is rare but commonly affects immunocompromised patients. Coronavirus disease 2019 (COVID-19) patients who were immunocompromised, due to comorbid conditions, such as hematological malignancy and diabetes mellitus (DM), and patients on immunosuppressive therapy such as steroid therapy were the important host for mucormycosis infection. Aim: This study aimed to study the clinicopathological correlation of mucormycosis in post-COVID-19 patients. Material and Methods: The study was a retrospective study conducted in the Department of Pathology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India, over four months from April 2021 to July 2021, and clinically diagnosed mucormycosis cases were included in this study. Clinical details, histology slides, and blocks were reviewed, and the data were analyzed. Three- to four-micrometer sections were taken from the blocks and stained with hematoxylin and eosin, and two more slides were made for each case for periodic acid-Schiff (PAS) and Grocott methenamine silver (GMS) staining. Result: In this study, the maximum cases were above the fifth decade of life. Males were more commonly affected than females with a male-to-female ratio of 2.09:1. Of the total of 65 cases, 46 (70.77%) cases were positive for mucormycosis and 19 (29.23%) cases were negative on histopathological examination and special stain PAS and GMS. A significant correlation was found between mucormycosis-positive cases on steroid therapy and oxygen supply during the treatment for COVID-19 with P- values of 0.001 and 0.027, respectively. Conclusion: For COVID-19 patients with altered glycemic control, receiving steroid therapy and oxygen supply poses a significant threat to the development of mucormycosis.

Cardiovascular Manifestations of Human Monkeypox Virus: An Updated Review.

Cardiovascular manifestations in human monkeypox virus (MPXV) infection has gained increasing recognition as significant complications with both social and clinical implications. Myocarditis, viral pericarditis, heart failure, and arrhythmias can occur, leading to adverse effects on individuals' health and quality of life. Understanding the detailed pathophysiology of these cardiovascular manifestations is essential for improved diagnosis and management. The social implications of these cardiovascular complications are multifaceted, ranging from public health concerns and the impact on individuals' quality of life to psychological distress and social stigma. Clinically, diagnosing, and managing these complications present challenges, requiring a multidisciplinary approach and specialized care. The burden on healthcare resources necessitates preparedness and resource allocation to effectively address these complications. We delve into the pathophysiological mechanisms involved, including viral-induced cardiac damage, immune response, and inflammatory processes. Additionally, we explore the types of cardiovascular manifestations and their clinical presentations. Addressing cardiovascular manifestations' social and clinical implications in MPXV infection requires a comprehensive approach involving healthcare professionals, public health authorities, and communities. By prioritizing research, enhancing diagnosis and treatment strategies, and promoting preventive measures, we can mitigate the impact of these complications, improve patient care, and protect public health.

Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies.

Background: Mutations in Myosin Binding Protein C (MYBPC3) are one of the most frequent causes of cardiomyopathies in the world, but not much data are available in India. Methods: We carried out targeted direct sequencing of MYBPC3 in 115 hypertrophic (HCM) and 127 dilated (DCM) cardiomyopathies against 197 ethnically matched healthy controls from India. Results: We detected 34 single nucleotide variations in MYBPC3, of which 19 were novel. We found a splice site mutation [(IVS6+2T) T>G] and 16 missense mutations in Indian cardiomyopathies [5 in HCM; E258K, T262S, H287L, R408M, V483A: 4 in DCM; T146N, V321L, A392T, E393K and 7 in both HCM and DCM; L104M, V158M, S236G, R272C, T290A, G522E, A626V], but those were absent in 197 normal healthy controls. Interestingly, we found 7 out of 16 missense mutations (V158M, E258K, R272C, A392T, V483A, G522E, and A626V) in MYBPC3 were altering the evolutionarily conserved native amino acids, accounted for 8.7% and 6.3% in HCM and DCM, respectively. The bioinformatic tools predicted that those 7 missense mutations were pathogenic. Moreover, the co-segregation of those 7 mutations in families further confirmed their pathogenicity. Remarkably, we also identified compound mutations within the MYBPC3 gene of 6 cardiomyopathy patients (5%) with more severe disease phenotype; of which, 3 were HCM (2.6%) [(1. K244K + E258K + (IVS6+2T) T>G); (2. L104M + G522E + A626V); (3. P186P + G522E + A626V]; and 3 were DCM (2.4%) [(1. 5'UTR + A392T; 2. V158M+G522E; and 3.V158M + T262T + A626V]. Conclusion: The present comprehensive study on MYBPC3 has revealed both single and compound mutations in MYBPC3 and their association with disease in Indian Population with Cardiomyopathies. Our findings may perhaps help in initiating diagnostic strategies and eventually recognizing the targets for therapeutic interventions.

