Pharmacogenomic biomarkers in coronary artery disease: a narrative review.

Coronary artery disease (CAD) has a high mortality rate. Despite various therapeutic targets, non-responsiveness to drugs remains a prevalent issue. Pharmacogenomics assesses the way an individual's genetic attributes affect their likely response to drug therapy. Single-nucleotide polymorphisms play a crucial role in determining these outcomes. This review offers an overview of single-nucleotide polymorphisms investigated in clinical studies and their associations with drug response/nonresponse in the treatment of CAD. A total of 104 studies of whole sets of chromosomes and several genes were explored. A total of 161 polymorphisms exhibited associations with drug response/nonresponse in CAD across diverse ethnic populations. This pool can serve as a pharmacogenomic biomarker for predicting response to drug therapy in patients with CAD.

Posttransplant lymphoproliferative disorder in a heart transplant recipient: a case report.

Malignancy in heart transplant recipients is a grave complication. Post-transplant lymphoproliferative disorder (PTLD) is the second most common tumour in adults and commonest in children. The incidence varies with the transplanted organ from 1 to 2% following kidney transplantation to as high as 10% following thoracic organ transplantation due to different immunosuppression intensity. PTLD include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissue to frank malignancy with aggressive behaviour (lymphoma). Epstein-Barr virus (EBV) infection and prolonged immunosuppressant therapy are implicated in the pathogenesis of PTLD. The incidence of PTLD varies from 2.6% at 1 year to 28% at 10 years post-transplant. Seronegativity for EBV in recipients with seropositive donors increases the risk of PTLD in recipients. The majority of early-onset PTLDs (85%) are of B-cell origin and associated with EBV. Timely and accurate diagnosis with histological examination of lymphoid tissue is essential for early intervention. Reduction of immunosuppressive therapy (IST) and rituximab usually are effective in remission of PTLD. In resistant cases, chemotherapy is given with or without rituximab. Adoptive T-cell transfer represents a promising therapeutic approach. Early PTLD respond well to lowering immunosuppression and has a favourable prognosis compared to late PTLD. Five-year survival is 30% for high-grade lymphomas. The prognosis of EBV-negative lymphomas is worse. One out of 40 heart transplant recipients followed up in our centre developed PTLD. He was treated to remission and we describe this case here.

Impact of COVID-19 on heart failure hospitalization and outcome in India - A cardiological society of India study (CSI-HF in COVID 19 times study - "The COVID C-HF study").

OBJECTIVES: The presentation and outcomes of acute decompensated heart failure (ADHF) during COVID times (June 2020 to Dec 2020) were compared with the historical control during the same period in 2019. METHODS: Data of 4806 consecutive patients of acute HF admitted in 22 centres in the country were collected during this period. The admission patterns, aetiology, outcomes, prescription of guideline-directed medical therapy (GDMT) and interventions were analysed in this retrospective study. RESULTS: Admissions for acute heart failure during the pandemic period in 2020 decreased by 20% compared to the corresponding six-month period in 2019, with numbers dropping from 2675 to 2131. However, no difference in the epidemiology was seen. The mean age of presentation in 2019 was 61.75 (±13.7) years, and 59.97 (±14.6) years in 2020. There was a significant decrease in the mean age of presentation (p = 0.001). Also. the proportion of male patients decreased significantly from 68.67% to 65.84% (p = 0.037). The in-hospital mortality for acute heart failure did not differ significantly between 2019 and 2020 (4.19% and 4.,97%) respectively (p = 0.19). The proportion of patients with HFrEF did not change in 2020 compared to 2019 (76.82% vs 75.74%, respectively). The average duration of hospital stay was 6.5 days. CONCLUSION: The outcomes of ADHF patients admitted during the Covid pandemic did not differ significantly. The length of hospital stay remained the same. The study highlighted the sub-optimal use of GDMT, though slightly improving over the last few years.

A Comprehensive Insight and Mechanistic Understanding of the Lipidomic Alterations Associated With DCM.

