Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity.

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.

Physical activity, smoking, and genetic predisposition to obesity in people from Pakistan: the PROMIS study.

BACKGROUND: Multiple genetic variants have been reliably associated with obesity-related traits in Europeans, but little is known about their associations and interactions with lifestyle factors in South Asians. METHODS: In 16,157 Pakistani adults (8232 controls; 7925 diagnosed with myocardial infarction [MI]) enrolled in the PROMIS Study, we tested whether: a) BMI-associated loci, individually or in aggregate (as a genetic risk score--GRS), are associated with BMI; b) physical activity and smoking modify the association of these loci with BMI. Analyses were adjusted for age, age(2), sex, MI (yes/no), and population substructure. RESULTS: Of 95 SNPs studied here, 73 showed directionally consistent effects on BMI as reported in Europeans. Each additional BMI-raising allele of the GRS was associated with 0.04 (SE = 0.01) kg/m(2) higher BMI (P = 4.5 × 10(-14)). We observed nominal evidence of interactions of CLIP1 rs11583200 (P(interaction) = 0.014), CADM2 rs13078960 (P(interaction) = 0.037) and GALNT10 rs7715256 (P(interaction) = 0.048) with physical activity, and PTBP2 rs11165643 (P(interaction) = 0.045), HIP1 rs1167827 (P(interaction) = 0.015), C6orf106 rs205262 (P(interaction) = 0.032) and GRID1 rs7899106 (P(interaction) = 0.043) with smoking on BMI. CONCLUSIONS: Most BMI-associated loci have directionally consistent effects on BMI in Pakistanis and Europeans. There were suggestive interactions of established BMI-related SNPs with smoking or physical activity.

Safety of primary percutaneous coronary intervention with and without (selective) thrombus aspiration.

OBJECTIVE: To determine the safety and efficacy of selective thrombus aspiration during Primary Percutaneous Coronary Intervention (PCI). METHODS: This observational prospective study was conducted in the catheterization laboratory of a tertiary care cardiovascular centre. A total of 150 consecutive patients who underwent primary PCI were enrolled. Aspiration was done only when thrombus burden was considered significant. After completion of procedure angiographic and electrocardiographic signs were recorded and clinical follow up was documented up to 1 year. RESULTS: No significant difference among the groups was found in age, height, weight and other risk factors like Hypertension, Diabetes Mellitus and Smoking. In general, left anterior descending artery was culprit in - 65% of patients and more than 90% of culprit vessels had visible thrombus. Multivessel disease was present in 38% of patients and 22.7% had past history of myocardial infarction. Out of 150 patients 117 (78%) underwent thrombus aspiration. No significant difference was found in ST resolution within 60 minutes (72.6 vs 81.8%; P < 0.285) and myocardial blush grade II & III (41.9 vs 27.3%; P < 0.128). No difference in event free survival was observed among the two groups (80.3 vs 84.8%; P < 0.708) at one year. CONCLUSION: Selective thrombus aspiration in definite thrombus laden arteries and no aspiration in low or negligible thrombus burden vessels may be a safe and effective strategy in patients undergoing primary PCI. Overall poor risk profile of our patients as compared to western population necessitates further evaluation of this matter in randomized studies.

Comparison of the TIMI and the GRACE risk scores with the extent of coronary artery disease in patients with non-ST-elevation acute coronary syndrome.

OBJECTIVE: To compare the accuracy of the Global Registry of Acute Coronary Events risk score and the Thrombolysis In Myocardial Infarction risk score in predicting the extent of coronary artery disease in patients with non-ST segment elevation acute coronary syndrome. METHODS: The cross-sectional study comprising 406 consecutive patients was conducted at the National Institute of Cardiovascular Diseases, Karachi, from August 2010 to March 2011. For all patients, the GRACE and TIMI RS's relevant scores on the two indices were calculated on admission using specified variables. The patients underwent coronary angiography to determine the extent of the disease. A significant level was defined as > or =70% stenosis in any major epicardial artery or > or =50% stenosis in the left main coronary artery. SPSS 19 was used for statistical analysis. RESULTS: Both the indices showed good predictive value in identifying the extent of the disease. A Thrombolysis In Myocardial Infarction score >4 and Global Registry of Acute Coronary Events score >133 was significantly associated with 3vessel disease and left main disease, while for the former score < or =4 and latter score < or =133 was associated with normal or non-obstructive coronary disease (p<0.01). On comparison of the two risk scores, the discriminatory accuracy of the latter was significantly superior to the former in predicting 2vessel, 3vessel and left main diseases (p<0.05). CONCLUSION: Although both the indices were helpful in predicting the extent of the disease, the Global Registry showed better performance and was more strongly associated with multi-vessel and left main coronary artery disease.

