Ethnic differences in ApoC-III concentration and the risk of cardiovascular disease: No evidence for the cardioprotective role of rare/loss of function APOC3 variants in non-Europeans.

Background: Hypertriglyceridemia is as an independent risk factor for cardiovascular disease (CVD). Apolipoprotein C-III (ApoC-III) is known to regulate triglyceride (TG) metabolism. However, the causal association between ApoC-III and CVD development is unclear. The objectives were to examine the impact of ApoC-III concentration on TG and lipoproteins and investigate the role of known rare loss-of-function APOC3 variants for modulating ApoC-III, TG concentrations and CVD risk in different ethnic groups. Methods: Plasma ApoC-III levels were measured in a multiethnic sample of 518 individuals comprising 271 Asian Indians (Sikhs), 87 Caucasians, 80 African Americans, and 80 Hispanics. Results: ApoC-III levels showed a robust association with TG in Asian Indians (r = 0.5, p = 1.1 × 10-23), Caucasians (r = 0.4, p = 7.2 × 10-4), and Hispanics (r = 0.9, p = 2.7x × 10-28). African Americans had lowest ApoC-III and TG concentrations and highest (44%) prevalence of coronary artery disease (CAD). ApoC-III levels correlated with fasting blood glucose (r = 0.25, p = 6.1 × 10-5) in Asian Indians and central adiposity in Hispanics (waist: r = 0.22, p = 0.05; waist-hip ratio: r = 0.24, p = 0.04). The carriers of rare variants IVS1-2G-A (rs373975305); A43T (rs147210663) and IVS3 + 1G-T (rs140621530) showed high TG but not low ApoC-III levels in Asian Indians and Caucasians. Conclusion: These results highlight the challenges of generalizing antisense ApoC-III inhibition for treating atherosclerotic disease in dyslipidemia that may benefit only specific sub-populations. The observed ethnic differences in ApoC-III concentrations and CAD risk factors, emphasize in-depth genetic and metabolomics evaluations on diverse ancestries.

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

BACKGROUND: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. METHODS: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. RESULTS: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). CONCLUSIONS: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Serum discrimination and phenotype assessment of coronary artery disease patents with and without type 2 diabetes prior to coronary artery bypass graft surgery.

Diabetes Mellitus (DM) accelerates coronary artery disease (CAD) and atherosclerosis, the causes of most heart attacks. The biomolecules involved in these inter-related disease processes are not well understood. This study analyzes biomolecules in the sera of patients with CAD, with and without type (T) 2DM, who are about to undergo coronary artery bypass graft (CABG) surgery. The goal is to develop methodology to help identify and monitor CAD patients with and without T2DM, in order to better understand these phenotypes and to glean relationships through analysis of serum biomolecules. Aorta, fat, muscle, and vein tissues from CAD T2DM patients display diabetic-related histologic changes (e.g., lipid accumulation, fibrosis, loss of cellularity) when compared to non-diabetic CAD patients. The patient discriminatory methodology utilized is serum biomolecule mass profiling. This mass spectrometry (MS) approach is able to distinguish the sera of a group of CAD patients from controls (p value 10-15), with the CAD group containing both T2DM and non-diabetic patients. This result indicates the T2DM phenotype does not interfere appreciably with the CAD determination versus control individuals. Sera from a group of T2DM CAD patients however are distinguishable from non-T2DM CAD patients (p value 10-8), indicating it may be possible to examine the T2DM phenotype within the CAD disease state with this MS methodology. The same serum samples used in the CAD T2DM versus non-T2DM binary group comparison were subjected to MS/MS peptide structure analysis to help identify potential biochemical and phenotypic changes associated with CAD and T2DM. Such peptide/protein identifications could lead to improved understanding of underlying mechanisms, additional biomarkers for discriminating and monitoring these disease conditions, and potential therapeutic targets. Bioinformatics/systems biology analysis of the peptide/protein changes associated with CAD and T2DM suggested cell pathways/systems affected include atherosclerosis, DM, fibrosis, lipogenesis, loss of cellularity (apoptosis), and inflammation.

Serum Monitoring and Phenotype Identification of Stage I Non-Small Cell Lung Cancer Patients.