Dilated cardiomyopathy (DCM) is one of the major causes of heart failure characterized by the enlargement of the left ventricular cavity and contractile dysfunction of the myocardium. Lipids are the major sources of energy for the myocardium. Impairment of lipid homeostasis has a potential role in the pathogenesis of DCM. In this review, we have summarized the role of different lipids in the progression of DCM that can be considered as potential biomarkers. Further, we have also explained the mechanistic pathways followed by the lipid molecules in disease progression along with the cardioprotective role of certain lipids. As the global epidemiological status of DCM is alarming, it is high time to define some disease-specific biomarkers with greater prognostic value. We are proposing an adaptation of a system lipidomics-based approach to profile DCM patients in order to achieve a better diagnosis and prognosis of the disease.

A Domain-Shift Invariant CNN Framework for Cardiac MRI Segmentation Across Unseen Domains.

The emergence of various deep learning approaches in diagnostic medical image segmentation has made machines capable of accomplishing human-level accuracy. However, the generalizability of these architectures across patients from different countries, Magnetic Resonance Imaging (MRI) scans from distinct vendors, and varying imaging conditions remains questionable. In this work, we propose a translatable deep learning framework for diagnostic segmentation of cine MRI scans. This study aims to render the available SOTA (state-of-the-art) architectures domain-shift invariant by utilizing the heterogeneity of multi-sequence cardiac MRI. To develop and test our approach, we curated a diverse group of public datasets and a dataset obtained from private source. We evaluated 3 SOTA CNN (Convolution neural network) architectures i.e., U-Net, Attention-U-Net, and Attention-Res-U-Net. These architectures were first trained on a combination of three different cardiac MRI sequences. Next, we examined the M&M (multi-center & mutli-vendor) challenge dataset to investigate the effect of different training sets on translatability. The U-Net architecture, trained on the multi-sequence dataset, proved to be the most generalizable across multiple datasets during validation on unseen domains. This model attained mean dice scores of 0.81, 0.85, and 0.83 for myocardial wall segmentation after testing on unseen MyoPS (Myocardial Pathology Segmentation) 2020 dataset, AIIMS (All India Institute of Medical Sciences) dataset and M&M dataset, respectively. Our framework achieved Pearson's correlation values of 0.98, 0.99, and 0.95 between the observed and predicted parameters of end diastole volume, end systole volume, and ejection fraction, respectively, on the unseen Indian population dataset.

NOTTO Guidelines for Vaccine Induced Thrombotic Thrombocytopenia in Organ Donation and Transplantation.

From the context of organ donation, COVID-19 vaccine-induced thrombotic thrombocytopenia (VITT) is important as there is an ethical dilemma in utilizing versus discarding organs from potential donors succumbing to VITT. This consensus statement is an attempt by the National Organ and Tissue Transplant Organization (NOTTO) apex technical committees India to formulate the guidelines for deceased organ donation and transplantation in relation to VITT to help in appropriate decision making. VITT is a rare entity, but a meticulous approach should be taken by the Organ Procurement Organization's (OPO) team in screening such cases. All such cases must be strictly notified to the national authorities like NOTTO, as a resource for data collection and ensuring compliance withprotocols in the management of adverse events following immunization. Organs from any patient who developed thrombotic events up to 4 weeks after adenoviral vector-based vaccination should be linked to VITT and investigated appropriately. The viability of the organs must be thoroughly checked by the OPO, and the final decision in relation to organ use should be decided by the expert committee of the OPO team consisting of a virologist, a hematologist, and atreating team. Considering the organ shortage, in case of suspected/confirmed VITT, both clinicians and patients should consider the risk-benefit equationbased on available experience, and an appropriate written informed consent of potential recipients and family members should be obtained before transplantation of organs from suspected or proven VITT donors.

Imaging Acute Myocarditis with 68Ga-DOTANOC PET/CT.

Somatostatin receptor (SSTR) imaging is a useful method in the diagnosis of acute myocarditis. We present a case of a 54-year-old male with a clinical diagnosis of acute myocarditis in whom, 68Ga-DOTANOC positron emission tomography/computed tomography PET/CT showed diffuse left ventricular myocardial uptake. SSTR imaging can act as a surrogate marker of active inflammation. SSTR imaging is useful in deciding site of biopsy, assessing response to therapy and for prognostication.

Lung water estimation on cardiac magnetic resonance imaging for predicting adverse cardiovascular outcomes in patients with heart failure.