Efficacy and Safety of Pitavastatin in Patients with Impaired Glucose Tolerance: An Updated Review.

This review provides an updated overview of the efficacy and safety of pitavastatin in patients with impaired glucose tolerance (IGT). IGT is a prediabetic state characterized by elevated blood glucose levels that do not meet the criteria for diabetes. The review explores the potential benefits of pitavastatin in reducing cardiovascular risk and improving lipid profiles in individuals with IGT. It also examines the glycemic effects of pitavastatin, including its impact on fasting blood glucose levels, insulin sensitivity, and beta-cell function. The review highlights the need for individualized treatment approaches, taking into account the patient's overall cardiovascular risk profile and glycemic control needs. While pitavastatin has shown modest improvements in glycemic control, it is not a substitute for lifestyle modifications or standard antidiabetic medications. Future directions for research include long-term follow-up studies, mechanistic investigations, and comparative analyses to further understand the glycemic effects of pitavastatin in IGT. Overall, this narrative review provides valuable insights for healthcare professionals involved in the management of individuals with IGT, emphasizing the importance of a comprehensive approach to reduce cardiovascular risk and optimize glycemic control.

High prevalence of Arginine to Glutamine substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians.

BACKGROUND: Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study. METHODS: We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India. RESULTS: Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing. CONCLUSION: Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.

Schwannoma of the Nasal Septum: A Rare Clinicopathological Case Report in an 18-Year-Old Female.

Schwannoma, a benign tumor, arise from schwann cells of myelin sheath; occur anywhere in the body but commonly occur on flexor aspect of extremities. Nasal septum being the rarer site. We report a case of nasal septum schwannoma in an 18-year-old female presented with intermittent epistaxis and progressively increasing nasal obstruction for 2-year duration. The differential diagnosis of juvenile angiofibroma, pyogenic granuloma, and pleomorphic adenoma was made and complete surgical excision was done. Histopathological examination revealed ciliated stratified columnar epithelium, underlying tumor area with two distinct patterns, mainly hypercellular and few hypocellular areas. The cells have spindle shaped pointed basophilic nuclei with abundant eosinophilic cytoplasm. Overall feature was suggestive of nasal septum schwannoma. For confirmation, immunohistochemical staining with S-100 was done and tumor was found positive. Herein, we report the clinicopathological features of nasal septum schwannoma in an 18-year-old female.

Evaluation of intubating conditions with rocuronium 0.6 mg/kg using train of four stimulation in elective surgery.

Background and Aims: Train of four (TOF) stimulation has been recommended to be used with neuromuscular blocking agents. The incidence of excellent intubating conditions with rocuronium, when used with TOF, is lacking. This study aimed to estimate the proportion of patients having excellent intubating conditions with rocuronium 0.6 mg/kg using TOF at adductor pollicis longus at T1 and T0, time to achieve T1 or T0 and incidence of sore throat, immediate and 24 hours post-extubation. Methods: This prospective non-randomised study was carried out in 250 patients of either sex, of American Society of Anesthesiologists physical status I-II, undergoing surgery under general anaesthesia with tracheal intubation after rocuronium 0.6 mg/kg monitored by TOF. Patients were divided among T1 and T0 groups. Intubating conditions were assessed using the Copenhagen scale. Results were analysed using the Chi-square test and the Student's t-test. A P value of <0.05 was considered significant. Results: Intubating conditions were excellent in 84% patients (87.9% in group T0 and 80.1% in group T1, P = 0.216). The mean onset time was 142.98 ± 27.04 seconds in group T0 and 122.38 ± 3 0.76 seconds in group T1 (p < 0.01). The incidence of immediate (p = 0.02) and late (p = 0.01) sore throat was higher in the T1 group. Conclusion: The proportion of patients having excellent intubating conditions with rocuronium 0.6 mg/kg was higher at T0 but not statistically significant. It takes 20 seconds longer to achieve T0 as compared to T1 with a lesser incidence of immediate and late sore throat.

Novel Mutations in ß-MYH7 Gene in Indian Patients With Dilated Cardiomyopathy.