A stage I non-small cell lung cancer (NSCLC) serum profiling platform is presented which is highly efficient and accurate. Test sensitivity (0.95) for stage I NSCLC is the highest reported so far. Test metrics are reported for discriminating stage I adenocarcinoma vs squamous cell carcinoma subtypes. Blinded analysis identified 23 out of 24 stage I NSCLC and control serum samples. Group-discriminating mass peaks were targeted for tandem mass spectrometry peptide/protein identification, and yielded a lung cancer phenotype. Bioinformatic analysis revealed a novel lymphocyte adhesion pathway involved with early-stage lung cancer.

Safety of a Rapidly Dissolving Buprenorphine/Naloxone Sublingual Tablet (BNX-RDT) for Treatment of Opioid Dependence: A Multicenter, Open-label Extension Study.

OBJECTIVE: To assess the safety of rapidly dissolving buprenorphine/naloxone sublingual tablets (BNX-RDT) in opioid-dependent patients. METHODS: This open-label, 24-week extension study enrolled patients who completed primary trials of BNX-RDT. Daily tablet doses ranged from 5.7 to 17.1 mg. The primary endpoint was safety; secondary assessments included opioid cravings, addiction severity, health-related quality of life (QOL), and workplace productivity at screening (final day of the primary trials) through study end, with changes measured from baseline of the primary trials. RESULTS: In all, 665 patients received treatment; 292 (43.9%) completed the study. A total of 258 patients (38.8%) reported 557 treatment-emergent adverse events, most commonly headache (3.2%) and constipation (3.0%). Craving scores showed continued improvement on 100-mm visual analog scale (mean change from primary trial baseline, -52.8 at screening; mean change from extension trial baseline, -60.5 at week 24). Reductions in addiction severity from baseline of both the primary and extension trial were maintained through week 24 on multiple assessments, as were improvements in QOL on Short Form 36. Employment increased by 15% and mean (SD) hours worked per week increased by 4.6 (20.1) from baseline to study end. Mean (SD) scores for impact of opioid dependence on work productivity improved from 4.7 (3.0) at baseline to 0.9 (1.8) at study end (11-point scale). CONCLUSIONS: Extended treatment with BNX-RDT demonstrated a safety profile similar to other BNX formulations, reduced opioid cravings, and improved both QOL and work productivity. Continued treatment may enable patients to advance in recovery and return to normal functioning.

Low-Level Vagus Nerve Stimulation Suppresses Post-Operative Atrial Fibrillation and Inflammation: A Randomized Study.

OBJECTIVES: This study sought to examine the efficacy of low-level vagus nerve stimulation (LLVNS) in suppressing post-operative atrial fibrillation (POAF) and inflammatory cytokines in patients undergoing cardiac surgery. BACKGROUND: POAF often complicates cardiac surgery. METHODS: Patients undergoing cardiac surgery were randomized to active or sham LLVNS. In all patients, a bipolar wire was sutured to the vagus nerve pre-ganglionic fibers alongside the lateral aspect of the superior vena cava. High-frequency (20 Hz) stimulation, 50% below the threshold for slowing the heart rate, was delivered for 72 h in the LLVNS group. The development of POAF was monitored continuously during the entire hospital stay by use of telemetry. Blood was collected on arrival in the intensive care unit and at 24 and 72 h for measurement of inflammatory cytokines. Patients were followed up within 1 month after cardiac surgery. RESULTS: A total of 54 patients were randomized to either active LLVNS (n = 26) or sham control (n = 28). The baseline characteristics of the patients were balanced in the 2 groups. POAF occurred in 3 patients (12%) in the LLVNS group and 10 patients (36%) in the control group (hazard ratio: 0.28; 95% confidence interval: 0.10 to 0.85; p = 0.027). None of the patients developed any complications as a result of wire placement. At 72 h, serum tumor necrosis factor-α and interleukin-6 levels were significantly lower in the LLVNS group than in the control group. CONCLUSIONS: These data suggest that LLVNS suppresses POAF and attenuates inflammation in patients undergoing cardiac surgery. Further studies are warranted.