OBJECTIVES: Pulmonary congestion is a central feature of heart failure (HF) seen in acute decompensated state as well as in chronic stable disease. The present study sought to determine whether simplified cardiac magnetic resonance imaging (CMR)-derived lung water density (LWD) measurement has prognostic relevance in predicting adverse cardiovascular outcomes in patients with HF and left ventricular ejection fraction (LVEF)<50%. METHODS: Eighty consecutive patients referred for CMR with HF and LVEF<50% along with 22 healthy age- and sex-matched controls were prospectively recruited. LWD was the lung-to-liver signal intensity ratio multiplied by 70% (estimated hepatic water density). The primary endpoint was composite of all-cause mortality or HF-related hospitalization within 6 months from CMR. RESULTS: The mean LWD was significantly higher in HF patients compared to healthy controls (19.78 ± 6.1 vs 13.6 ± 2.3; p < 0.001). The mean LWD was significantly different among patients with NYHA class I/II and NYHA class III/IV (17.88 ± 4.8 vs 21.77 ± 1.08; p = 0.004). At 6 months, the primary endpoint was reached in 12 (15%) patients. Patients with "wet lungs" (LWD > 18.1%) had higher incidence of adverse cardiovascular outcomes compared to patients with "dry lungs". LWD was an independent predictor of adverse cardiovascular outcomes in multivariable analysis. At the optimal cut-off of LWD > 23.38%, the sensitivity and specificity were 91.67 and 91.18%, respectively, to predict adverse cardiovascular outcomes. CONCLUSION: LWD on CMR is independently associated with increased risk of mortality and HF-related hospitalization in HF patients with LVEF<50%. ADVANCES IN KNOWLEDGE: Non-invasive quantitative estimation of LWD on CMR can improve risk stratification and guide management in HF patients.

Utility of 68Ga-DOTANOC PET/CT in therapeutic monitoring of cardiac sarcoidosis.

Cardiac sarcoidosis usually occurs as a manifestation of systemic sarcoidosis, even though isolated cardiac involvement is not uncommon. The usefulness of 68Ga-DOTANOC PET/CT in the diagnosis of CS has been previously documented in the literature. We present a case of cardiac sarcoidosis, where 68Ga-DOTANOC PET/CT was used for monitoring response to therapy.

Imaging of cardiac sympathetic dysfunction with 18F-FDOPA PET/CT in patients with heart failure: a pilot study.

BACKGROUND: Routine use of cardiac sympathetic imaging in HF has been limited by the lower availability/sensitivity of radiotracers. This study was aimed to assess the feasibility of 18F-FDOPA (commonly available PET-radiotracer) in assessment of cardiac autonomic dysfunction. METHODS: Twenty-four controls (46.5 ± 11.1 years, 16men) and 24 patients (43.5 ± 11.0 years, 18men) with diagnosed HF (Framingham-Criteria) underwent cardiac-PET/CT. Region(s) Of Interest were drawn over entire left ventricular myocardium (LV), individual walls, and mediastinum (M). Coefficient of Variation (CV) was calculated from individual wall counts. RESULTS: HF patients had significantly lower myocardial 18F-FDOPA uptake (P < .001, independent t test) than controls [32.4% ± 9.5% global reduction; highest in apex (39.9% ± 7.0%)]. A cut-off of LV/M ≤ 1.68 could differentiate patients from controls with sensitivity and specificity of 100% and 95.8%, respectively. LV/M correlated positively with EF (Pearson coefficient = 0.460, P .031). During follow-up, 3 patients were lost to follow-up, 4 died (survival-20.5 ± 4 months), 2 worsened, and 15 remained stable/showed mild improvement. Patients who worsened/died during follow-up had higher CV than those with stable/improving symptoms [0.16 ± 0.05 vs 0.11 ± 0.05, P value .069 (independent t test); Cox regression P = .084]. CONCLUSION: Myocardial 18F-FDOPA uptake in patients with HF is significantly reduced. Higher reduction is seen in those with lower EF. CV, a maker of regional heterogeneity, is a potential prognostic marker.

Differential effect of basal vitamin D status in monocrotaline induced pulmonary arterial hypertension in normal and vitamin D deficient rats: Possible involvement of eNOS/TGF-ß/α-SMA signaling pathways.