Presentation of tuberculosis as isolated massive pericardial effusion in a patient with rheumatoid arthritis.

The case of a 60 year old male patient, diagnosed with rheumatoid arthritis presenting with recurrent massive pericardial effusion, and unresponsive to treatment of rheumatoid arthritis is documented. Pericardial biopsy proved Tuberculous pericarditis with positive fluid culture for Mycobacterium Tuberculosis. Anti-tuberculous treatment was started along with corticosteroids. Follow up after three months showed no evidence of pericardial effusion.

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.

Percutaneous transvenous mitral commissurotomy (PTMC) and percutaneous coronary intervention (PCI) successfully applied in one patient in same sitting.

Sixty years old male with severe rheumatic mitral stenosis (MS), presented with dyspnoea New York Heart Association (NHYA) class III to IV. Coronary angiogram revealed severe occlusive coronary artery disease in left anterior coronary artery (LAD). Percutaneous Transvenous Mitral Commissurotomy (PTMC) and Percutaneous Coronary Intervention (PCI) of Left Anterior Descurery (LAD) were done in same sitting. Both procedures were successful and ended without complication. After, half an hour while shifting to coronary care unit (CCU) patient developed cardiac tamponade, which was managed successfully. Patient was followed up for three month, he is doing well and recent echocardiogram showed mild mitral stenosis with normal left ventricular function. This case demonstrates the feasibility of the combined appliance on interventional techniques in selected patients as an alternative to cardiac surgery.

Outcome of primary percutaneous coronary intervention at public sector tertiary care hospital in Pakistan.

OBJECTIVES: To determine the outcome of Primary Precutaneous Coronary Intervention (PCI) in our setup and compare the results with the west. METHODS: This study was conducted at a tertiary care teaching Hospital (National Institute of Cardiovascular Diseases Karachi, Pakistan) during January 1st, 2008 to December 31st, 2008. A total of 113 patients were enrolled who came with STEMI and agreed to go for Primary PCI. We excluded the patients who had history of Thrombolytic therapy within 24 hours, presented with Non ST-elevation Myocardial Infarction (NSTEMI) and coronary angiogram revealed significant left Main or equivalent disease. All Patients received Aspirin, Clopidogrel and Platelet Glycoprotein IIB IIIA Inhibitor. After Primary PCI patients were planned to follow at one month, 3 months and 6 months. Primary end point was to document death, MI, CABG and rehospitalization. RESULTS: Out of 113 cases, 102 (90.3%) were male and 11 (9.7%) were female, Mean age was 51.2 +/- 11.7 years, 54 (47.8%) patients had Hypertension, 28 (24.8%) were Diabetics and 44 (38.9%) were Smokers. Immediate success was achieved in 111 (98.2%) cases. In hospital mortality was 5.3% (3.5% in cardiogenic shock, 1.7% in non-shock patients). Mean Door to Balloon time remained 98.4 minutes. Twelve patients were lost to follow up. Therefore at 6 months, out of 101 patients, 8 (7.9%) died, 5 (4.9%) underwent Coronary Artery Bypass Graft (CABG) surgery and 5 (4.9 %) had been re-hospitalized either for recurrent myocardial infarction or heart failure. CONCLUSION: Optimal results of primary percutaneous coronary intervention can be achieved for acute STEMI in a developing country at a tertiary care public sector hospital. The results are comparable and nearly similar to the west.

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.

Determinants of decrease in pulmonary hypertension following percutaneous transvenous mitral commissurotomy.

