Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci.

BACKGROUND: Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies. METHODS: We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci. RESULTS: We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci. CONCLUSIONS: Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.

Peri-procedural outcome of saphenous vein graft intervention.

BACKGROUND: Patients who develop recurrent myocardial ischemia after coronary artery bypass graft (CABG) surgery are often referred for percutaneous coronary intervention. The objective of this study was to evaluate the clinical characteristics and peri-procedural outcomes in patients with prior CABG referred for percutaneous coronary intervention (PCI) over a 3 year period. METHODS: Data were collected on patients who underwent coronary interventional procedures following CABG surgery. We evaluated angiographic procedural success and immediate outcome among patients who had undergone such procedures from Nov 2006 to Oct 2009 (n = 113). RESULTS: Patients in the 2006-2009 cohort had mean age 58.2 years, more patients were male (109 vs 4) and were more likely to have hypertension (57.5%), hyperlipidaemia (72.6%) and family history of ischemic heart disease (IHD) (65.5%), but less likely to have smoking (42.5%). Acute closure of stent leading to procedural failure was seen in 1 (0.9%) patient, sub-acute thrombosis of stent was seen in 1 (0.9%) patient, dissection or perforation of target vessel was seen in 3 (2.7%) and 1 (0.9%) patients respectively. Slow flow phenomenon was seen in 13 (11.5%) and post-procedural cardiac enzymes were raised in 6 (5.3%) patients. CONCLUSION: Success rates of saphenous vein graft (SVG) intervention and survival rate have improved with time as a result of improvements in technique and greater use of stents, filter devices and adjunctive medications.

Association of the 9p21.3 locus with risk of first-ever myocardial infarction in Pakistanis: case-control study in South Asia and updated meta-analysis of Europeans.

OBJECTIVE: To examine variants at the 9p21 locus in a case-control study of acute myocardial infarction (MI) in Pakistanis and to perform an updated meta-analysis of published studies in people of European ancestry. METHODS AND RESULTS: A total of 1851 patients with first-ever confirmed MI and 1903 controls were genotyped for 89 tagging single-nucleotide polymorphisms at locus 9p21, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium. Minor allele frequencies and extent of linkage disequilibrium observed in Pakistanis were broadly similar to those seen in Europeans. In the Pakistani study, 6 variants were associated with MI (P<10(-2)) in the initial sample set, and in an additional 741 cases and 674 controls in whom further genotyping was performed for these variants. For Pakistanis, the odds ratio for MI was 1.13 (95% CI, 1.05 to 1.22; P=2 x 10(-3)) for each copy of the C allele at rs1333049. In comparison, a meta-analysis of studies in Europeans yielded an odds ratio of 1.31 (95% CI, 1.26 to 1.37) for the same variant (P=1 x 10(-3) for heterogeneity). Meta-analyses of 23 variants, in up to 38,250 cases and 84,820 controls generally yielded higher values in Europeans than in Pakistanis. CONCLUSIONS: To our knowledge, this study provides the first demonstration that variants at the 9p21 locus are significantly associated with MI risk in Pakistanis. However, association signals at this locus were weaker in Pakistanis than those in European studies.

Frequency of anaemia and renal insufficiency in patients with heart failure.

BACKGROUND: Heart Failure (HF) is a common disease with a high mortality rate. Anaemia and renal failure (RF) are often present in patients with HF and associated with worse prognosis. Objective of study was to evaluate the prevalence of anaemia and RF in patients with HF. METHODS: Patients admitted in Punjab institute of cardiology Lahore with diagnosis of heart failure were enrolled from February, 2008 to December, 2008. Anaemia was defined as haemoglobin levels < 13 mg/dl for men and 12 mg/dl for women. Renal function was assessed by the glomerular filtration rate (GFR), calculated by the simplified formula of the MDRD (Modification of Diet in Renal Disease) study. RESULTS: Of the 276 patients included in this study, 42.03% (116) had anaemia and 38.40% (106) had moderate to severe renal failure (GFR < 60 ml/min). CONCLUSION: The prevalence of anaemia and renal failure was high in this population and was associated with the severity of the HF (functional classes III and IV).

Role of 64-slice multi detector computed tomography for non-invasive visualisation of coronary artery bypass grafts for follow up in post CABG patients.

