Approaches in Managing Resistant Hypertension: A Review.

In India, around 234 million adults (one in three) suffer from hypertension (HTN). An average of 10% of these cases are likely to be resistant hypertension (RH). This load of 23 million patients is expected to expand further with revisions in diagnostic criteria. The treatment and control rates of hypertension in India average around 30% and 15%, respectively. Pharmacological management involves a stepwise approach starting with optimizing the A-C-D (angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide-like diuretics) triple-drug combination, followed by substitution with a thiazide-like diuretic and use of spironolactone as a next step (fourth drug). The subsequent steps are suggestions based on expert input and must be individualized. These include using a ß-blocker as the fifth drug and an α1-blocker or a peripheral vasodilator as a final option when target blood pressure (BP) values are not achieved. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are likely to be helpful in managing RH due to their renal and cardiovascular protection as well as mortality benefits. SGLT2i lowers BP independent of the dosage and concomitant anti-hypertensive medications. Patient education and tools to monitor BP and treatment compliance will improve outcomes with these medications. In addition to therapeutic intervention, a preventive approach for RH mandates a need to identify patients at risk and use appropriate preventive and optimal therapy to prevent uncontrolled hypertension in patients with cardiovascular disorders.

The Promise of Cilnidipine in Hypertension with Comorbidities: National Consensus Statement: National Consensus Group Comprises Cardiologists, Nephrologists, and Diabetologists from India in a National Meet at New Delhi held on 22nd May 2022.

The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.

Does epigenetic markers of HLA gene show association with coronary artery disease in Indian subjects?

BACKGROUND: DNA methylation, one of the most stable forms of epigenetic modification is associated with the development and progression of coronary artery disease (CAD). Our previously reported study on epigenome-wide microarray analysis showed significantly methylated CpG sites. Top 5 significant CpGs from HLA gene were selected and analysed by Pyrosequencing (PSQ) to determine their association with severity of CAD. METHODS: Blood samples of 50-age matched angiographically CAD positive male cases with 50 angiographically CAD negative male controls were subjected to lipid profile estimation and PSQ for methylation level analysis. Findings and subgroup analysis were evaluated by Mann-Whitney U; Kruskal-Wallis' rank test and two-way ANOVA by MedCalc (v19.6). RESULTS: Methylation levels in HLA-DQA1 for cg10217052 was 78.5 (37-85) and 76.5 (24-84); cg09411910 was 81 (72.0 to 93.0) and 81.5 (50.0 to 89.0) in cases and controls respectively. Levels in HLA-DQB1-cg03344051, were 28.88 + 9.41 for cases and 30.36 + 9.37 in controls. For HLA-DRB1-cg07889003, levels in cases and controls were 15.5 (5.00-39.00) and 10.5 (5.00-29.0); while in cg08269402 were 52 (16-65) and 42.5 (17-61) respectively. No association was observed between methylation levels and lipid profile. cg03344051, cg07889003 and cg08269402 were significantly differentiated in double or triple vessel disease (DVD or TVD) as compared to single vessel disease (SVD) suggesting an increase in the extent of methylation with the increase in CAD severity. CONCLUSION: The present study shows significant increase in the extent of methylation in 3 CpG sites in DVD/TVD cases as compared to SVD cases. Additionally, a novel site, cg07889003 identified in our discovery phase has shown association with the severity of CAD.

Blocking common γ chain cytokine signaling ameliorates T cell-mediated pathogenesis in disease models.

The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies recognizing IL-2RG has made it difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. Here, we generated a γc cytokine receptor antibody, REGN7257, to determine whether γc cytokines might be targeted for T cell-mediated disease prevention and treatment. Biochemical, structural, and in vitro analysis showed that REGN7257 binds with high affinity to IL-2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that γc cytokines drive T cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis by affecting multiple aspects of the pathogenic response. We found that our xenogeneic GVHD mouse model recapitulates hallmarks of acute and chronic GVHD, with T cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. Our findings indicate that γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases.

Telmisartan Plus Amlodipine as the Preferred Initial Combination in Newly Diagnosed Indian Patients with Hypertension: An Expert Consensus Statements.