OBJECTIVE: To identify the determinants of decrease in pulmonary hypertension after percutaneous balloon mitral commissurotomy. STUDY DESIGN: Quasi experimental study. PLACE AND DURATION OF STUDY: National Institute of Cardiovascular Diseases, Karachi, from March to October 2007. METHODOLOGY: Adult patients with severe mitral stenosis and pliable valve having no significant mitral regurgitation, aortic valve disease, or left atrial thrombus were selected for Percutaneous Transvenous Mitral Commissurotomy (PTMC) by double balloon method. All patients underwent echocardiography of left and right heart catheterization before and after PTMC. Univariate and multivariate analysis was done to assess the relation of age, gender, left atrial size, right ventricular size, gradient across mitral valve, valve area, valve area per meter, 2 body surface area, and presence of Tricuspid Regurgitation (TR) on the decrease in pulmonary arterial pressure. RESULTS: Of the 100 cases included in the final analysis, 60% were female, 84% were in sinus rhythm and had a mean age of 27 years. There was a 48% decrease in mean left atrial and 29% decrease in right ventricular systolic pressure immediately postprocedure. The mitral valve area increased from 0.883 +/- 0.1261 cm(2), pre-ballooning to 1.7864+/-0.28445 cm(2) post-PTMC, a percent change of 102.41%. In multivariate analysis, mean left atrial pressure (p=0.00: CI=0.317 - 0.007), younger age (p=0.010: CI=-0.667 to -0.095) and right ventricular size (p=0.038: CI: 0.25-0.871) were independent predictors of decrease in systolic pulmonary arterial pressure post-PTMC. CONCLUSION: Younger age, mean and left atrial pressure and right ventricular size were independent predictors of decrease in pulmonary systolic pressure immediately post-PTMC.

High degree Atrioventricular block in patients with acute inferior Myocardial Infarction with and without Right Ventricular involvement.

OBJECTIVE: To determine the influence of time on development of high degree Atrioventricular (AV) block in patients with inferior Myocardial Infarction (MI), its association with Right Ventricular (RV) infarction and its ultimate morbidity and mortality. STUDY DESIGN: A descriptive study. PLACE AND DURATION OF STUDY: The Emergency Department (ED) and the units of adult cardiology at National Institute of Cardiovascular Diseases (NICVD), Karachi, from October 2006 to March 2007. METHODOLOGY: Patients presented at ED with typical chest pain and subsequently diagnosed by standardized diagnostic criteria as having inferior MI were recruited prospectively. Patients were first analyzed on the basis of absence (Group A) or presence (Group B) of high degree AV block regardless of RV infarction. Then after patients were divided into two groups, those without RV infarction (Group I) and with RV infarction (Group II). Each group was further sub-divided as Ia, IIa and Ib, IIb depending on absence or presence of high degree AV block respectively. Each group was analyzed for comparisons with different variables for prediction of influence of time, proportion of RV infarction, association of AV block with RV infarction, complication profile and inmortality. RESULTS: Of the 220 patients with inferior MI, 52 (23.6%) had high degree AV block and 83 (37.7%) had RV infarction. They were older in age (p< 0.003). Patients who took more time to seek medical treatment from onset of symptoms were more prone to develop AV block (p<0.001). Among patients with block, 73% received thrombolytic therapy (p<0.009) and temporary pacemaker (TPM) was implanted in 75% (p<0.0001). Mortality was significantly high in those patients (p<0.0001). In group II, 61.4% presented with sinus rhythm (p<0.001). TPM was implanted to 31.3% (p<0.0001). In the 4 days of hospital course, 8.4% of patients with RV infarction developed AV block (p<0.005), whereas 10.8% of patients without RV infarction experienced post MI angina (p<0.031). Mortality was found significantly high when block was associated with RV infarction (p<0.007). No significant difference was found in response to atropine, volume replacement or streptokinase administration and reverting of block to sinus rhythm. CONCLUSION: Patients with inferior MI who took more time to seek medical treatment were found to be more prone to develop high degree AV block. RV infarction was found in about 38% of patients defined a high risk subgroup. High degree AV block significantly influenced the outcome when associated with RV infarction, leading to high mortality.

Aspiration of thrombus in ST segment elevation myocardial infarction.

