The effects of saxagliptin on cardiac structure and function using cardiac MRI (SCARF).

PURPOSE: A recent large cardiovascular outcome trial in patients with type 2 diabetes (T2DM) demonstrated excess heart failure hospitalization with saxagliptin. We sought to evaluate the impact of saxagliptin on cardiac structure and function using cardiac magnetic resonance imaging (CMR) in patients with T2DM without pre-existing heart failure. METHODS: In this prospective study, patients with T2DM without heart failure were prescribed saxagliptin as part of routine guideline-directed management. Clinical assessment, CMR imaging and biomarkers were assessed in a blinded fashion and compared following 6 months of continued treatment. The primary outcome was the change in left ventricular (LV) ejection fraction (LVEF) after 6 months of therapy. Key secondary outcomes included changes in LV and right ventricular (RV) end-diastolic volume, ventricular mass, LV global strain and cardiac biomarkers [N terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP)] over 6 months. RESULTS: The cohort (n = 16) had a mean age of 59.9 years with 69% being male. The mean hemoglobin A1c (HbA1c) was 8.3%. Mean baseline LVEF was 57% ± 3.4, with no significant change over 6 months (- 0.2%, 95% CI - 2.5, 2.1, p = 0.86). Detailed CMR analyses that included LV/RV volumes, LV mass, and feature tracking-derived strain showed no significant change (all p > 0.50). NT-proBNP and hsCRP levels did not significantly change (p > 0.20). CONCLUSIONS: In this cohort of stable ambulatory patients with T2DM without heart failure, saxagliptin treatment was not associated with adverse ventricular remodeling over 6 months as assessed using CMR and biomarkers.

Fingerprint of long non-coding RNA regulated by cyclic mechanical stretch in human aortic smooth muscle cells: implications for hypertension.

Emerging evidence suggests that long non-coding RNAs (lncRNAs) represent a cellular hub coordinating various cellular processes that are critical in health and disease. Mechanical stress triggers changes in vascular smooth muscle cells (VSMCs) that in turn contribute to pathophysiological changes within the vasculature. We sought to evaluate the role that lncRNAs play in mechanical stretch-induced alterations of human aortic smooth muscle cells (HASMCs). RNA (lncRNA and mRNA) samples isolated from HASMCs that had been subjected to 10 or 20% elongation (1 Hz) for 24 h were profiled with the Arraystar Human LncRNA Microarray V3.0. LncRNA expression was quantified in parallel via qRT-PCR. Of the 30,586 human lncRNAs screened, 580 were differentially expressed (DE, P < 0.05) in stretched HASMCs. Amongst the 26,109 protein-coding transcripts evaluated, 25 of those DE were associated with 25 of the aforementioned DE lncRNAs (P < 0.05). Subsequent Kyoto Encyclopedia of Genes and Genomes analysis revealed that the DE mRNAs were largely associated with the tumor necrosis factor signaling pathway and inflammation. Gene Ontology analysis indicated that the DE mRNAs were associated with cell differentiation, stress response, and response to external stimuli. We describe the first transcriptome profile of stretch-induced changes in HASMCs and provide novel insights into the regulatory switches that may be fundamental in governing aberrant VSMC remodeling.

A global profile of glucose-sensitive endothelial-expressed long non-coding RNAs.

Hyperglycemia-related endothelial dysfunction is believed to be the crux of diabetes-associated micro- and macro-vascular complications. We conducted a systematic transcriptional survey to screen for human endothelial long non-coding RNAs (lncRNAs) regulated by elevated glucose levels. lncRNAs and protein-coding transcripts from human umbilical vein endothelial cells (HUVECs) cultured under high (25 mmol/L) or normal (5 mmol/L) glucose conditions for 24 h were profiled with the Arraystar Human LncRNA Expression Microarray V3.0. Of the 30 586 lncRNAs screened, 100 were significantly upregulated and 186 appreciably downregulated (P < 0.05) in response to high-glucose exposure. In the same HUVEC samples, 133 of the 26 109 mRNAs screened were upregulated and 166 downregulated. Of these 299 differentially expressed mRNAs, 26 were significantly associated with 28 differentially expressed long intergenic non-coding RNAs (P < 0.05). Bioinformatics analyses indicated that the mRNAs most upregulated are primarily enriched in axon guidance signaling pathways; those most downregulated are notably involved in pathways targeting vascular smooth muscle cell contraction, dopaminergic signaling, ubiquitin-mediated proteolysis, and adrenergic signaling. This is the first lncRNA and mRNA transcriptome profile of high-glucose-mediated changes in human endothelial cells. These observations may prove novel insights into novel regulatory molecules and pathways of hyperglycemia-related endothelial dysfunction and, accordingly, diabetes-associated vascular disease.

Adiponectin limits monocytic microparticle-induced endothelial activation by modulation of the AMPK, Akt and NFκB signaling pathways.

