Mechanical Circulatory Support Prior to Heart Transplantation Predicts Early Post-Operative Stroke.

BACKGROUND: Mechanical circulatory support (MCS) devices are often deployed to treat patients with refractory cardiogenic shock, rapid deterioration of heart failure, and inotrope-dependent patients. Stroke is a common complication of MCS therapy. This study assesses the risk of stroke during the early post-heart transplantation (HT) period (days from successful HT to discharge or death) in patients who received MCS therapy leading to HT. METHODS: Data were derived from the United Organ Sharing (UNOS) database. MCS modalities studied include left ventricular assist devices (LVAD), right ventricular assist devices (RVAD), biventricular ventricular assist devices (BiVAD), and extra-corporeal membrane oxygenation (ECMO). A multiple logistic regression model was used to determine the risk of stroke during the early post-HT period associated in patients treated with MCS leading to HT. RESULTS: Between 1988 and 2014, 10,258 patients received MCS therapy leading to HT. Of these, 160 patients (1.96%) developed stroke during the early post-HT period. Multiple regression analysis showed that MCS modalities and associated odds ratios for early post-HT stroke and associated 95% confidence intervals were as follows: LVAD (1.44, 0.70-2.94), RVAD (2.89, 1.03-8.05, BiVAD (3.24, 1.15-9.10), ECMO (2.27 (1.17-4.40), and any MCS (1.60 (1.20-2.12). CONCLUSIONS: With the exception of left ventricular assist devices, use of MCS modalities leading to HT is significantly and independently associated with stroke during the early post-HT period.

Sudden Cardiac Death in Famous Athletes, Lessons Learned, Heterogeneity in Expert Recommendations and Pitfalls of Contemporary Screening Strategies.

Sudden cardiac death (SCD) in competitive athletes, though relatively uncommon, invariably leads to controversy. Specific limitations of an extensive screening process include lack of robust evidence to support prevention of SCD, poor cost-effectiveness and uncertain downstream implications of a positive screening test. An emerging body of evidence points to enhanced neurologically intact survival to hospital discharge when automated external defibrillators (AEDs) are used in a timely manner following sudden cardiac arrest (SCA). A viable alternative to an expansive screening process could be a robust secondary prevention system comprising of improvements in AED availability, stringent enforcement of CPR training in athletes and trainers to provide timely and effective resuscitation to reduce death following SCA. This strategy could widen the window to diagnose and treat the underlying etiology and prevent recurrence of SCA while also offering financial feasibility. Restricting athletes from competitive sports is a difficult decision for physicians owing to a lack of well-defined cutoffs for acceptable and prohibitive risk from pathology predisposing to SCD, especially in the absence of a protective medico-legal framework. In this review, we highlight a few cases that generated intense scrutiny by the public, media and medical professionals about the efficacy, feasibility and pitfalls of the existing screening process to diagnose cardiovascular pathology predisposing to SCD. Furthermore, contrasting approaches to screening, diagnosis and downstream workup protocols between the European Society of Cardiology and the American Heart Association are analyzed.

Prognostic significance, angiographic characteristics and impact of antithrombotic and anticoagulant therapy on outcomes in high versus low grade coronary artery ectasia: A long-term follow-up study.

OBJECTIVES: To assess the prognostic significance of high vs. low grade coronary artery ectasia (CAE) and the impact of antithrombotic or anticoagulant therapy on adverse cardiac outcomes. BACKGROUND: There is paucity of knowledge on the impact of angiographic characteristics in CAE or that of antithrombotic or anticoagulant therapy on outcomes. METHODS AND RESULTS: In this retrospective study, we reviewed angiograms and medical records of all cases of confirmed CAE (2001-2011). Extent of CAE was categorized using the Markis classification. Types 1 and 2 were categorized as high-grade and types 3 and 4 as low-grade CAE. Angiographic flow was recorded as normal or sluggish (

Successful Percutaneous Closure of Traumatic Right Ventricular Free Wall Rupture Using Amplatzer Vascular Plug Devices.