BACKGROUND: Coronary artery bypass graft surgery is a commonly performed revascularization procedure in ischemic heart disease patients. Conventional coronary angiography is an invasive method for evaluation of grafts in such patients. Non-invasive evaluation of grafts in post CABG patient has been made possible with the advent of 64-Slice Multi Detector Computed Tomography (MDCT) The Objective of the study was to non-invasively assess the graft patency with MDCT. METHODS: Sixty post CABG patients (52 male, 8 female) with atypical chest pain or stable angina were evaluated with MDCT for graft patency. The grafts were considered as patent if there was continuous lumen visualisation at origin, in the body and at its insertion with native recipient vessels. Grafts were defined as blocked when only stumps were seen. They were classified as stenotic if there was > or = 50% diameter narrowing. RESULTS: The mean age of the patients was 60.1 +/- 9.7 years, mean duration since CABG was 8.01 +/- 6 years. Total number of grafts assessed was 175 including 124 (71%) venous grafts and 51 (28.9%) arterial grafts. A total of 82/124 (66.1%) venous grafts and 47/51 (92%) arterial grafts were patent. Forty-two (34%) venous grafts were blocked whereas 4 arterial grafts were not developed. Arterial grafts patency was 92% and venous grafts patency was 67.7% after a mean follow up of 8.01 +/- 6 years. CONCLUSION: The study shows that 64 slice MDCT can be used for the evaluation of patency and occlusion of venous and arterial grafts in post CABG patients for follow up.

Direct Stenting Versus Balloon Pre-Dilatation In Elective Percutaneous Coronary Intervention.

BACKGROUND: Stents are now deployed in almost 95% of all percutaneous coronary interventions (PCIs). Recent advances in balloon and stent technology has improved the technique of direct stent (DS) strategy, i.e., stent delivery without pre-dilatation instead of conventional stenting (CS), i.e., stent implantation after balloon pre-dilatation with multiple advantages. METHODS: This randomized controlled trial was conducted at the Cardiology. Department, Punjab Institute of Cardiology, Lahore from April to September, 2017. One hundred patients who were being treated by percutaneous coronary intervention (PCI) were enrolled into two Groups e.g., Group I & group II. 50 patients undergoing direct stenting were enrolled in group I and 50 patients undergoing stenting after balloon pre-dilatation were enrolled in group II after randomization. All patients were treated by single type drug eluting or bare metal stents. Chi square test was used for association and t-test for mean difference between two groups in comparison to post dilatation, fluoroscopy time, procedure time, amount of contrast used, procedural success, side branch compromise, slow flow. The p-value of ˂ 0.05 was significant. RESULTS: This study consisted of 76 males and 24 females out of a total count of 100, with the average age of 52.2±0.01 years. Overall, 43 (43%) patients were diabetic and overall, 44 (44%) were hypertensive. Most of the patients 55 (55%) had PCI to LAD. Average fluoroscopy time 4.l±2.5 minutes in Group I was significantly lesser as compared to 6.7±3.8 minute group II (p-value <0.05). The average procedure time was also marginally lesser in Group I, 23.4±11.6 in comparison to the second Group 33.7±14 (p-value <0.05). Side branch compromise was observed in 10 (20%) in the first group as compared to 8 (16%) the second group. CONCLUSIONS: In comparison to stenting preceded by balloon predilatation, direct stenting is a safer and more feasible procedure with respect to radiation exposure, cost and time duration of the procedure.

The Pakistan Risk of Myocardial Infarction Study: a resource for the study of genetic, lifestyle and other determinants of myocardial infarction in South Asia.