INTRODUCTION: Hypertension (HTN) remains one of the most important risk factors for cardiovascular (CV) diseases and a leading cause of mortality worldwide. Despite improvement in detection and treatment, poor blood pressure (BP) control rates are observed globally. The situation in India is alarming with only 22.5% of patients maintaining their BP under control. Initiating early and effective treatment for HTN helps control BP within normal limits and reduces associated health risks. In India, currently, there are no guidelines on the choice of dual combination treatment that can be considered an initial treatment for newly diagnosed HTN patients to achieve effective BP control and reduce CV risks. OBJECTIVE: To provide consensus recommendations for preferred initial combinations in newly diagnosed Indian patients with HTN. METHODOLOGY: A core group of 100 experts with HTN expertise conceptualized and formulated the four key questions based on answerability, effectiveness, potential for translation to clinical practice, novelty, and potential impact on the healthcare burden. A mix of Delphi and Child Health and Nutrition Research Initiative (CHNRI) methods was adopted for acceptance or refusal of recommendations. Likert scale 1-9 was used for scoring. A score of ≥7 was considered "statement accepted," >6.50 "near to acceptance" and <6.50 "not accepted." A vote of ≥7 by at least two-thirds of the experts (66.66%) was mandatory for acceptance of the recommendation. CONCLUSION: Combination therapy could be necessary for a majority of newly diagnosed Indian patients for effective BP control. It can manage HTN with better clinical outcomes. Based on mean rating scores from experts, telmisartan plus amlodipine can be considered the preferred initial combination in the management of newly diagnosed Indian patients with HTN to achieve better BP control and improve CV outcomes.

Fondaparinux: A cornerstone drug in acute coronary syndromes.

In acute coronary syndrome (ACS), the use of anticoagulants in conjunction with antiplatelet agents in the acute phase has resulted in reduced ischemic events and is more effective than either class of drug used alone. Though parenteral anticoagulation is essential at the time of diagnosis, a balance must be made between ischemic benefit and the increased risk of bleeding when prescribing anticoagulants. Adverse events associated with anticoagulants, such as heparin-induced thrombocytopenia, bleeding problems, and the need for close monitoring of anticoagulant activity, have contributed to finding agents that reduce these limitations. Studies like the Organization to Assess Strategies in Ischemic Syndromes 5 and 6 and their meta-analysis have proven the efficacy of Fondaparinux over the entire ACS spectrum. The convenience of administration (once daily), lack of monitoring, reduction in mortality, and better safety profile make Fondaparinux a simple and effective anti-coagulant for the management of ACS.

Nonedible Vegetable Oil-Based Polyols in Anticorrosive and Antimicrobial Polyurethane Coatings.

This review describes the preparation of nonedible vegetable oil (NEVO)-based polyols and their application in anticorrosive and antimicrobial polyurethane (PU) coatings. PUs are a class of versatile polymers made up of polyols and isocyanates. Renewable vegetable oils are promising resources for the development of ecofriendly polyols and the corresponding PUs. Researchers are interested in NEVOs because they provide an alternative to critical global food issues. The cultivation of plant resources for NEVOs can also be popularized globally by utilizing marginal land or wastelands. Polyols can be prepared from NEVOs following different conversion routes, including esterification, etherification, amidation, ozonolysis, hydrogenation, hydroformylation, thio-ene, acrylation, and epoxidation. These polyols can be incorporated into the PU network for coating applications. Metal surface corrosion and microbial growth are severe problems that cause enormous economic losses annually. These problems can be overcome by NEVO-based PU coatings, incorporating functional ingredients such as corrosion inhibitors and antimicrobial agents. The preferred coatings have great potential in high performance, smart, and functional applications, including in biomedical fields, to cope with emerging threats such as COVID-19.

Performance enhancement of solar photovoltaic system for roof top garden.

The photovoltaic (PV) for irrigation system is an emerging technology to harness the solar energy. The performance of the PV modules depends on the incident solar radiation, geographical location, and the surface temperature of the modules. The performance of the PV system needs to be monitored by manually or embedded controllers. The commercially available technologies for monitoring the system are costlier and need to be optimized. The Arduino controller is used to monitor the performance of the photovoltaic (PV) system in Coimbatore (11.016° N, 76.9558° E), Tamilnadu, India. The PV surface temperature is monitored and controlled by flowing the water above the module by setting the mean ambient temperature as a reference temperature 34 °C when the system exceeds the reference temperature. PV surface temperature is reduced up to 16°C thus improved the electrical efficiency by 17% compare to the reference module. The Arduino controller control the relay to switch on the motor to control the mass flow rate of the water at 0.0028kg/s. The various parameters are measured such as voltage, current, and solar radiation of the location and analyzed. The estimated cost of monitoring system and various sensor is 10$ which cost comparatively 50% lower than the other PV monitoring controllers. This method can be employed in the medium and large-scale irrigation system.