Ventricular free wall rupture (VFWR) is a rare entity and is mostly related to post myocardial infarction (MI) complications usually involving left ventricle. In traumatic chest injuries, the right ventricle (RV) is more commonly involved due to its anatomic and structural vulnerability, as in our case. Survival, although rare, has almost always been secondary to urgent surgical repair, which is the current standard of care for such cases. However, extremely tenuous hemodynamic parameters preclude urgent surgical interventions in most of these cases. Surgical repair was considered to have prohibitive risk in our case also due to multiple comorbidities. Our case offers a unique perspective into the feasibility and safety of percutaneous closure of VFWR with devices such as Amplatzer Vascular Plug (AVP) II under transesophageal echocardiography (TEE) and angiographic guidance in patients who survive VFWR. The lack of randomized evidence to standardize the duration and regimen of antiplatelet therapy following placement of these devices is to be noted.

Safety and utility of dobutamine and pressure wire use in the hemodynamic assessment of low-flow, low-gradient aortic stenosis with reduced left ventricular ejection fraction.

BACKGROUND: The ACC/AHA guidelines recommend low-dose dobutamine challenge for hemodynamic assessment of the severity of AS in patients with low flow, low gradient aortic stenosis with reduced ejection fraction (EF) (LFLG-AS; stage D2). Inherent pitfalls of echocardiography could result in inaccurate aortic valve areas (AVA), which have downstream prognostic implications. Data on the safety and efficacy of coronary pressure wire and fluid-filled catheter use for low dose dobutamine infusion is sparse. METHODS: We retrospectively analyzed 39 consecutive patients with EF<50%, AVA<1cm2 and SVI<35ml/m2 on echocardiography who underwent simultaneous right and left heart catheterization. Hemodynamic assessments were performed at baseline and at every increment in the dobutamine infusion rate (The infusion was continued until maximal dose of dobutamine or a mean AV gradient>40mmHg was attained. The occurrence of sustained ventricular arrhythmias, symptomatic hypotension or intolerable symptoms leading to cessation of infusion was recorded. Transient ischemic attacks (TIAs) or clinically apparent strokes periprocedurally or up to 30days after the procedure were recorded. RESULTS: Dobutamine challenge confirmed true AS in 26 patients (67%) and pseudosevere AS in 34%. No sustained arrhythmias, hypotension or cessation of infusion from intolerable symptoms were observed. No clinical strokes or TIAs were observed up to 30days after procedure in any of these patients. CONCLUSIONS: Hemodynamic assessment of AS using a pressure wire with dobutamine challenge is a safe and effective tool in identifying truly severe AS in patients with LFLG-AS with reduced EF.

Implications of the 2013 ACC/AHA cholesterol guidelines on contemporary clinical practice for patients with atherosclerotic coronary and peripheral arterial disease.

BACKGROUND: Cholesterol management guidelines from the American College of Cardiology/American Heart Association (ACC/AHA-2013) recommend fixed statin dosing (dose depends on age ≤ or >75years) compared to the earlier adult treatment panel III (ATPIII) guidelines which recommended specific low-density lipoprotein-cholesterol (LDL-C) targets. Clinical implications of this recommendation are not known. METHODS: We retrospectively compared cholesterol levels and statin utilization across cohorts with coronary artery disease (CAD) (n=9563), peripheral arterial disease (PAD) (n=596) and CAD+PAD (n=975) by applying both guidelines. The percentage of patients who achieved guideline-specific targets using 2013 ACC/AHA (use of moderate/high intensity statins) or ATPIII guidelines (LDL-C<100mg/dl) was compared between all groups. RESULTS: Using both guidelines, the PAD only group demonstrated lower utilization and lower statin doses than the CAD or CAD+PAD groups. When applying the ACC/AHA guidelines, more patients in the CAD only group (age ≤75 years) were considered at goal as compared to the ATPIII guidelines (92.2% vs. 75%), primarily driven by the group placed on moderate/high intensity statins but had an LDL-C level >100mg/dl. CONCLUSIONS: Application of the ACC/AHA guidelines results in a higher percentage of patients considered to be 'at goal' when compared to the ATP III guidelines without changes in clinical practice. This is due to patients ≤75 years old on adequate statin doses but still have LDL-C levels >100mg/dl, thereby raising concerns that physicians may not pursue alternate LDL reduction strategies since they are now considered at goal despite LDL-C >100mg/dl. Lipid management of PAD patients remains sub-optimal as compared to CAD and CAD+PAD.