Vitamin D deficiency is common and linked to poor prognosis in pulmonary arterial hypertension (PAH). We investigated the differential effect of basal vitamin D levels in monocrotaline (MCT) induced PAH in normal and vitamin D deficient (VDD) rats. Rats were fed a VDD diet and exposed to filtered fluorescent light to deplete vitamin D. Normal rats were pretreated with vitamin D 100 IU/d and treated with vitamin D 100 and 200 IU/d, while VDD rats received vitamin D 100 IU/d. Vitamin D receptor (VDR) silencing was done in human umbilical vein endothelial cells (HUVECs) using VDR siRNA. Calcitriol (50 nM/mL) was added to human pulmonary artery smooth muscle cells (HPASMCs) and HUVECs before and after the exposure to TGF-ß (10 ng/mL). Vitamin D 100 IU/d pretreatment in normal rats up-regulated the expression of eNOS and inhibited endothelial to mesenchymal transition significantly and maximally. Vitamin D 100 IU/d treatment in VDD rats was comparable to vitamin D 200 IU/d treated normal rats. These effects were significantly attenuated by L-NAME (20 mg/kg), a potent eNOS inhibitor. Exposure to TGF- ß significantly reduced the expression of eNOS and increased the mesenchymal marker expression in normal and VDR-silenced HUVECs and HPASMCs, which were averted by treatment and maximally inhibited by pretreatment with calcitriol (50 nM). To conclude, this study provided novel evidence suggesting the beneficial role of higher basal vitamin D levels, which are inversely linked with PAH severity.

Role of Cardiac MRI Including LGE, T1 and T2 Mapping in the Assessment of Cardiac Involvement in Patients of Nonspecific Aorto-arteritis: A Prospective Study.

Objective Nonspecific aorto-arteritis (NSAA) may involve the myocardium in the form of edema and fibrosis. We conducted this study to investigate role of cardiac MRI including late gadolinium enhancement (LGE), T1 and T2 mapping in the assessment of cardiac involvement in NSAA. Methods and Materials Over the period between 2016 and 2019, 36 patients with NSAA presenting with uncontrolled hypertension, left ventricular dysfunction, congestive cardiac failure, or tachyarrhythmia were included in the study. We also had 16 voluntary control patients for providing normal T1 and T2 mapping values. Results The average age of patients was 27.1 years and the majority were females. MRI is more sensitive than echocardiography in the detection of LV dysfunction and RWMA. Out of 36 patients, 10 (27.8%) had LGE. The most common pattern of midmyocardial enhancement was present in 5 out of 10 patients. Five (13.8%) patients show mid-myocardial enhancement, followed by epicardial enhancement, which was seen in four (11.11%) patients. The values of post-gad T1 mapping values were significantly lower than pre-gad T1 mapping values. At a cut-off global native T1 mapping value of 1019 milliseconds had the sensitivity of 83.3% and specificity of 81.2% in detecting an abnormal T1 map. No significant association of MRI contrast enhancement with elevated ESR and CRP levels. There was no significant relation of myocardial T2 mapping values between NSAA and control groups. Conclusion Quantitative tissue characterization in the myocardium with native T1 mapping values help in the detection of cardiac involvement in patients with NSAA. T1 mapping may provide incremental value in the assessment of myocardial involvement in NSAA in addition to LGE imaging.

Detection of cardiac allograft vasculopathy on dual source computed tomography in heart transplant recipients: comparison with invasive coronary angiography.

