Abdul Hakeem

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=2×10−3) 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=1×10−3 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. Conclusion—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.

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 30–80xa0years. 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.

When the Worst Headache Becomes the Worst Heartache

Background and Purpose— Although a great deal of literature has been generated regarding left ventricular wall abnormalities, ECG changes and cardiac enzyme leaks associated with subarachnoid hemorrhage (SAH), there have been only a few reports of true transient left ventricular apical ballooning syndrome in patients with SAH. Several pathophysiological mechanisms have been proposed to explain the unusual features of this syndrome, such as multivessel coronary vasospasm, abnormalities in coronary microvascular function, and catecholamine-mediated cardiotoxicity. Summary of Case— A previously healthy 64-year-old woman with no history of vascular disease was found unresponsive at home. She was taken to the emergency room where a CT head revealed an SAH due to a ruptured aneurysm of the posterior communicating artery. On admission, an ECG showed deeply inverted T-waves and QT prolongation, typical of SAH. Cardiac troponin was measured at 1.2 ng/mL, and later increased to 3.7 ng/mL. A transthoracic echocardiogram on the next day revealed a large left ventricular wall abnormality, characteristic of apical ballooning with an ejection fraction of 25% to 30%. The patient remained hemodynamically stable and was started on low dose &bgr;-blocker and angiotensin-converting enzyme inhibitor. She had an uneventful cardiac recovery within 5 days at which time a repeat transthoracic echocardiogram revealed a normal ejection fraction with no wall motion abnormality. Conclusions— This report adds to the growing list of “stressors” for Takotsubo cardiomyopathy. Clinicians should be aware of the existence and the typical clinical manifestations of this syndrome, which is increasingly recognized in various populations. In particular, neurologists should consider this syndrome in the differential diagnosis of ECG changes and apical wall motion abnormalities in patients with SAH. Prognosis is generally very good with full recovery in most patients; however, there may be increased morbidity associated in patients with SAH.

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.

Coronary Steal Due to Bilateral Internal Mammary Artery—Pulmonary Artery Fistulas: A Rare Cause of Chest Pain After Coronary Artery Bypass Grafting

A 54-year-old man with a history of coronary artery bypass grafting (CABG) presented with chest pain and was found to have non—ST-segment elevation myocardial infarction. Left heart catheterization with coronary angiography demonstrated 100% occlusion of the right internal mammary artery (IMA) to the right coronary artery graft in its midsegment and a patent left IMA to the left anterior descending graft. An unusually large extensive fistulous collateral formation was observed between the right IMA and the left IMA to the pulmonary arterial system, causing left to right shunting. His angina was attributed to substantial coronary steal caused by the shunt. The patient refused any further intervention or surgery and opted for medical treatment. As a complication of CABG, IMA to pulmonary artery (PA) fistulas are rare. Thus far, more than 20 cases have been reported; most have been unilateral. This is the second reported case to date of bilateral IMA-PA fistula formation after CABG. An IMA-PA fistula should be considered in the differential diagnosis of patients presenting with chest pain after CABG and can be diagnosed by selective angiography of IMA grafts.

Noninvasive Modalities for Coronary Angiography

Optimal diagnostic quality non-invasive alternatives for visualization of the coronary arteries has been a major goal with the advent of newer cardiovascular imaging mo‐ dalities such as coronary computed tomography angiography (CCTA) and magnetic resonance coronary angiography (MRCA). The challenges in imaging coronaries are ob‐ vious. The technology must be capable of visualizing arteries as small as 1.5 mm to delineate luminal and wall pathology which becomes challenging as many of the arter‐ ies are engulfed in tissue of similar composition. Coronary arteries exhibit rapid mo‐ tion which poses major issues with blurring of images due to substantial limitations of temporal resolution. Invasive coronary angiography current enjoys the best temporal resolution (less than 20 msec ) for real time visualization of coronaries and its branch‐ es but comes with its obvious limitations. CCTA has rapidly risen to this challenge and is already widely employed using 64 slice detector technology and is outstanding for exclusion of CAD with substantial advances in radiation reduction and speed of acquisition. MRCA has made significant improvements in technology which has made coronary imaging less challenging using navigator gating, whole heart imaging and us‐ ing 3Tesla magnets, with the big advantage of no radiation and capability of non-con‐ trast coronary imaging and most of all the promise of a true “ one stop “ comprehensive assessment. However, it is still suboptimal compared to CCTA as dis‐ cussed subsequently in detail. This chapters aims to discuss MRCA and CCTA with regards to coronary imaging and compare and contrast both these imaging modalities with one another and also highlight some emerging comparisons of CCTA to invasive coronary luminal assessment technologies.

Early and long term outcome of rescue percutaneous coronary intervention (R-PCI): experience from a tertiary care center in Pakistan

Background Thrombolysis is the standard of care for STEMI in Pakistan. Failed thrombolysis has a very high morbidity and mortality. Rescue PCI then remains the only option to salvage the myocardium. We sought to analyze the angiographic, immediate and long term clinical outcome of patients undergoing Rescue PCI at our institution in Karachi, Pakistan. Methods 58 consecutive patients who underwent rescue PCI for failed thrombolysis between 2002 and 2005 were reviewed. Clinical characteristics, angiographic and procedural details with clinical outcomes including total mortality, recurrent angina, and repeat revascularization were studied. Sources included cardiac catheterization lab database, medical records and follow up at outpatient clinics. Results Rescue PCI was performed in 58 patients with a mean age 55xa0±xa012xa0years with 47 (79%) male and 11 (21%) females. CAD risk factors were hypertension (53%), dyslipidemia (48%), smoking (34%) and diabetes (34%). 53% had anterior MI, 39% inferior and 8% had a lateral wall MI. The median time frames were: onset of chest pain to ERxa0=xa099xa0min, door to needle timexa0=xa035xa0min, ER to procedure start timexa0=xa0250xa0min. The culprit vessels were: Left Anterior Descending (LAD) (53%), Right Coronary Artery (RCA) (32%) and Circumflex (CX) (15%). TIMI flow grades pre-procedural were 0/Ixa0=xa052%, IIxa0=xa034%, IIIxa0=xa014% and post procedure 0/Ixa0=xa08%, IIxa0=xa06%, IIIxa0=xa086%. The mean follow-up duration was 16.15xa0months at which 50 (86%) were alive and 43 (74.13%) had event free survival. Conclusion Procedural success, event free survival and mortality in our series of Rescue PCI from Pakistan are comparable to recent international trials and registries. It should be considered as a reasonable option for patients with failed thrombolysis.