Incremental Value of Two Dimensional Speckle Tracking Echocardiography in the Functional Assessment and Characterization of Subclinical Left Ventricular Dysfunction.

Subclinical left ventricular (LV) dysfunction refers to subtle abnormalities in LV function which typically precede a reduction in the left ventricular ejection fraction (LVEF). The assessment of myocardial function using LVEF, a radial metric of systolic function, is subject to load dependence, intra-observer and inter-observer variability. Reductions in LVEF typically manifest late in the disease process thus compromising the ability to intervene before irreversible impairment of systolic performance sets in. 2-Dimensional speckle tracking echocardiography (2D-STE), a novel strain imaging modality has shown promise as a sensitive indicator of myocardial contractility. It arms the clinician with a powerful and practical tool to rapidly quantify cardiac mechanics, circumventing several inherent limitations of conventional echocardiography. This article highlights the incremental utility of 2D-STE in the detection of subclinical LV dysfunction.

Intravenous Adenosine Infusion is Safe and Well Tolerated During Coronary Fractional Flow Reserve Assessment in Elderly Patients With Severe Aortic Stenosis.

BACKGROUND: This study assessed the safety of intravenous adenosine infusion during fractional flow reserve (FFR) evaluation of intermediate coronary lesions in severe aortic stenosis (AS). In severe AS, the extent of underlying coronary artery disease (CAD) can be an important determinant for deciding between surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). Hemodynamic assessment of coronary lesion severity using FFR may reduce the extent of revascularization needed and make TAVR more feasible in higher-risk patients (compared with coronary artery bypass surgery with SAVR). METHODS AND RESULTS: We retrospectively analyzed the demographic, clinical, and hemodynamic parameters of 72 patients with severe AS who underwent FFR procedure with intravenous adenosine infusion for hemodynamic assessment of intermediate coronary artery lesions. Severe AS patients were elderly, predominantly male, and had a high prevalence of peripheral arterial disease, prior myocardial infarction, left ventricular hypertrophy, and chronic kidney disease. Mean aortic valve area in these patients was 0.71 ± 0.24 cm². No patient with severe AS required discontinuation of the adenosine and all patients tolerated the infusion well. We observed a statistically significant reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) during adenosine infusion compared with the baseline values. However, no clinically significant adverse events occurred. CONCLUSION: In elderly patients with severe AS, adenosine infusion is safe and well tolerated during FFR evaluation of intermediate coronary lesions. There was a significantly greater drop in SBP, DBP, MAP, and HR with adenosine infusion as compared with baseline values. This, however, was not associated with clinically significant adverse events.

Periprocedural Management of Non-Vitamin K Oral Anticoagulants in Chronic Kidney Disease: A Review of Existing Heterogeneity and Contemporary Evidence.

Non vitamin-K oral anticoagulants (NOAC) have considerably enhanced anticoagulation practice for non-valvular atrial fibrillation with specific advantages of fixed dosing, non-fluctuant therapeutic levels and obviation of therapeutic level monitoring. NOAC pharmacology is remarkable for considerable renal excretion. Heterogeneity in the precise time cut-offs for discontinuation of NOACs prior to elective surgical or percutaneous procedures arise from the non-linear variations of drug excretion with different levels of creatinine clearances as in chronic kidney disease. Multiple authors have suggested cut-offs leading to ambiguity among practicing clinicians. Recent data pertaining to systemic thromboembolism, stroke and major bleeding derived from randomized controlled clinical trials have simplified the periprocedural management of NOACs. This review focusses on heterogeneity in the management of NOACs in patients with CKD in this peculiar scenario and highlights the contemporary evidence to support a unified approach towards perioperative management of NOACs. Multiple antidotes targeted towards binding of specific NOACs have been developed and are in the testing phase, thereby offering immense potential for rapid and complete reversal of NOAC activity in emergent procedures and major bleeding episodes. Targeted research on thromboembolism, stroke and major bleeding following temporary periprocedural interruption of NOACs using multicentric registries could further expand the clinical utility of these agents.