OBJECTIVE: Monocyte-derived microparticles (mono-MPs) are emerging as critical transducers of inflammatory signals, and have been suggested to link cardiovascular risk factors to vascular injury. Since adiponectin has been proposed to exert multiple anti-inflammatory and vasculoprotective effects, we hypothesized that it might serve to limit the production and/or action of mono-MPs. METHODS: Flow cytometry and western blot studies were conducted on THP-1 cells, THP-1-derived MPs, human umbilical vein endothelial cells (HUVECs), peripheral blood CD14+ monocytes and mice to evaluate the effects of adiponectin on mono-MPs. RESULTS: Adiponectin attenuated lipopolysaccharide (LPS)-evoked MP release from THP-1 monocytes (30% difference) and peripheral blood monocytes (both P < 0.05) as well as dampened LPS-induced mono-MP generation in vivo. Furthermore, peritoneal monocytes from Adipoq(-/-) mice generated significantly greater MPs than those from Adipoq(+/+) littermates in the absence (2.3 fold difference, P < 0.05) and presence (1.6 fold difference, P < 0.05) of LPS. LPS-induced MP expression of NLRP3 inflammasome and its key components, namely cleaved ASC, caspase-1 and IL-1ß (pro- and cleaved), were markedly attenuated by adiponectin. HUVECs incubated with MPs from LPS-treated THP-1 cells exhibited increased VCAM-1 levels and adhesion to THP-1 cells. Adiponectin abrogated these effects. From a mechanistic standpoint, the effects of adiponectin on MP release and molecular signaling occurred at least in part through the AMPK, Akt and NFκB pathways. CONCLUSION: Adiponectin exerts novel effects to limit the production and action of mono-MPs, underscoring yet another pleiotropic effect of this adipokine.

Cardiac complications of arteriovenous fistulas in patients with end-stage renal disease.

Cardiovascular disease is the leading cause of the death in dialysis patients. Arteriovenous fistulas (AVFs) are associated with lower mortality and are viewed as the desired access option in most patients with advanced kidney disease needing dialysis. However, AVFs have significant and potentially deleterious effects on cardiac functions particularly in the setting of preexisting heart disease. This article provides a comprehensive and contemporary review to what is known about the impact of AVFs on: congestive heart failure, left ventricular hypertrophy, pulmonary hypertension, right ventricular dysfunction, coronary artery disease and valvular heart disease.

Cardiac complications of arteriovenous fistulas in patients with end-stage renal disease / Complicaciones cardiacas de las fístulas arteriovenosas en pacientes con enfermedad renal terminal

Cardiovascular disease is the leading cause of the death in dialysis patients. Arteriovenous fistulas (AVFs) are associated with lower mortality and are viewed as the desired access option in most patients with advanced kidney disease needing dialysis. However, AVFs have significant and potentially deleterious effects on cardiac functions particularly in the setting of preexisting heart disease. This article provides a comprehensive and contemporary review to what is known about the impact of AVFs on: congestive heart failure, left ventricular hypertrophy, pulmonary hypertension, right ventricular dysfunction, coronary artery disease and valvular heart disease (AU)

La enfermedad cardiovascular es la principal causa de muerte en los pacientes dializados. Las fístulas arteriovenosas (FAV) se asocian a una menor mortalidad y se consideran la opción preferible de vía de acceso en la mayor parte de los pacientes con enfermedad renal avanzada que requieren diálisis. Sin embargo, las FAV tienen efectos importantes y potencialmente nocivos sobre las funciones cardíacas, en especial en presencia de una cardiopatía preexistente. En este artículo se presenta una revisión completa y actualizada de los conocimientos existentes sobre las repercusiones que tienen las FAV en los trastornos de: insuficiencia cardiaca congestiva, hipertrofia ventricular izquierda, hipertensión pulmonar, disfunción ventricular derecha, enfermedad coronaria y valvulopatías cardíacas (AU)

The essential autophagy gene ATG7 modulates organ fibrosis via regulation of endothelial-to-mesenchymal transition.

Pulmonary fibrosis is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix components. Although the origin of fibroblasts is multifactorial, recent data implicate endothelial-to-mesenchymal transition as an important source of fibroblasts. We report herein that loss of the essential autophagy gene ATG7 in endothelial cells (ECs) leads to impaired autophagic flux accompanied by marked changes in EC architecture, loss of endothelial, and gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition. Loss of ATG7 also up-regulates TGFß signaling and key pro-fibrotic genes in vitro. In vivo, EC-specific ATG7 knock-out mice exhibit a basal reduction in endothelial-specific markers and demonstrate an increased susceptibility to bleomycin-induced pulmonary fibrosis and collagen accumulation. Our findings help define the role of endothelial autophagy as a potential therapeutic target to limit organ fibrosis, a condition for which presently there are no effective available treatments.

Elevated Cardiac Troponin in Acute Stroke without Acute Coronary Syndrome Predicts Long-Term Adverse Cardiovascular Outcomes.