The burden of coronary heart disease (CHD) is increasing at a greater rate in South Asia than in any other region globally, but there is little direct evidence about its determinants. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is an epidemiological resource to enable reliable study of genetic, lifestyle and other determinants of CHD in South Asia. By March 2009, PROMIS had recruited over 5,000 cases of first-ever confirmed acute myocardial infarction (MI) and over 5,000 matched controls aged 30-80 years. For each participant, information has been recorded on demographic factors, lifestyle, medical and family history, anthropometry, and a 12-lead electrocardiogram. A range of biological samples has been collected and stored, including DNA, plasma, serum and whole blood. During its next stage, the study aims to expand recruitment to achieve a total of about 20,000 cases and about 20,000 controls, and, in subsets of participants, to enrich the resource by collection of monocytes, establishment of lymphoblastoid cell lines, and by resurveying participants. Measurements in progress include profiling of candidate biochemical factors, assay of 45,000 variants in 2,100 candidate genes, and a genomewide association scan of over 650,000 genetic markers. We have established a large epidemiological resource for CHD in South Asia. In parallel with its further expansion and enrichment, the PROMIS resource will be systematically harvested to help identify and evaluate genetic and other determinants of MI in South Asia. Findings from this study should advance scientific understanding and inform regionally appropriate disease prevention and control strategies.

Usefulness of ST segment depression limited to the recovery phase of exercise stress test.

OBJECTIVE: To determine the diagnostic value of ST segment depression limited to recovery phase of Exercise Tolerance Test (ETT). STUDY DESIGN: An observational cross-sectional study. PLACE AND DURATION OF STUDY: The study was carried out at Punjab Institute of Cardiology, Lahore, from March to August 2007 for a period of 6 months. METHODOLOGY: In this study, 100 patients were selected with purposive non-probability sampling technique and were divided into two groups, group A having ST segment depression during exercise phase of ETT, and group B having ST segment depression only in recovery phase after undergoing ETT according to Bruce protocol. The patients were subjected to coronary angiography later on. The chi-square or Fischer's exact test of significance was applied at 0.05 level of significance to compare the coronary angiographic finding between two groups. Diagnostic value of ST segment depression was computed keeping angiographic finding as Gold standard. RESULTS: There were no major differences between the two groups regarding angiographic finding. Significant coronary artery stenosis (> 50% narrowing) was found in 68 (93%) patients of group A and 23 (85%) patients of group B (p=0.18). Three vessel disease was found in 30 (41%) patients in group A and 7 (26%) patients in group B (p=0.08). Left main stem disease was found in 5 (6.8%) patients of group A and 1 (3.7%) patient of group B. Normal coronaries were found in 6% of patients among group A and 14% of patients among group B (p=0.12). Specificity, sensitivity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of ST segment depression in recovery phase was 55, 25, 85 and 6 percent respectively (95% CI; 1.16 - 2.25). CONCLUSION: In patients undergoing exercise stress test, ST segment depression occurring only in recovery phase of ETT has a diagnostic value largely comparable with that of ST segment depression induced during exercise phase of ETT. Thus careful evaluation of ST segment depression occurring only in recovery phase may add significantly to the clinical information derived from the results of ETT.

Metabolic syndrome in patients with ischemic heart disease.

OBJECTIVE: To determine the frequency of metabolic syndrome in patients with Ischemic Heart Disease (IHD). STUDY DESIGN: Cross-sectional, descriptive study. PLACE AND DURATION OF STUDY: Cardiology Department of Punjab Institute of Cardiology, Lahore, from June 2006 to June 2007. METHODOLOGY: A total of 100 subjects with ischemic heart disease, fulfilling the inclusion criteria, were enrolled in the study. Demographic data (age and gender) and the 5 component conditions of the metabolic syndrome were noted. Subjects were physically assessed for the abdominal obesity, based on waist circumference. Fasting blood samples for glucose and lipid profile in first 24 hours after acute coronary insult were drawn and tested in central laboratory. Variables were processed for descriptive statistics. RESULTS: In this study population, 68% were male and 32% were female with mean age of 52 +/-13.6 years in men and 56 +/- 12.5 years in women. Frequency of metabolic syndrome was 32% in men and 28% in women. It increased with age. The highest rate of metabolic syndrome was in men diagnosed as STEMI (odds ratio: 3.39, 95% CI=1.36-8.41). CONCLUSION: Frequency of metabolic syndrome was high among the patients with IHD. It supports the potential for preventive efforts in persons with high-risk of IHD.

Significance of perfusion defects on dipyridamole thallium cardiac SPECT in patients with left bundle branch block.