COSMIC: exploring the world's knowledge of somatic mutations in human cancer.

COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://cancer.sanger.ac.uk) is the world's largest and most comprehensive resource for exploring the impact of somatic mutations in human cancer. Our latest release (v70; Aug 2014) describes 2 002 811 coding point mutations in over one million tumor samples and across most human genes. To emphasize depth of knowledge on known cancer genes, mutation information is curated manually from the scientific literature, allowing very precise definitions of disease types and patient details. Combination of almost 20,000 published studies gives substantial resolution of how mutations and phenotypes relate in human cancer, providing insights into the stratification of mutations and biomarkers across cancer patient populations. Conversely, our curation of cancer genomes (over 12,000) emphasizes knowledge breadth, driving discovery of unrecognized cancer-driving hotspots and molecular targets. Our high-resolution curation approach is globally unique, giving substantial insight into molecular biomarkers in human oncology. In addition, COSMIC also details more than six million noncoding mutations, 10,534 gene fusions, 61,299 genome rearrangements, 695,504 abnormal copy number segments and 60,119,787 abnormal expression variants. All these types of somatic mutation are annotated to both the human genome and each affected coding gene, then correlated across disease and mutation types.

Left ventricular hypertrophy and risk reclassification for coronary events in multi-ethnic adults.

BACKGROUND: Left ventricular hypertrophy (LVH) has not been evaluated for reclassification improvement in the intermediate Framingham risk category for incident hard coronary events in a large multi ethnic population free of cardiovascular disease at baseline. DESIGN: A post-hoc analysis on the Multi Ethnic Study of Atherosclerosis (MESA) dataset (n = 4921) was performed. METHODS: LVH was defined as the upper 95 th percentile of cardiac magnetic resonance imaging derived left ventricular mass (LVM) indexed based on body surface area (BSA) and height. Multivariate Cox proportional hazards models were used to assess the independent association between LVH and composite outcomes like all cardiovascular disease (CVDa) and hard coronary heart disease (CHDh) events over a mean follow-up period of 4.5 years. To assess the incremental value of LVH over traditional CV risk factors for CHDh prediction, we compared the discrimination, calibration and net reclassification index (NRI) of models comprising of traditional CV risk factors with and without LVH. RESULTS: LVH derived from LVM indexed by BSA (LVH-BSA) and height(1.7)(LVH-height) showed an independent association with CVDa (LVH-BSA: hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.05-2.20, p = 0.03; LVH-height(1.7): HR 1.58, 95% CI 1.14-2.18, p = 0.012) and CHDh (LVH-BSA: HR 2.36, 95% CI 1.37-4.04, p = 0.002; LVH-height(1.7): HR: 1.95, 95% CI: 1.17-3.26, p = 0.01). Addition of LVH to the model based on traditional CV risk factors demonstrated no significant improvement in NRI for CHDh in either the entire cohort (LVH-BSA: NRI 1.7%, 95% CI: -8.3% to 11.7%, p = 0.74; LVH-height(1.7): NRI 2.7%, 95% CI: -5.8% to 11.3%, p = 0.62) or the intermediate risk group (LVH-BSA: NRI 12.0%, 95% CI: -5.7% to 29.8%, p = 0.19; LVH-height(1.7): NRI 14.5%, 0.1% to 28.8%, p = 0.05). CONCLUSIONS: Although an independent predictor of cardiovascular events, LVH does not lead to clinically meaningful reclassification of the overall and intermediate risk population for CHDh.

Is bacteriostatic saline superior to normal saline as an echocardiographic contrast agent?

Objective data on the performance characteristics and physical properties of commercially available saline formulations [normal saline (NS) vs. bacteriostatic normal saline (bNS)] are sparse. This study sought to compare the in vitro physical properties and in vivo characteristics of two commonly employed echocardiographic saline contrast agents in an attempt to assess superiority. Nineteen patients undergoing transesophageal echocardiograms were each administered agitated regular NS and bNS injections in random order and in a blinded manner according to a standardized protocol. Video time-intensity (TI) curves were constructed from a representative region of interest, placed paraseptally within the right atrium, in the bicaval view. TI curves were analyzed for maximal plateau acoustic intensity (Vmax, dB) and dwell time (DT, s), defined as time duration between onset of Vmax and decay of video intensity below clinically useful levels, reflecting the duration of homogenous opacification of the right atrium. To further characterize the physical properties of the bubbles in vitro, fixed aliquots of similarly agitated saline were injected into a glass well slide-cover slip assembly and examined using an optical microscope to determine bubble diameter in microns (µm) and concentration [bubble count/high power field (hpf)]. A higher acoustic intensity (a less negative dB level), higher bubble concentration and longer DT were considered properties of a superior contrast agent. For statistical analysis, a paired t test was conducted to evaluate the differences in means of Vmax and DT. Compared to NS, bNS administration was associated with superior opacification (video intensity -8.69 ± 4.7 vs. -10.46 ± 4.1 dB, P = 0.002), longer DT (17.3 ± 6.1 vs. 10.2 ± 3.7 s) in vivo and smaller mean bubble size (43.4 vs. 58.6 µm) and higher bubble concentration (1,002 vs. 298 bubble/hpf) in vitro. bNS provides higher intensity and more sustained opacification of the right atrium compared to NS. Higher bubble concentration and stability appear to be additional desirable rheological characteristics favoring bNS as a contrast agent.

Comparison of patients with peripartum heart failure and normal (≥55%) versus low (<45%) left ventricular ejection fractions.

The current definition of peripartum cardiomyopathy (PC) is restricted to patients with left ventricular systolic dysfunction (ejection fraction [EF]<45%). Data on peripartum heart failure (HF) with normal EF are sparse. We describe clinical characteristics of patients with normal (≥55%) and patients with low (<45%) left ventricular ejection fractions (LVEFs). Electronic medical records (2006 to 2013) of our tertiary care center were retrospectively screened to identify peripartum HF with normal EF, defined as an entity meeting Framingham criteria for HF with symptom onset during the last month of pregnancy or up to 5 months after delivery and with an EF of ≥55%. Clinical characteristics, echocardiographic parameters, and outcomes of these patients were compared with age-matched control patients with traditionally defined PC (EF<45%). A total of 25 patients with PC and EF≥55% were identified. Exclusion of hypertension (n=9), preeclampsia (n=1), and diabetes mellitus (n=2) yielded 13 patients with PC and EF≥55%. Age-matched patients with traditional PC (EF<45%) constituted controls (n=16). Compared with patients with PC and low LVEF, patients with PC and normal LVEF had lower B-type natriuretic peptide levels, systolic and diastolic left ventricular dimensions, left atrial size, and incidence of decompensated HF during delivery (p<0.05). Compared with historical age-matched controls, patients with normal LVEF exhibited attenuated E' mitral annular velocities. On follow-up, these patients were associated with a lower New York Heart Association functional class. In conclusion, peripartum HF with normal LVEF appears to be a distinct entity.

Data mining using the Catalogue of Somatic Mutations in Cancer BioMart.

Catalogue of Somatic Mutations in Cancer (COSMIC) (http://www.sanger.ac.uk/cosmic) is a publicly available resource providing information on somatic mutations implicated in human cancer. Release v51 (January 2011) includes data from just over 19,000 genes, 161,787 coding mutations and 5573 gene fusions, described in more than 577,000 tumour samples. COSMICMart (COSMIC BioMart) provides a flexible way to mine these data and combine somatic mutations with other biological relevant data sets. This article describes the data available in COSMIC along with examples of how to successfully mine and integrate data sets using COSMICMart. DATABASE URL: http://www.sanger.ac.uk/genetics/CGP/cosmic/biomart/martview/.

The Pfam protein families database.

Pfam is a widely used database of protein families and domains. This article describes a set of major updates that we have implemented in the latest release (version 24.0). The most important change is that we now use HMMER3, the latest version of the popular profile hidden Markov model package. This software is approximately 100 times faster than HMMER2 and is more sensitive due to the routine use of the forward algorithm. The move to HMMER3 has necessitated numerous changes to Pfam that are described in detail. Pfam release 24.0 contains 11,912 families, of which a large number have been significantly updated during the past two years. Pfam is available via servers in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden (http://pfam.sbc.su.se/).