Background. Elevated cardiac troponin in acute stroke in absence of acute coronary syndrome (ACS) has unclear long-term outcomes. Methods. Retrospective analysis of 566 patients admitted to Temple University Hospital from 2008 to 2010 for acute stroke was performed. Patients were included if cardiac troponin I was measured and had no evidence of ACS and an echocardiogram was performed. Of 200 patients who met the criteria, baseline characteristics, electrocardiograms, and major adverse cardiovascular events (MACE) were reviewed. Patients were characterized into two groups with normal and elevated troponins. Primary end point was nonfatal myocardial infarction during follow-up period after discharge. The secondary end points were MACE and death from any cause. Results. For 200 patients, 17 patients had positive troponins. Baseline characteristics were as follows: age 63.1 ± 13.8, 64% African Americans, 78% with hypertension, and 22% with previous CVA. During mean follow-up of 20.1 months, 7 patients (41.2%) in elevated troponin and 6 (3.3%) patients in normal troponin group had nonfatal myocardial infarction (P = 0.0001). MACE (41.2% versus 14.2%, P = 0.01) and death from any cause (41.2% versus 14.5%, P = 0.017) were significant in the positive troponin group. Conclusions. Elevated cardiac troponin in patients with acute stroke and no evidence of ACS is strong predictor of long-term cardiac outcomes.

Extracardiac findings on routine echocardiographic examinations.

BACKGROUND: Incidental extracardiac findings (ECFs) have been described and studied in myocardial perfusion imaging, cardiac computed tomography, and cardiac magnetic resonance scanning. The literature is surprisingly limited with regard to ECFs in echocardiography. The aim of this study was to evaluate the prevalence and the clinical significance of ECFs in routine echocardiographic studies. METHODS: The literature in other cardiovascular modalities was searched to identify and classify ECFs. ECFs in reports of transthoracic and transesophageal echocardiographic studies performed at Temple Health Network between 2009 and 2011 were sought. A sensitivity analysis was performed by reviewing the actual echocardiographic images for a subset of studies (n = 350) to determine the sensitivity and specificity of the results. The electronic medical records of patients with ECFs on echocardiography were then retrospectively reviewed, except for those with pleural effusions and descending aortic atheroma. RESULTS: A total of 41,067 echocardiographic studies performed between September 2008 and September 2011 (39,269 transthoracic and 1,798 transesophageal studies) were screened. Of these studies, 66.5% were performed in the inpatient setting and 33.5% in the outpatient setting. The prevalence of ECFs was 4.4% (1,797 findings) and was constant during the study years. Pleural effusion was the most common ECF on transthoracic echocardiography, while descending aortic atheroma was the most common ECF on transesophageal echocardiography. Detailed chart reviews were performed in all patients with ECFs, except those with pleural effusion and descending aortic atheroma (351 cases). ECFs on echocardiography led to new diagnoses and altered management in the majority of patients with vascular or liver findings. CONCLUSIONS: In this large consecutive series, ECFs on echocardiography were relatively uncommon and had variable clinical implications. The majority or ECFs are likely low-risk findings (pleural effusion, ascites, and hiatal hernia) and can be managed conservatively. "Higher risk" findings such as liver abnormalities, inferior vena cava filling defects, mediastinal masses, and descending aortic dilatation frequently lead to significant changes in clinical management. There is a need for uniform reporting, appropriate training, and the establishment of national guidelines for ECFs on echocardiography.

Atrial arrhythmias after lung and heart-lung transplant: effects on short-term mortality and the influence of amiodarone.

BACKGROUND: The incidence and effect of atrial fibrillation or flutter (AF) after lung transplant are variable. An effect of pharmacologic treatment on outcomes is undetermined. METHODS: One hundred thirty-seven consecutive lung or heart-lung transplant patients were reviewed retrospectively. Uni- and multivariate analyses were performed to determine statistically significant risk factors for AF and short-term mortality. RESULTS: AF occurred in 45.0% of patients within 26 days. By univariate analysis, male gender was predictive of AF (hazard ratio [HR] = 2.25, 95% confidence interval [CI] 1.21 to 4.20, p = 0.011). Mortality within 200 days occurred in 36 of 137 (22.6%) patients. Those with AF had higher mortality than those without AF (27 of 62 [43.5%] vs 9 of 75 [12%]; p < 0.0001). Twenty-four of the 38 (63.1%) patients treated with amiodarone died, whereas 3 of 26 (11.5%) patients treated without amiodarone died (p < 0.0001). Mortality was similar among patients without AF, and those with AF not receiving amiodarone (9 of 75 [12%] vs 3 of 26 [11.5%], p = 1.00). By multivariate analysis, chronic obstructive pulmonary disease (HR = 0.395, CI 0.175 to 0.892, p = 0.025), primary pulmonary hypertension (HR = 7.245, CI 1.89 to 27.84, p = 0.0039), and use of amiodarone (HR = 2.967, CI 1.187 to 7.415, p = 0.020) were associated with death. Amiodarone was shown to be a significant statistical moderator (p < 0.0001) and mediator (p < 0.001) of mortality in AF patients. CONCLUSIONS: There was a high incidence of AF after lung or heart-lung transplant, and a significant increase in mortality in AF patients treated with amiodarone. In patients with severe lung pathology, amiodarone pulmonary toxicity may be more common than previously known, and may be a significant contributor to mortality. Amiodarone use should be restricted in the lung transplant patient population.