Cardiac conduction disease (CCD), which causes altered electrical impulse propagation in the heart, is a life-threatening condition with high morbidity and mortality. It exhibits genetic and clinical heterogeneity with diverse pathomechanisms, but in most cases, it disrupts the synchronous activity of impulse-generating nodes and impulse-conduction underlying the normal heartbeat. In this study, we investigated a consanguineous Pakistani family comprised of four patients with CCD. We applied whole exome sequencing (WES) and co-segregation analysis, which identified a novel homozygous missense mutation (c.1531T>C;(p.Ser511Pro)) in the highly conserved kinase domain of the cardiac troponin I-interacting kinase (TNNI3K) encoding gene. The behaviors of mutant and native TNNI3K were compared by performing all-atom long-term molecular dynamics simulations, which revealed changes at the protein surface and in the hydrogen bond network. Furthermore, intra and intermolecular interaction analyses revealed that p.Ser511Pro causes structural variation in the ATP-binding pocket and the homodimer interface. These findings suggest p.Ser511Pro to be a pathogenic variant. Our study provides insights into how the variant perturbs the TNNI3K structure-function relationship, leading to a disease state. This is the first report of a recessive mutation in TNNI3K and the first mutation in this gene identified in the Pakistani population.

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IntroductionEnvironmental triggers of acute myocardial infarction (AMI) have gained mounting evidence from various geographies of the world. However, due to geographic variations in seasonal temperature and other metrological parameters, it is difficult to generalize the findings in one population to another population with different climatic conditions. Therefore, the aim of this study was to assess the relationship between meteorological parameters and the number of primary percutaneous coronary intervention (PCI) procedures for AMI at a tertiary care cardiac hospital in Karachi, Pakistan.MethodsFor this cross-sectional study, data was obtained on the number of primary PCI procedures conducted at the National Institute of Cardiovascular Diseases (NICVD) Karachi, Pakistan during 1st June 2016 to 31st May 2018. Daily meteorological data of the Karachi region for the same period was obtained from the Pakistan Meteorological Department. It consists of temperature, atmospheric pressure, and relative humidity. Based on the weather conditions of Karachi, the data was divided into two seasons; summer (April to October) and winter (November to March). Multiple linear regression analysis was performed taken the number of primary PCI performed as regressand and time trend, average temperature, temperature variation, and relative humidity as regressors.ResultsA total of 115,494 hospital admissions were recorded during the study period out of which rate of primary PCI was 10.5% (12,107). A negative relationship between average temperature and number of primary PCI was observed with standardized regression coefficients of -0.13 (p < 0.001) on the overall regression model. A similar significant negative relationship of average temperature was observed on the regression model for the cold season with standardized regression coefficients of -0.17 (p < 0.001). While no such relationship was observed for the warm season.ConclusionThe average daily temperature was found to be negatively related to the number of primary PCI. Subgroup analysis revealed that the average daily temperature had a significant negative relationship with the number of primary PCI in the cold season; however, no such impact was observed in the warm season.

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