BACKGROUND: Left Bundle Branch Block (LBBB) is a known cause of false positive results in myocardial perfusion studies. We aimed at investigation of correlation between degree of severity of perfusion defect on cardiac Single Photon Emission Computed Tomography (SPECT) and presence of coronary artery disease on angiography in patients with LBBB. STUDY DESIGN: This was an analytical study and was carried out at Department of Nuclear Cardiology and Department of Cardiac Catheterisation of Punjab Institute of Cardiology, Lahore from January 2007 to April 2007. METHODS: In this study patients having LBBB without known coronary artery disease (CAD) referred for myocardial perfusion studies to the Nuclear Cardiology Department from outpatient, indoor and emergency departments were included. Thallium201 stress/rest Single-Photon Emission Tomography (SPECT) acquisition scanning was performed. The myocardial perfusion pattern was classified as normal, fixed defect and reversible defect. Coronary angiography was used to confirm CAD only in patients with abnormal scan. RESULTS: Thirty consecutive patients having LBBB were studied. All patients underwent myocardial perfusion imaging using dipyridamole pharmacologic stress. Fourteen patients (47%) revealed normal Thallium201 uptake and distribution at the septum. Reversible defects were noted in 13 (43%) patients. Fixed defects were noted in 3 (10%) patients. Among four patients with mild perfusion defects only 1 (25%) had significant coronary artery disease. In patients with moderate perfusion defects, coronary angiogram was positive for significant coronary artery disease in 1 (33%) patient. In six patients having severe perfusion defects significant coronary artery disease was noted in 5 (83%) patients. All patients with fixed defects had significant coronary artery disease. False positive studies were found to be significantly greater in patients with reversible defects particularly with mild to moderate defects. CONCLUSIONS: Patients with left bundle branch block showing moderate to severe reversible perfusion defects on dipyridamole thallium cardiac SPECT have high likelihood of coronary artery disease.

Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study.

BACKGROUND: Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain. OBJECTIVES: Through a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF). METHODS: This study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls. RESULTS: Serum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations. CONCLUSIONS: Evidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.

In-hospital outcome of acute myocardial infarction (st segment elevation type) in diabetics and non-diabetics.

OBJECTIVE: To evaluate the in-hospital mortality and complications of acute myocardial infarction in diabetic and non-diabetic patients. DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Coronary Care Unit and Cardiology Ward of Nishtar Hospital, Multan from 1st October 2002 till 15th May 2003. PATIENTS AND METHODS: Four hundred and forty-eight (448) consecutive patients who fulfilled the inclusion criteria were studied while they were admitted to the hospital. Patients were divided into two groups of diabetics and non-diabetics depending on the presence of diabetes mellitus. In-hospital mortality and complications were compared between the two groups by Chi-square method. RESULTS: Diabetic patients presented in more advanced Killip class as 32(26.7%) patients presented in Killip class II, 13(10.8%) patients presented in Killip class III and 6(5%) patients presented in Killip class IV. In the non-diabetic group, 68(20.7%), 24(7.3%) and 11(3.4%) patients presented in these Killip classes respectively (p<0.042). The total in-hospital mortality was 17%. Mortality was 28(23.3%) in diabetics and 48(14.6%) in non-diabetics (p<0.03). In-hospital mortality was almost double in diabetics as compared to non-diabetics. Mechanical complications were observed in 42(35%) patients in diabetic group and 80(24.4%) patients in non-diabetic group. Left ventricular failure was the most commonly observed mechanical complication. Electrical complications were observed in 84(70%) diabetic and 162(49.4%) non-diabetic patients (p<0.205). CONCLUSION: In patients with acute myocardial infarction, presence of diabetes mellitus was associated with worse in-hospital outcome leading to increased mortality and complications as compared to non-diabetic patients.

Genetic determinants of major blood lipids in Pakistanis compared with Europeans.

BACKGROUND: Evidence is sparse about the genetic determinants of major lipids in Pakistanis. METHODS AND RESULTS: Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as CETP associated with HDL-C levels (rs711752; P<10(-13)), APOA5/ZNF259 (rs651821; P<10(-13)) and GCKR (rs1260326; P<10(-13)) with triglyceride levels; and CELSR2 variants with LDL-C levels (rs646776; P<10(-9)). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in APOA5 among Pakistanis was higher and its impact on triglyceride concentration was greater (P-value for difference <10(-4)). CONCLUSIONS: Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans.