Fahad Waqar

Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks.

Although common APOE genetic variation has a major influence on plasma LDL-cholesterol, its role in affecting HDL-cholesterol and triglycerides is not well established. Recent genome-wide association studies suggest that APOE also affects plasma variation in HDL-cholesterol and triglycerides. It is thus important to resequence the APOE gene to identify both common and uncommon variants that affect plasma lipid profile. Here, we have sequenced the APOE gene in 190 subjects with extreme HDL-cholesterol levels selected from two well-defined epidemiological samples of U.S. non-Hispanic Whites (NHWs) and African Blacks followed by genotyping of identified variants in the entire datasets (623 NHWs, 788 African Blacks) and association analyses with major lipid traits. We identified a total of 40 sequence variants, of which 10 are novel. A total of 32 variants, including common tagSNPs (≥5% frequency) and all uncommon variants (<5% frequency) were successfully genotyped and considered for genotype-phenotype associations. Other than the established associations of APOE*2 and APOE*4 with LDL-cholesterol, we have identified additional independent associations with LDL-cholesterol. We have also identified multiple associations of uncommon and common APOE variants with HDL-cholesterol and triglycerides. Our comprehensive sequencing and genotype-phenotype analyses indicate that APOE genetic variation impacts HDL-cholesterol and triglycerides in addition to affecting LDL-cholesterol.

Survival of patients receiving fibrinolytic therapy for acute ST-segment elevation myocardial infarction in a developing country – patient characteristics and predictors of mortality

There is paucity of outcomes data on patients receiving fibrinolytic therapy (FT) for acute ST-elevation myocardial infarction (STEMI) in Indo-Asians. We conducted this study to determine survival as well as correlates of mortality in this population. Hospital charts of 230 patients receiving FT for acute STEMI between January 2002 and December 2004 were reviewed. Primary outcome variable was total mortality. Cox proportional hazards regression models were constructed. At a median follow-up of 717 days, 13.5% died, majority (23) during the in-hospital period. Multivariate predictors of mortality included (adjusted hazards ratio [HR], 95% confidence interval [CI]) age (HR 1.06, 95% CI 1.01–1.13), ejection fraction (HR 0.93, 95% CI 0.89–0.97), admission white cell count (HR 1.02, 95% CI 1.01–1.04) and change in ST-segment elevation (HR 0.96, 95% CI 0.92–0.99). We conclude that patients receiving FT for acute STEMI in Pakistan are a relatively high-risk group with a 10% in-hospital mortality and high frequency of recurrent events. Comparison data with primary angioplasty as an alternative strategy are needed.

Cardiac autonomic innervation

The autonomic nervous system plays a key role in regulating changes in the cardiovascular system and its adaptation to various human body functions. The sympathetic arm of the autonomic nervous system is associated with the fight and flight response, while the parasympathetic division is responsible for the restorative effects on heart rate, blood pressure, and contractility. Disorders involving these two divisions can lead to, and are seen as, a manifestation of most common cardiovascular disorders. Over the last few decades, extensive research has been performed establishing imaging techniques to quantify the autonomic dysfunction associated with various cardiovascular disorders. Additionally, several techniques have been tested with variable success in modulating the cardiac autonomic nervous system as treatment for these disorders. In this review, we summarize basic anatomy, physiology, and pathophysiology of the cardiac autonomic nervous system including adrenergic receptors. We have also discussed several imaging modalities available to aid in diagnosis of cardiac autonomic dysfunction and autonomic modulation techniques, including pharmacologic and device-based therapies, that have been or are being tested currently.

What will be the role of I-123 MIBG in improving the outcome of medically treated heart failure patients?