Intravenous leiomyomatosis disguised as a large deep vein thrombosis.

Intravenous leiomyomatosis is a benign smooth muscle tumor which despite its histology can have devastating consequences. Furthermore, the clinical manifestations are variable and nonspecific, typically leading to delayed or missed diagnosis. Thus, it is critical for clinicians to be aware of this condition and have a high index of suspicion in a middle-aged woman with a history of uterine leiomyoma presenting with an inferior vena cava mass to enable early diagnosis and treatment. We report a case of a large intravenous leiomyoma which was initially considered to be a very large deep venous thrombosis; with thorough preoperative planning, it was successfully removed intact and in entirety with a single-stage operation.

Discriminating patients with early-stage pancreatic cancer or chronic pancreatitis using serum electrospray mass profiling.

Blood tests are needed to aid in the early detection of pancreatic ductal adenocarcinoma (PDAC), and monitoring pancreatitis development into malignancy especially in high risk patients. This study exhibits efforts and progress toward developing such blood tests, using electrospray-mass spectrometry (MS) serum profiling to distinguish patients with early-stage PDAC or pancreatitis from each other and from controls. Identification of significant serum mass peak differences between these individuals was performed using t tests and "leave one out" cross validation. Serum mass peak distributions of control individuals were distinguished from those of patients with chronic pancreatitis or early-stage PDAC with P values <10(-15), and patients with chronic pancreatitis were distinguished from those of patients with early-stage PDAC with a P value <10(-12). Sera from 12 out of 12 patients with PDAC stages I, IIA and IIB were blindly validated from controls. Tandem MS/MS identified a cancer phenotype with elements of PDAC involved in early-stage PDAC/control discrimination. These studies indicate electrospray-MS mass profiling can detect serum changes in patients with pancreatitis or early-stage pancreatic cancer. Such technology has the potential to aid in early detection of pancreatic cancer, biomarker development, and in monitoring development of pancreatitis into PDAC.

Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.

BACKGROUND: Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. METHODS AND RESULTS: Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P<10(-6)) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (ß=-0.38; P=4.5×10(-8)). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P<10(-5)) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis. CONCLUSIONS: By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.

Two different presentations of sinus of valsalva aneurysm.

Sinus of Valsalva aneurysm (SVA) is a rare cardiac anomaly that can be congenital or acquired. We report 2 cases of SVA. The first case involves a 59-year-old male presenting with frequent syncope. Echocardiogram revealed a large right SVA obstructing the right ventricular outflow tract (RVOT). The second case involves a 21-year-old female presenting with sudden onset chest pain and a continuous machinery murmur. Echocardiogram revealed a ruptured right SVA into the right atrium. Although advanced percutaneous techniques have been implemented in the correction of this anomaly, open-heart surgery with or without aortic valve replacement remains the treatment of choice.

Distinguishing patients with stage I lung cancer versus control individuals using serum mass profiling.

Serum mass profiling can discern physiological changes associated with specific disease states and their progression. Sera (86 total) from control individuals and patients with stage I nonsmall cell lung cancer or benign small pulmonary nodules were discriminated retrospectively by serum changes discerned by mass profiling. Control individuals were distinguished from patients with Stage I lung cancer or benign nodules with test sensitivities of 89% and 83%. Lung cancer patients versus those with benign nodules were distinguished with 80% sensitivity. This study exhibits progress toward a minimally-invasive aid in early detection of lung cancer and monitoring small pulmonary nodules for malignancy.

Isolated right ventricular infarction after modified Cabrol operation.

We report the case of a 27-year-old woman with a rare presentation of right ventricular failure secondary to isolated right ventricular myocardial infarction, 3 weeks after an uncommon surgical procedure, the modified Cabrol operation. Her medical history also included a Ross procedure at the age of 12 years. On the basis of her subacute presentation and a consultation with cardiac surgeons, we decided on medical management. Follow-up echocardiography at 6 months revealed that the right ventricular systolic function remained severely impaired, but the patient was asymptomatic with excellent functional capacity.We review the surgical techniques of aortic graft replacement and their respective complications. We also discuss the impact of conservative and reperfusion strategies on prognosis and long-term outcomes in the setting of right ventricular infarction.

Cytogenetic and comparative genomic hybridization studies of an esophageal giant fibrovascular polyp: a case report.

Esophageal giant fibrovascular polyps are rare and are thought to represent redundant tumorlike or hamartomatous esophageal folds. Although most patients present with slowly evolving dysphagia, a minority present with acute respiratory distress or even death caused by asphyxia. We present the pathologic and cytogenetic findings of an 18-cm esophageal giant fibrovascular polyp in a 49-year-old woman who presented with odynophagia and dysphagia. The histologic findings are that of classic esophageal giant fibrovascular polyp as previously described in the literature. Cytogenetic study revealed an abnormal karyotype, and comparative genomic hybridization analysis showed regional amplifications of chromosomes 3 and 12 and a possible loss of 22q13.3-qter. The significance of these cytogenetic findings is unclear but may suggest a neoplastic process in the pathogenesis of esophageal giant fibrovascular polyps.

Serum profiling to distinguish early- and late-stage ovarian cancer patients from disease-free individuals.

Sera mass spectrometry (MS) peak differences were analyzed from 35 ovarian cancer patients and 16 disease-free individuals. "Leave one out" cross validation was used to assign "% cancer peaks" in control and ovarian cancer sera samples. Sera MS discriminated stage I/II and stage III/V ovarian cancer patients versus controls with ROC curve area values of 0.82 and 0.92. Test sensitivities for ovarian cancer stage I/II and III/V were 80% and 93% respectively. These results indicate that MS is useful for distinguishing sera from early-stage ovarian cancer patients, and has potential as a test for early detection of this disease.

Distinguishing non-small cell lung adenocarcinoma patients from squamous cell carcinoma patients and control individuals using serum profiling.

Goals of this study were to analyze the ability of mass spectrometry serum profiling to distinguish non-small cell lung adenocarcinoma from squamous cell carcinoma patients and healthy controls. Sera were obtained from 19 adenocarcinoma patients, 24 squamous cell carcinoma patients, and 21 controls. Identifications of significant mass-to-charge ratio (m/z) peak differences between these groups were performed using t-tests. A "leave one out" cross-validation procedure yielded discriminatory lung adenocarcinoma versus squamous cell carcinoma p and ROC curve values of <.0001 and 0.92, respectively. Test sensitivity and specificity were 84% and 79%, respectively. This approach could aid in lung cancer diagnosis and sub-typing.

Abdominal aortic aneurysms (AAA) post heart transplantation: a systematic review of literature.

Peripheral vascular disease is highly prevalent post heart transplantation (HTx). The prevalence of abdominal aortic aneurysms (AAA) post HTx ranges from 1.1-10%. We performed a Pub Med, EMBASE and Cochrane review search to identify articles on AAA post HTx. Data gathered from published data included: risk factors, progression of the aneurysm and clinical outcomes. Five studies were included in the systematic review. Baseline demographic data, clinical characteristics, data on AAA prevalence and characteristics, the treatment strategies and follow up were extracted from each of these studies. Our systematic review showed that the prevalence of AAA post HTx ranged from 2-10% in the retrospective studies and 6.5% in a single prospective study. Rupture rates during a follow up period ranged from 11-38% and during that time period the mean aneurysmal expansion rate ranged from 0.78±0.41 cm/yr to 1.2±0.4 cm/yr. Male gender, ischemic heart disease, corticosteroid use, smoking and improved hemodynamics and ejection fraction post HTx were reported as possible associated risk factors in the development of AAA. Open surgical management was the treatment of choice although endovascular treatment was used in a minority of patients. AAA is increasingly prevalent post HTx and may be associated with greater rupture and expansion rates. Meticulous follow up and further prospective clinical studies are warranted to determine risk factors, expansion rates and clinical outcomes.

Serum discrimination of early-stage lung cancer patients using electrospray-ionization mass spectrometry.