BACKGROUND: Heart failure is a hallmark of severe hypertrophic cardiomyopathy and dilated cardiomyopathy (DCM). Several mutations in the ß-MYH7 gene lead to hypertrophic cardiomyopathy. Recently, causative mutations in the ß-MYH7 gene have also been detected in DCM from different populations. METHODS: Here, we sequenced the ß-MYH7 gene in 137 Indian DCM patients and 167 ethnically matched healthy controls to detect the frequency of mutations and their association. RESULTS: Our study revealed 27 variations, of which 7 mutations (8.0%) were detected exclusively in Indian DCM patients for the first time. These included 4 missense mutations-Arg723His, Phe510Leu, His358Leu, and Ser384Tyr (2.9%); a frameshift mutation-Asn676_T-del (1.5%); and 2 splice-site mutations (IVS17+2T) T>G and (IVS19-1G) G>A (3.6%). Remarkably, all 4 missense mutations altered evolutionarily conserved amino acids. All 4 missense mutations were predicted to be pathogenic by 2 bioinformatics tools-polymorphism phenotyping v2 (PolyPhen-2) and sorting intolerant from tolerant (SIFT). In addition, the 4 homology models of ß-MYH7-p.Leu358, p.Tyr384, p.Leu510, and p.His723-displayed root-mean-square deviations of ∼2.55 Å, ∼1.24 Å, ∼3.36 Å, and ∼3.86 Å, respectively. CONCLUSIONS: In the present study, we detected numerous novel, unique, and rare mutations in the ß-MYH7 gene exclusively in Indian DCM patients (8.0%). Here, we demonstrated how each mutant (missense) uniquely disrupts a critical network of non-bonding interactions at the mutation site (molecular level) and may contribute to development of dilated cardiomyopathy (DCM). Therefore, our findings may provide insight into the understanding of the molecular bases of disease and into diagnosis along with promoting novel therapeutic strategies (through personalized medicine).

INTRODUCTION: L'insuffisance cardiaque est une caractéristique de la cardiomyopathie hypertrophique grave et de la cardiomyopathie dilatée (CMD). Plusieurs mutations dans le gène ß-MYH7 conduisent à la cardiomyopathie hypertrophique. Récemment, les mutations causales dans le gène ß-MYH7 ont également été détectées au sein de différentes populations atteintes de CMD. MÉTHODES: Ici, nous avons séquencé le gène ß-MYH7 de 137 patients indiens atteints de CMD et de 167 témoins sains appariés selon l'origine ethnique pour détecter la fréquence des mutations et leur association. RÉSULTATS: L'étude nous a permis de révéler 27 variations, dont sept mutations (8,0 %) étaient exclusivement détectées chez les patients indiens atteints de CMD pour la première fois. Parmi ces mutations, nous avons observé quatre mutations faux-sens­Arg723His, Phe510Leu, His358Leu et Ser384Tyr (2,9 %), une mutation par déphasage­Asn676_T-del (1,5 %) et deux mutations des sites d'épissage (IVS17+2T) T>G et (IVS19-1G) G>A (3,6 %). Étonnamment, les quatre mutations faux-sens changeaient les acides aminés évolutivement conservés. Selon deux outils bioinformatiques­PolyPhen-2 (de l'anglais, polymorphism phenotyping v2) et SIFT (de l'anglais, sorting intolerant from tolerant), les quatre mutations faux-sens devaient être pathogènes. De plus, les quatre modélisations de ß-MYH7 par homologie­p.Leu358, p.Tyr384, p.Leu510 et p.His723­affichaient de façon respective des écarts quadratiques moyens de ∼2,55 Å, ∼1,24 Å, ∼3,36 Å et ∼3,86 Å. CONCLUSIONS: Dans la présente étude, nous avons détecté de nombreuses nouvelles mutations, uniques et rares, dans le gène ß-MYH7, exclusivement chez les patients indiens atteints de CMD (8,0 %). Ici, nous avons démontré comment chaque mutant (faux-sens) perturbe de manière unique un réseau essentiel d'interactions non liantes au site de mutation (moléculaire) et peut contribuer à la survenue de la CMD. Par conséquent, les conclusions de notre étude peuvent donner un aperçu des bases moléculaires de la maladie et du diagnostic tout en favorisant la promotion de nouvelles stratégies thérapeutiques (par la médecine personnalisée).