Heart failure (HF) remains the most common cause for hospital admissions in the Medicare age population. In recent decades, major advances in medical treatment of HF patients have resulted in longer survival and improved quality of life. Randomized clinical trials have documented that beta-adrenergic blockers (b-blockers), angiotensin-converting enzyme inhibitors (ACE-inhibitors), angiotensin receptor blockers (ARBs), and aldosterone inhibitors have provided improved outcomes for HF patients. Although widely used, these medications have frequently not been used in the doses validated in large clinical trials. This likely reflects concerns about using the full doses of b-blockers in patients with baseline bradycardia and/or using increasing doses of b-blockers, ACE-inhibitors, or ARBs in patients with low baseline systolic blood pressure. Maximum benefit of pharmacologic therapy is limited by inadequate data for drug selection for individual HF patients and inadequate data documenting the optimal therapeutic target for blood pressure and heart rate. Excessive activity of the sympathetic nervous system is a major contributor to HF progression, by increasing cardiac work, promoting myocardial fibrosis, and causing down-regulation of post-synaptic adrenergic receptors. The impact of the sympathetic nervous system in HF patients can be assessed non-invasively by imaging cardiac neuronal uptake and retention of the norepinephrine congener, I-123 metaiodobenzylguanidine (I-123 MIBG). A growing literature addresses the potential role of I-123 MIBG for identifying HF patients at high risk for sudden cardiac death, in whom implantation of a cardioverter-defibrillator may be life-saving. Relatively little attention has been focused on the potential role of I-123 MIBG in guiding medical therapy of HF and avoidance of HF progression. Therefore, this review focuses on the question of whether sympathetic cardiac neural imaging with I-123 MIBG has the potential to guide medical therapy of properly selected patients with advanced HF, thereby improving symptoms and outcome.

Coronary thrombosis in acute pancreatitis

The incidence of acute myocardial infarction in the setting of acute pancreatitis is very rare. The recognition of such complex diagnosis may be clinically challenging, as the symptoms of both conditions are often indistinguishable. We report a case in which we encountered both conditions concurrently, and hypothesize that the ambient inflammatory and pro-thrombotic milieu of acute pancreatitis resulted in acute coronary thrombosis despite the absence of significant coronary atherosclerosis. Among multiple coronary imaging modalities currently in use, optimal cohesion tomography provided a unique capability for direct visualization of the coronary thrombus. (1) Inflammatory processes such as acute pancreatitis promote a thrombogenic state. (2) Presentation of acute myocardial infarction is variable and can mimic a variety of medical conditions. (3) Intravascular imaging is emerging as a useful tool in delineating details of intra-coronary pathology not clear on standard fluoroscopy. (4) The above case highlights the likely concurrence of pathologies that follow common pathways such as system-wide inflammation and coagulation. Clinicians must be aware of this uncommon yet very likely possibility and keep a low threshold to perform ECG and cardiac biomarker testing if symptoms are suggestive of a myocardial infarction, even in the presence of a clear alternative diagnosis.

Role of I-123 MIBG in sepsis-induced cardiomyopathy.

Incidence of cardiac dysfunction, both right ventricular (RV) and left ventricular (LV), as well as systolic and diastolic, is high among patients with sepsis and septic shock. The term ‘‘septic cardiomyopathy’’ is often used to describe the spectrum of cardiac dysfunction associated with clinical effects of sepsis. Although commonly thought to be reversible in most survivors, cardiac dysfunction is associated with overall worse outcome and mortality. The study by Landesberg and colleagues is one of the largest and most important human studies on this subject. For patients with severe sepsis and septic shock, those authors showed that both LV systolic and diastolic dysfunction are associated with significantly higher mortality when present. In experimental animal models of sepsis and in the relatively small available human studies that have explored the pathophysiology of cardiac dysfunction in sepsis, several associated and, likely, causative mechanisms have been described. Among these, notable mechanisms include alterations and dysfunction of cardiac calcium channels, cardiomyocyte damage caused by excessive nitrous oxide, cytokines including IL-1, TNF-alpha and IL-6, oxidative stress and, to some extent, microvascular myocardial ischemia. However, it is worth emphasizing that unlike earlier hypotheses had suggested, decrease in coronary perfusion is usually not seen in sepsis and in fact, there might be an increase in global coronary perfusion. Methodology suggested in the literature regarding diagnosis of myocardial dysfunction in sepsis is inconsistent. Although traditionally ejection fraction is a commonly used measure of LV systolic dysfunction, its relationship with and influence by hemodynamic changes involving preload and afterload in sepsis is complex. This makes LV ejection fraction (LVEF) an unreliable measure of myocardial performance in septic patients. LVEF alone precludes assessment of diastolic and RV dysfunction, which are commonly impaired in patients with sepsis. These limitations have led to more common use of echocardiography with tissue Doppler technique, contrast echocardiography, and strain imaging. These newer techniques, although extensively studied and showing substantial promise for non-septic conditions, lack strong documentation of their effectiveness for evaluation of sepsis. Importantly, current guidelines focus directly on the therapeutic approach to treatment of sepsis rather than on prevention or treatment of the component of ventricular dysfunction in these patients. The present study focuses attention on the cardiac autonomic nervous system, to investigate the occurrence of autonomic dysfunction in the development of cardiac dysfunction in sepsis. Improved understanding of the role of cardiac autonomic dysfunction in the pathophysiology of sepsis may lead to new methods to mitigate the development of ventricular dysfunction and improve outcomes.