The goal of this study was to evaluate the usefulness of electrospray ionization-mass spectrometry (ESI-MS) technology to distinguish sera of early-stage lung cancer patients from control individuals. ESI-MS m/z (mass divided by charge) data were generated from sera of 43 non-small cell lung cancer patients (pathological stages I and II) and 21 control individuals. Identifications of m/z peak area significances between cancer and control ESI-MS sera spectra were performed using t-tests. A "leave one out" cross validation procedure, which mimics blinded sera analysis and corrects for "over-fitting" of data, yielded discriminatory cancer versus control distribution p value and ROC curve area value of <0.001 and 0.87, respectively. Analysis without the "leave one out" cross validation procedure yielded a ROC curve area of 0.99 for discrimination of sera from lung cancer patients versus control individuals. Predictive value measurements revealed overall test efficiency and sensitivity for distinguishing sera from lung cancer patients from controls (using "leave one out" cross validation) of 80% and 84%, respectively. ESI-MS serum analysis between control individuals and lung cancer patients who smoked or did not smoke had p values in ranges indicating that smoking effects are not pronounced in our analysis. These studies indicate that ESI-MS analyses of sera from early stage non-small cell lung cancer patients were helpful in distinguishing these patients from control individuals.

Distinguishing early-stage pancreatic cancer patients from disease-free individuals using serum profiling.

This study evaluated the usefulness of electrospray mass spectrometry to distinguish sera of early-stage pancreatic cancer patients from disease-free individuals. Sera peak data were generated from 33 pancreatic cancer patients and 30 disease-free individuals. A "leave one out" cross-validation procedure discriminated stage I/II pancreatic cancer versus disease-free sera with a p value <.001 and a receiver-operator characteristic curve area value of 0.85. Predictive values for cancer stage I/II test efficiency, specificity, and sensitivity were 78%, 77%, and 79%, respectively. These studies indicate that electrospray mass spectrometry is useful for distinguishing sera of early-stage pancreatic cancer patients from disease-free individuals.

Prolonged postsurgical survival without a pulmonic valve: case report and review of the literature.

Pulmonic valve stenosis is usually congenital and causes right-sided heart failure secondary to pressure overload. We report the case of a 56-year-old male with congenital pulmonary valve stenosis who presented with severe right heart failure 32 years after pulmonary valvectomy. He subsequently underwent pulmonary valve replacement and did well. Pulmonary valvectomy is an uncommon treatment for pulmonary stenosis and this is the longest documented survival of a patient without a pulmonic valve.

Linear left atrial lesions in minimally invasive surgical ablation of persistent atrial fibrillation: techniques for assessing conduction block across surgical lesions.

Minimally invasive surgical (MIS) ablation, with pulmonary vein (PV) isolation and ganglionated plexi (GP) ablation, has proven highly successful for paroxysmal atrial fibrillation but has limited success in patients with persistent and long-standing persistent (P-LSP) AF. A set of linear left atrial (LA) lesions has been added to interrupt some macroreentrant components of P-LSP AF. This includes a Transverse Roof Line and Left Fibrous Trigone Line (from Roof Line to mitral annulus at the left fibrous trigone). With complete conduction block (CCB), these lesions should prevent single- or double-loop macroreentrant LA tachycardias from propagating around the PVs or mitral annulus. It is critical to identify whether CCB has been achieved and, if not, to locate the gap for further ablation, since residual gaps will support macroreentrant atrial tachycardias. Confirming CCB involves pacing close to one side of the ablation line and determining the direction of activation on the opposite side, by recording close bipolar electrograms at multiple paired sites (perpendicular and close to the ablation line) along the entire length of the line. Simpler approaches have been used, but all have limitations, especially when the conduction time across a gap is long. The extended lesion set was created after PV isolation and GP ablation in 14 patients with P-LSP AF. Mapping after the first set of radiofrequency applications for the Transverse Roof and Left Trigone Lines confirmed CCB in only 3/14 (21%) patients for each line, showing the importance of checking for CCB. During follow-up (median 8 months), 10/14 (71%) patients had no symptoms of atrial arrhythmia (7/10 off antiarrhythmic drugs). Of the remaining four patients, three have only infrequent episodes (self-terminating in 2/3). These preliminary results suggest that adding Roof and Trigone Lines may increase MIS success in patients with P-LSP AF. Accurate mapping techniques verify CCB and effectively locate gaps in ablation lines for further ablation.