OBJECTIVE: We aimed to evaluate the diagnostic accuracy (DA) of dual-source CT coronary angiography (DSCTCA) against invasive coronary angiography (ICA) in assessing stenotic cardiac allograft vasculopathy (CAV) in heart transplant (HTX) recipients. METHODS: Consecutive HTX recipients(n = 38) on annual surveillance, underwent DSCTCA prior to ICA on a 192-detector 384-slice DSCT scanner. Cases were classified as no CAV (no stenosis), any CAV (any degree of stenosis) or significant CAV (>50% stenosis). RESULTS: Mean age was 33.66 ± 11.45 years (M:F = 27:11, median time from HTX-23.5 months). Prevalence of any CAV on DSCTCA and ICA was 44.7%(n = 17) and 39.5%(n = 15), respectively and that of significant CAV was 21.1%(n = 8) and 15.8%(n = 6), respectively. 557 (96.7%) segments were interpretable on DSCTCA. Mean radiation dose was 4.24 ± 2.15 mSv. At patient-level, the sensitivity, specificity, positive-predictive value, negative-predictive value (NPV), and DA of DSCTCA for detection of any CAV and significant CAV were 100%, 91.3%, 88.2%, 100%, 94.73% and 100%, 94%, 75%, 100%, 95% respectively. The same on segment-based analysis were 96%, 97.6%, 80%, 99.6%, 97.5% and 100%, 99.6%,86.7%,100%, 99.6%, respectively. There was excellent agreement between the two modalities for detection of any CAV and significant CAV [κ = 0.892 and 0.826 (patient-level), 0.859 and 0.927 (segment-level)]. CAC score correlated significantly with the presence of any CAV on both modalities. A diagnosis of rejection on biopsy did not correlate with any/significant CAV on DSCTCA or ICA. CONCLUSION: High sensitivity and NPV of DSCTCA in the evaluation of stenotic CAV suggests that it can be an accurate and non-invasive alternative to ICA for routine surveillance of HTX recipients. ADVANCES IN KNOWLEDGE: DSCTCA detects the stenotic CAV non-invasively in transplant recipients with high sensitivity, specificity and NPV when compared with catheter coronary angiography, at lower radiation doses. There is excellent agreement between CT angiography and catheter coronary angiography for detection of any CAV and significant CAV. A diagnosis of rejection on biopsy does not correlate with any/significant CAV on CT angiography or catheter angiography.

An Untargeted LC-MS based approach for identification of altered metabolites in blood plasma of rheumatic heart disease patients.

Rheumatic heart disease (RHD) is often considered as a disease of developing countries and India is the home of about 40% of RHD patients. Environment seems to play a major role in its causation. Since gene environment interactions can lead to alterations of various metabolic pathways, identification of altered metabolites can help in understanding the various pathways leading to RHD. Blood plasma samples from 51 RHD and 49 healthy controls were collected for the study. Untargeted metabolomics approach was used to identify the metabolites that are altered in RHD patients. Data showed 25 altered metabolites among RHD patients. These altered metabolites were those involved in Purine, Glutamine, Glutamate, Pyrimidine, Arginine, Proline and Linoleic metabolism. Thus, the present study illuminates metabolic alterations among RHD patients which can help in determining the potential therapeutic targets.

Diphtheritic myocarditis: An unusual and reversible cause of heart failure.

Diphtheria is a life-threatening infectious disease caused by Corynebacterium diphtheriae. Although the disease is seen infrequently in the postvaccination era, sporadic cases continue to occur. Cardiac involvement, in the form of myocarditis, is the most serious manifestation of diphtheria and is the most common cause of mortality in these patients. The features of diphtheritic myocarditis on cardiac magnetic resonance imaging (MRI) have not been reported previously. In this brief report, we describe the cardiac MRI and histopathologic features on endomyocardial biopsy of a patient with acute heart failure who was later diagnosed to be a case of diphtheritic myocarditis.

Effectiveness of enteral ivabradine for heart rate control in septic shock: A randomised controlled trial.

Persistent tachycardia in patients with septic shock predicts poor outcome. This study sought to investigate the effect of the cardiac pacemaker current inhibitor ivabradine on heart rate and cardio-circulatory function in patients with septic shock. After informed consent, 60 patients with septic shock and persistent tachycardia (heart rate >95 /minute) were prospectively randomly assigned to receive either standard therapy for septic shock (group S) or standard therapy along with enteral ivabradine (group I) for the initial 96 hours after enrolment. Primary outcome was the difference in heart rate between the two groups during the first 96 hours. Secondary outcomes included the effect of ivabradine on haemodynamic, oxygenation, myocardial function and organ function parameters, incidence of adverse events and 30-day overall survival. Heart rate was lower in group I compared to group S (median difference in area under the curve -25.6 (95% confidence intervals -31.4 to -15.9) /minute; P <0.001). Vasopressor requirements, blood lactate levels, Sequential Organ Failure Assessment scores and E/e' ratio were lower in group I compared to group S. Stroke volume index and ejection fraction were higher in group I while cardiac index and oxygen delivery parameters were maintained similar to group S. There was no difference in 30-day mortality or in the incidence of serious adverse events. Enteral ivabradine is effective in reducing heart rate, and improving haemodynamic parameters and cardiac function in patients with septic shock and persistent tachycardia, without increasing the incidence of adverse events.