OBJECTIVE: To evaluate the impact of Export Aspiration Catheter with restoration of ECG changes, arterial flow and myocardial perfusion in patients with ST segment elevation Myocardial Infarction undergoing Percutaneous Coronary Intervention (PCI). METHODS: A total of 40 consecutive patients with ST Segment Elevation Myocardial Infarction (STEMI) were selected. They underwent treatment according to the surgeon's discretion to either standard PCI or PCI with thrombus aspiration Catheter. Primary end points of the study were ST Segment resolution (STR) > 70% and myocardial blush grade (MBG) > 2. RESULTS: The base line clinical and procedural characteristics were same for both the groups. In the post intervention comparison the thrombus aspiration group was found to have significantly better outcomes as compared to the standard PCI group with regards to TIMI flow grade (p = 0.009) and myocardial blush grade (p = 0.001). Considering the criteria for MBG and STR together, the thrombus aspiration was found to have significantly better outcome than the standard PCI group (p = 0.017). CONCLUSION: This non-randomized study shows that Export Aspiration Catheter group with STEMI undergoing primary PCI is feasible and results in better angiographic ECG and myocardial perfusion rates compared with standard PCI. Role of export catheter in rescue PCI and thrombus Sapheneous Venous Graft (SVG) as primary PCI is questionable and needs larger randomized studies to prove its efficacy.

Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis.

BACKGROUND: The lipoprotein(a) pathway is a causal factor in coronary heart disease. We used a genetic approach to distinguish the relevance of two distinct components of this pathway, apolipoprotein(a) isoform size and circulating lipoprotein(a) concentration, to coronary heart disease. METHODS: In this mendelian randomisation study, we measured lipoprotein(a) concentration and determined apolipoprotein(a) isoform size with a genetic method (kringle IV type 2 [KIV2] repeats in the LPA gene) and a serum-based electrophoretic assay in patients and controls (frequency matched for age and sex) from the Pakistan Risk of Myocardial Infarction Study (PROMIS). We calculated odds ratios (ORs) for myocardial infarction per 1-SD difference in either LPA KIV2 repeats or lipoprotein(a) concentration. In a genome-wide analysis of up to 17 503 participants in PROMIS, we identified genetic variants associated with either apolipoprotein(a) isoform size or lipoprotein(a) concentration. Using a mendelian randomisation study design and genetic data on 60 801 patients with coronary heart disease and 123 504 controls from the CARDIoGRAMplusC4D consortium, we calculated ORs for myocardial infarction with variants that produced similar differences in either apolipoprotein(a) isoform size in serum or lipoprotein(a) concentration. Finally, we compared phenotypic versus genotypic ORs to estimate whether apolipoprotein(a) isoform size, lipoprotein(a) concentration, or both were causally associated with coronary heart disease. FINDINGS: The PROMIS cohort included 9015 patients with acute myocardial infarction and 8629 matched controls. In participants for whom KIV2 repeat and lipoprotein(a) data were available, the OR for myocardial infarction was 0·93 (95% CI 0·90-0·97; p<0·0001) per 1-SD increment in LPA KIV2 repeats after adjustment for lipoprotein(a) concentration and conventional lipid concentrations. The OR for myocardial infarction was 1·10 (1·05-1·14; p<0·0001) per 1-SD increment in lipoprotein(a) concentration, after adjustment for LPA KIV2 repeats and conventional lipids. Genome-wide analysis identified rs2457564 as a variant associated with smaller apolipoprotein(a) isoform size, but not lipoprotein(a) concentration, and rs3777392 as a variant associated with lipoprotein(a) concentration, but not apolipoprotein(a) isoform size. In 60 801 patients with coronary heart disease and 123 504 controls, OR for myocardial infarction was 0·96 (0·94-0·98; p<0·0001) per 1-SD increment in apolipoprotein(a) protein isoform size in serum due to rs2457564, which was directionally concordant with the OR observed in PROMIS for a similar change. The OR for myocardial infarction was 1·27 (1·07-1·50; p=0·007) per 1-SD increment in lipoprotein(a) concentration due to rs3777392, which was directionally concordant with the OR observed for a similar change in PROMIS. INTERPRETATION: Human genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein(a) concentration are independent and causal risk factors for coronary heart disease. Lipoprotein(a)-lowering interventions could be preferentially effective in reducing the risk of coronary heart disease in individuals with smaller apolipoprotein(a) isoforms. FUNDING: British Heart Foundation, US National Institutes of Health, Fogarty International Center, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, and Pfizer.