A comprehensive association study of apolipoprotein E-C1-C4-C2 gene cluster variation with plasma lipoprotein traits

Apolipoproteins are major determinants of plasma lipoprotein-lipid distribution. Dyslipidemia with elevated level of low-density lipoprotein cholesterol (LDL-C) and decreased level of high-density lipoprotein cholesterol (HDL-C) is associated with increased risk of cardiovascular disease (CVD), which is a major public health problem worldwide. Therefore, unraveling the genetic basis of plasma lipoprotein-lipid traits would provide insight into risk prediction and contribute to the developing of new therapeutic and intervention measures to reduce the CVD burden, which has a public health importance. The objective of this study was to characterize genetic variation in the APOE-C1-C4-C2 gene cluster on chromosome 19q13.32 by resequencing selected individuals from non-Hispanic White (NHW) and African Black populations with extreme lipid profile and then genotyping the identified sequence variants (common tagSNPs and rare variants) along with the HapMap tagSNPs covering the intergenic regions in the entire datasets (623 NHWs, and 788 Blacks) to evaluate their association with major lipid traits. Sequencing of the four apolipoprotein genes along with their hepatic control regions in subjects falling in the upper (47 NHWs, 48 Blacks), and lower (48 NHWs, 47 Blacks) 10th percentile distribution of HDL-C/triglycerides (TG) revealed 230 variants (215 substitution, 15 indels), of which 63 were shared in both populations, 52 were NHW-specific and 115 were Black-specific. A total of 70 variants (65 sequencing-identified, 5 HapMap tagSNPs) in NHWs and 108 variants (103 sequencing-identified, 5 HapMap tagSNPs) in Blacks were successfully genotyped in the entire datasets and were considered for the association analyses. Twenty variants in NHWs and twenty-four variants in Blacks (MAF>1%) showed nominally significant association (P<0.05) with at least one lipid trait. Although the major contribution of the APOE-C1-C4-C2 gene cluster was on LDL-C and apolipoprotein (apo) B, we observed multiple associations with other lipid traits, including TG, HDL-C, and apoA1. In addition to the significant contribution of common variants, rare/less common variants showed significant association with lipid traits. Our findings confirm the significant contribution of APOE-C1-C4-C2 genetic variation in affecting plasma lipid profile in the general population and consequently the CVD risk.

Idiopathic Atrial Fibrillation and Coronary Arteriovenous Fistulae: Is There a Link?

Despite being one of the most prevalent cardiac arrhythmias, the cause of atrial fibrillation (AF) in a vast majority of patients remains unknown. There is growing evidence of associated AF in patients diagnosed with coronary arteriovenous fistula. In this discussion, we have included an example of a patient who presented with new-onset AF and was subsequently diagnosed with an anomalous fistula between the right coronary artery and the superior vena cava. Definitive treatment of the fistula resulted in permanent resolution of the AF. Based on this case and a similar case reported in the literature, it is proposed that further research will unmask this possibly underdiagnosed and very treatable cause of AF.

Cardiac Tamponade Physiology Secondary to Tense Ascites

Cardiac tamponade is a common and often life-threatening process, which is typically associated with a pericardial effusion or, in rare cases, with a large pleural effusion. Theoretically, as reported in only a single prior case, it can be caused by extrinsic compression from tense ascites. We present a case in which dynamic inferior wall collapse was secondary to increased abdominal pressure from tense ascites. This phenomenon may be more common than previously diagnosed, especially in patients with liver disease. These patients often develop frequent ascites and present with clinical signs and symptoms similar to cardiac tamponade (tachycardia, hypotension and dyspnea). Presently, no formal practice guidelines exist regarding cardiac imaging for these patients. A high index of suspicion is required for timely diagnosis and management.

Contents Vol. 134, 2016

136 The Heart Valve Society 2nd Annual Meeting, March 17–19, 2016, New York City, N.Y., USA