Screening of PCSK9 and LDLR genetic variants in Familial Hypercholesterolemia (FH) patients in India.

Familial Hypercholesterolemia (FH) is an autosomal, dominant, inherited disorder characterized by severely elevated LDL-cholesterol (LDL-C) levels with high risk for Coronary Artery Disease (CAD). There are limited genetic studies especially on genes other than Low Density Lipoprotein receptor (LDLR) conducted in Indian population. Thus, our aim was to screen the entire Proprotein Convertase Subtilisin/Kexin type 9 gene (PCSK9) gene & hotspot exons 3, 4 and 9 of LDLR gene in FH cases and controls. 50 FH cases were categorized into definite, probable and possible cases according to Dutch Lipid Network Criteria (DLNC) who were gender matched with 50 healthy controls. All 12 exons of PCSK9, and hotspot exons 3, 4 & 9 of LDLR gene were screened through High Resolution Melt (HRM) curve analysis. Enzyme linked immunosorbent assay was performed to measure circulating PCSK9 levels. Total cholesterol and LDL-C were significantly high in all three groups of cases. Total 8 nonpathogenic variants in exon 1, 5, 7 and 9 of the PCSK9 gene were detected. In LDLR gene, 3 known pathogenic and 1 benign variant were found in exon 3 & 4. In FH cases, PCSK9 levels were significantly high compared to controls (P = 0.0001), and were directly correlated to LDL-C (P = 0.0001) and Total Cholesterol (P = 0.0001). Our study is first to screen the entire PCSK9 gene in western part of India. Since no pathogenic variants were identified, it is possible that PCSK9 variants are clinically less relevant. However, 3 known pathogenic variants were found in the LDLR gene. These findings support our understanding of the genetic spectrum of FH in India.

Self-blood pressure measurement as compared to office blood pressure measurement in a large Indian population; the India Heart Study.

OBJECTIVE: India Heart Study (IHS) is aimed at investigating the agreement between office blood pressure measurement (OBPM) and self (S)BPM in a hypertension-naive population. METHODS: A total of 18 918 individuals (aged 42.6 ±â€Š11.7 years, 62.7% men), visiting 1237 primary care physicians across India, underwent OBPM. They performed SBPM for a period of 1 week using a validated oscillometric BP monitor that was preprogrammed to adhere to a guideline-based SBPM-schedule and blinded to the results. Thereafter, individuals underwent a second OBPM. Available laboratory results were obtained. Thresholds for elevated OBPM and SBPM were 140/90 and 135/85 mmHg, respectively. RESULTS: On the basis of first-visit OBPM and SBPM, there were 5787 (30.6%) individuals with normotension; 5208 (27.5%) with hypertension; 4485 (23.7%) with white-coat hypertension (WCH) and 3438 (18.2%) with masked hypertension. Thus, a diagnosis contradiction between SBPM and first-visit OBPM was seen in 9870 (41.9%) individuals. On the basis of second-visit OBPM, the normotension, hypertension, WCH and masked hypertension prevalence values were 7875 (41.6%); 4857 (25.7%); 2397 (12.7%) and 3789 (20.0%). There was poor agreement (kappa value 0.37) between OBPM of visit 1 and 2 with a diagnosis difference in 6027 (31.8%) individuals. The majority of masked hypertension and WCH individuals had BP values close to thresholds. CONCLUSION: There was a poor agreement between OBPM of visit1 and visit 2. Likewise, the agreement between OBPM at both visits and SBPM was poor. SBPM being considered to have a better correlation with patient prognosis should be the preferred method for diagnosing hypertension.

Blood pressure related to age: The India ABPM study.