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.

Predictors of successful percutaneous transvenous mitral commissurotomy using the Bonhoeffer Multi-Track system in patients with moderate to severe mitral stenosis: Can we see beyond the Wilkins score?

OBJECTIVE: To know the predictors of a successful outcome of percutaneous transvenous mitral commissurotomy (PTMC) other than described in the Wilkins scoring system. METHODS: Two hundred fifty-eight consecutive patients were enrolled for this observational study in a tertiary care heart center of Pakistan who had a Wilkins score of ≤ 8. Patients with more than mild mitral regurgitation (MR) or having a clot in the left atrium were excluded. The Bonhoeffer multi-track system was used as a default technique. Successful PTMC was defined as achieving a mitral valve area (MVA) of ≥ 1.5 cm(2) with no more than mild MR. RESULTS: Out of 258 PTMC procedures, 197 were successful. The Bonhoeffer multi-track system was used in ~94% cases. Among unsuccessful procedures, 41 patients did not achieve the required valve area, and 21 patients developed more than mild MR, including those 8 patients who did not achieve the required valve area and had more than mild MR. Bigger mean annulus size (33.5 ± 2.6 versus 32.8 ± 2.1 mm; p=0.02) and preprocedure MVA (0.93 ± 0.1 versus 0.87 ± 0.1 cm(2); p=0.002) had a significant effect on successful PTMC. Lower mean preprocedure systolic right ventricular pressure on echo (65.4 ± 19.4 versus 75.3 ± 18 mm Hg; p=0.000) and on cath (74 ± 21.5 versus 81.5 ± 24.6 mm Hg; p=0.002), lower grade of left ventricular dysfunction (p=0.04), and tricuspid regurgitation on echo (p=0.003) also had positive effects on the outcome. CONCLUSION: Bigger preprocedure mitral valve annulus size and mitral valve area, and better left and right ventricular hemodynamics are correlated with successful PTMC.

Comparison of fluoroscopy time during coronary angiography and interventions by radial and femoral routes- can we decrease the fluoroscopy time with increased experience? An observational study.

OBJECTIVE: Radial route of access is increasingly being used for coronary angiograms and intervention. However, radiation exposure of operators was not known in our set up with either transfemoral or transradial procedures. The objective of the study was to compare related peripheral arterial route radiation exposure of operators by assessing fluoroscopy time. The secondary objective was to determine the relationship of operator experience with fluoroscopy time. METHODS: This observational study was conducted in a tertiary care center - Cardiovascular Institute of Karachi (Pakistan) during the period of July 1(st) 2009 to September 30(th) 2009. We studied 1016 consecutive adult patients referred for coronary angiography (CA) or percutaneous coronary intervention (PCI). Patients who underwent right heart catheterization or for valvuloplasty were excluded from the study. Out of these 1016 patients, 928 were diagnostic CAs (734 via femoral route [f-CA] and 194 via radial route [r-CA]) and 88 were PCI (64 via femoral route [f-PCI] and 24 via radial route [r-PCI]). Fluoroscopy time was recorded as a surrogate of radiation exposure. Statistical analysis was performed using unpaired t, Mann-Whitney U, Chi-square and ANOVA tests. RESULTS: Mean fluoroscopy time was found to be significantly higher in patients who underwent r-CA (6.3±3.8 vs 4.0±2.9 min; p<0.001) and r-PCI (15.1±11.8 vs 10.3±7.4 min; p=0.02) as compared with those underwent f-CA and f-PCI. Mean fluoroscopy time of well experienced operators was also high in r-CAs (5.4±2.9 vs 4.2±3.5 min; p=0.004). CONCLUSION: Radial procedures are associated with longer fluoroscopy time that may result in high radiation exposure to radial operators. Even well experienced radial operators cannot minimize their fluoroscopy time to the level of well experienced femoral operators.

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.