The present paper reports trends in office blood pressure (BP) measurement (OBPM) and ambulatory blood pressure measurement (ABPM) with age in a large multi-center Indian all comers' population visiting primary care physicians. ABPM and OBPM data from 27 472 subjects (aged 51 ± 14 years, males 68.2%, treated 45.5%) were analyzed and compared. Individual differences between OBPM and ABPM patterns were compared for patients according to 10-year age categories. Results showed that systolic (S) BP values started to increase with age from the age of 40, BP variability (SD) increased from the age of 30 years. Diastolic (D) BP values started to decrease from the age of 50 years. Mean OBPM values were higher than daytime ABPM values (all P < .001) in all age-groups. The prevalence of white coat hypertension (WCH) and masked hypertension (MH) was based on OBPM and daytime, 24-hour, and nighttime average BPs together. WCH decreased with age from 15.1% and 12.4% in treated and untreated subjects at the youngest age to 7.2% and 6.9% in the oldest age, respectively. MH prevalence was higher for untreated than for treated subjects but remained similar for all age-groups (range of 18.6%-21.3%). The prevalence of reverse dippers increased with age from the youngest to oldest group with 7.3%-34.2% (P < .001 for trend). Dippers prevalence decreased from 42.5% to 17.9% from the youngest to oldest age-groups, respectively (P < .001 for trend). These findings confirm that BP patterns show clear differences in trends with age, particularly regarding nighttime BP.

Differential methylation pattern in patients with coronary artery disease: pilot study.

Epidemiological studies have revealed that coronary artery disease (CAD) is highly heritable. However, genetic studies have not been able to fully elucidate its etiology. Accumulating evidences suggest that epigenetic alterations like DNA methylation may provide an alternative and additional explanation of its pathophysiology. DNA methylation regulates hypomethylation and hypermethylation of various genes which are involved in the development of CAD. Our aim was to identify differentially methylated regions (DMRs) in genome of CAD patients by using the microarray chip having a coverage of > 4,50,000 CpG sites (Illumina's Infinium HumanMethylation450 BeadChip). In this pilot study, an epigenome-wide analysis of DNA methylation from whole blood was performed in six angiographically positive male cases, who were age and gender matched with six angiographically negative controls. All subjects were non-smokers, non-diabetic, non-alcoholic, with no previous history of cardiac ailment. Illumina's GenomeStudio (v 2011.1) software was used to identify DMRs and pathway analysis, gene ontology was carried out using DAVID (Database for Annotation, Visualisation and Integrated Discovery). 429 DMRs were found to be significant of which 222 were hypomethylated and 207 were hypermethylated. Antigen processing and presentation was identified to be the most significant biological function with a statistical significance of p = 4.35 × 10- 5. HLA-DRB1, HLA-DQA1, HLA-DQB1 along with non-classical HLA molecules HLA-G, HLA-C are responsible for triggering the inflammatory pathway which have been identified in our study. To the best of our knowledge, this is the first study to identify a panel of DMRs using a high coverage microarray chip in India.

Circulating miRNA-33: a potential biomarker in patients with coronary artery disease.

BACKGROUND: Circulating microRNAs (miRNA) are present in body fluids in stable, cell-free form. Likewise, these miRNAs can be identified in various stages of coronary artery disease (CAD) such as inflammation, endothelial dysfunction, proliferation and atherosclerosis among others. miRNA expression levels can be identified. AIMS AND OBJECTIVES: To determine the expression of circulating miRNAs (miR-126, miR-92, miR-33, miR-145 and miR-155) in CAD patients of Indian origin. MATERIAL AND METHODS: miRNA profiling analysis in blood plasma was performed by quantitative real-time-PCR (qRT-PCR) in 60 angiographically verified subjects including 30 CAD patients and 30 age- and gender-matched controls. Association between the expression of all five circulating miRNAs and clinical characteristics of patients with CAD were analysed using Medcalc statistics. The severity of CAD was assessed using SYNTAX score (SS). RESULTS: Expression of plasma miR-33 increased by 2.9 folds in CAD patients than in control group (p value ≥0.002) also it was found that miR-33 expression levels in mild cases (SS: ≤22) were significantly higher than CAD controls. There was a modest negative correlation between miR-33 and total cholesterol/high density lipoprotein ratio, triglycerides and very low density lipoprotein. CONCLUSION: The study reports a significant association between increased levels of plasma miR-33 and CAD. Thus, plasma miR-33 appears to be a promising non-invasive biomarker, but requires further validation in a large cohort.

Novel plasmid conferring kanamycin and tetracycline resistance in the turkey-derived Campylobacter jejuni strain 11601MD.

In Campylobacter spp., resistance to the antimicrobials kanamycin and tetracycline is frequently associated with plasmid-borne genes. However, relatively few plasmids of Campylobacter jejuni have been fully characterized to date. A novel plasmid (p11601MD; 44,095nt) harboring tet(O) was identified in C. jejuni strain 11601MD, which was isolated from the jejunum of a turkey produced conventionally in North Carolina. Analysis of the p11601MD sequence revealed the presence of a high-GC content cassette with four genes that included tet(O) and a putative aminoglycoside transferase gene (aphA-3) highly similar to kanamycin resistance determinants. Several genes putatively involved in conjugative transfer were also identified on the plasmid. These findings will contribute to a better understanding of the distribution of potentially self-mobilizing plasmids harboring antibiotic resistance determinants in Campylobacter spp. from turkeys and other sources.

Association of CYBA G640A variation with coronary artery disease in Indians.

INTRODUCTION: Oxidative stress induces atherosclerosis by triggering an inflammatory cascade within the vascular wall. OBJECTIVE: To investigate the role of pro-oxidant and antioxidant gene variations with CAD in Indian subjects. MATERIALS & METHODS: It's a case-control study and genotyping for the variants MPO G-463A, CYBA G640A, SOD2 Val16Ala and CAT C-262T were performed by conventional PCR techniques. RESULTS: Only CYBA G640A variant allele was found to be significantly (p = 0.0075) associated with CAD. CONCLUSION: Although CYBA G640A variation was found to be significant, a larger study is needed to validate these results and establish its role as a biomarker.

Troponin T and Heart Type Fatty Acid Binding Protein (h-Fabp) as Biomarkers in Patients Presenting with Chest Pain.

Acute coronary syndrome (ACS) is a term for a range of clinical signs and symptoms suggestive of myocardial ischemia. It results in functional and structural changes and ultimately releasing protein from injured cardiomyocytes. These cardiac markers play a major role in diagnosis and prognosis of ACS. This study aims to assess the efficacy of heart type fatty acid binding protein (h-FABP) as a marker for ACS along with the routinely used hs-TropT. In our observational study, plasma h-FABP (cut-off 6.32 ng/ml) and routinely done hs-Trop T (cutoff 0.1 and 0.014 ng/ml) were estimated by immunometric laboratory assays in 88 patients with acute chest pain. Based on the clinical and laboratory test findings the patients were grouped into ACS (n = 41) and non-ACS (n = 47). The diagnostic sensitivity, specificity, NPV, PPV and ROC curve at 95 % CI were determined. Sensitivity of hs-TropT (0.1 ng/ml), hs-TropT (0.014 ng/ml) and h-FABP were 53, 86 and 78 % respectively and specificity for the same were 98, 73 and 70 % respectively. Sensitivity, specificity and NPV calculated for a cut-off combination of hs-TropT 0.014 ng/ml and h-FABP was 100, 51 and 100 % respectively. These results were substantiated by ROC analysis. Measurement of plasma h-FABP and hs-TropT together on admission appears to be more precise predictor of ACS rather than either hs-Trop T or h-FABP.

Limit of detection of genomic DNA by conventional PCR for estimating the load of Staphylococcus aureus and Escherichia coli associated with bovine mastitis.

Detection of mastitis-associated bacteria can be accomplished by culturing or by molecular techniques. On the other hand, rapid and inexpensive methods to enumerate bacterial load without culturing can be better achieved by molecular methods. Staphylococcus aureus and Escherichia coli are the predominant bacterial pathogens associated with bovine mastitis. Here, we describe the application of conventional PCR for the limit of detection (LOD) of genomic DNA of S. aureus and E. coli based on single-copy genes. The selected genes were thermonuclease (nuc), aureolysin (aur), and staphopain A (scpA) for S. aureus and ß-D-glucuronidase A (uidA), cytochrome d oxidase (cyd), and rodA (a gene affecting cell shape and methicillin sensitivity) for E. coli. The LOD was 5.3, 15.9, and 143 pg for aur, nuc, and scpA genes, corresponding to S. aureus genomic copies of 1.75 × 10(3), 5.16 × 10(3), and 4.71 × 10(4), respectively. The LOD was 0.45, 12.3 and 109 pg for uidA, rodA and cyd genes, corresponding to E. coli genome copies of 8.91 × 10(1), 2.43 × 10(3), and 2.16 × 10(4), respectively. Application of uidA and aur PCRs to field strains revealed that as low as approximately 100 genome copies of E. coli and 1000-10,000 copies of S. aureus could be detected. This study is the first to report LOD of genomic DNA using conventional PCR for aur and scpA genes of S. aureus, and rodA and cyd genes of E. coli. The results should be useful for developing assays to assess bacterial load in milk and to determine the load that contributes to subclinical or clinical mastitis.