H. Akashi

Cardiomyocyte Aldose Reductase Causes Heart Failure and Impairs Recovery from Ischemia

Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the α–myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism. These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure.

Outcome of patients with cardiac sarcoidosis undergoing cardiac transplantation—Single-center retrospective analysis

BACKGROUNDnControversy exists whether heart transplantation (HTx) is an appropriate treatment option for patients with cardiac sarcoidosis due to its potential recurrence and multi-organ involvement. Recent data from the United Network for Organ Sharing dataset suggest that the clinical outcome of cardiac sarcoidosis patients is equivalent or even better than that of the general HTx population.nnnMETHODSnWe retrospectively reviewed the clinical course of 14 patients with cardiac sarcoidosis among a total of 825 patients who underwent HTx at Columbia University Medical Center between 1997 and 2010. Post-transplant survival of patients with sarcoidosis was compared with that of non-sarcoidosis patients.nnnRESULTSnMore than half of cardiac sarcoidosis patients were initially diagnosed after HTx by tissue analysis of the explanted heart. While only 2/14 cases showed recurrence of cardiac sarcoidosis, the clinical outcome of sarcoid patients showed a trend toward higher mortality than that of non-sarcoidosis patients following HTx (1- and 5-year survival, 78.5 versus 87.2%, 52.4 versus 76.2%, respectively, p=0.09).nnnCONCLUSIONSnAlthough this is a single-center, retrospective analysis of a small number of cardiac sarcoidosis patients who underwent HTx, a concerning trend toward a higher mortality of patients with cardiac sarcoidosis was noted. A careful candidate selection in patients with known cardiac sarcoidosis should be discussed.

Markers of extracellular matrix turnover and the development of right ventricular failure after ventricular assist device implantation in patients with advanced heart failure

BACKGROUNDnCardiac extracellular matrix (ECM) is a dynamic and metabolically active collagenous network that responds to mechanical strain. The association between ECM turnover and right ventricular failure (RVF) development after left ventricular assist device (LVAD) implantation in patients with advanced heart failure (HF) was investigated.nnnMETHODSnCirculating levels of osteopontin, metalloproteinases (MMP)-2 and MPP-9, and tissue inhibitor of MMP (TIMP)-1 and TIMP-4 were measured in 61 patients at LVAD implantation and explantation and in 10 control subjects. RVF was defined as the need for RVAD, nitric oxide inhalation > 48 hours and/or inotropic support > 14 days.nnnRESULTSnAll ECM markers were elevated in patients with HF compared with controls (all p < 0.05). RVF developed in 23 patients (37.7%) on LVAD support. All ECM markers decreased on LVAD support in patients without RVF (all p < 0.05), but serum MMP-2, TIMP-1, TIMP-4, and osteopontin remained elevated in RVF patients. Multivariate analysis identified that right ventricular stroke work index (RVSWI), circulating B-type natriuretic peptide, and osteopontin were associated with RVF (all p < 0.05). Osteopontin correlated inversely with RVSWI (r = -0.44, p < 0.001). Osteopontin levels > 260 ng/ml discriminate patients who develop RVF from those without RVF (sensitivity, 83%; specificity, 82%).nnnCONCLUSIONSnMarked elevation of osteopontin levels before LVAD placement is associated with RVF development. Persistent elevation of circulating ECM markers after LVAD implantation characterizes patients who develop RVF. These novel biomarkers would have a potential role in the prediction of RVF development in patients undergoing LVAD implantation.

Vascular inflammation and abnormal aortic histomorphometry in patients after pulsatile- and continuous-flow left ventricular assist device placement

BACKGROUNDnLeft ventricular assist devices are increasingly being used in patients with advanced heart failure as both destination therapy and bridge to transplant. We aimed to identify histomorphometric, structural and inflammatory changes after pulsatile- and continuous-flow left ventricular assist device placement.nnnMETHODSnClinical and echocardiographic data were collected from medical records. Aortic wall diameter, cellularity and inflammation were assessed by immunohistochemistry on aortic tissue collected at left ventricular assist device placement and at explantation during heart transplantation. Expression of adhesion molecules was quantified by Western blot.nnnRESULTSnDecellularization of the aortic tunica media was observed in patients receiving continuous-flow support. Both device types showed an increased inflammatory response after left ventricular assist device placement with variable T-cell and macrophage accumulations and increased expression of vascular E-selectin, ICAM and VCAM in the aortic wall.nnnCONCLUSIONSnLeft ventricular assist device implantation is associated with distinct vascular derangements with development of vascular inflammation. These changes are pronounced in patients on continuous-flow left ventricular assist and associated with aortic media decellularization. The present findings help to explain the progressive aortic root dilation and vascular dysfunction in patients after continuous-flow device placement.

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF.

Structural and Functional Cardiac Profile after Prolonged Duration of Mechanical Unloading: Potential Implications for Myocardial Recovery

Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy ( nu2009= 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts ( n = 4) and normal serum from age-matched control hearts ( n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase-4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all Pu2009< 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.

One-Year Outcome of Endovenous Micropulsed Laser Ablation for Incompetent Great Saphenous Vein

Methods: Filling and drainage maneuvers using APG (Fig 1) were performed 48 times on healthy legs (16 controls) and 41 times on legs (15 patients) with superficial venous insufficiency awaiting intervention. Tests were performed three times per leg for reproducibility. The VFI (mL/s) was calculated in the usual way, by dividing 90% of the venous filling volume (90VV) by the venous filling time (VFT90); therefore, VFI 1⁄4 90VV/VFT90. The VDI (mL/s) was calculated in the same way: 90% of the venous drainage volume (VDV90) divided by the venous drainage time (VDT90); therefore VDI 1⁄4 90VDV/VDT90. Results: Controls: median (interquartile range) age, 47 (33-53) years; weight, 70 (57-87) kg; height, 170 (162-173) cm; competent proximal thigh saphenous diameter, 4 (3.1-4.6) mm. Patients: age 58 (53-69) years; weight, 85 (65-96) kg; height, 174 (166-183) cm; refluxing proximal thigh saphenous diameter, 6.2 (5.6-7.1) mm; Venous Clinical Severity Score, 4 (3-7); clinical CEAP (C2 1⁄4 8;C3 1⁄4 1,C4 1⁄4 6). The median (interquartile range) VFI and VDI in the controls were 1 (0.8-3) mL/s and 33 (22.354.9) mL/s, respectively. As shown in the boxplots, the VFI and VDI in the patients were significantly faster at 7.7 (3.5-11.9) mL/s and 51.4 (34-65) mL/s, respectively (Fig 2). Although the drainage rate (VDI) was faster in the patients, the drainage time (VDT90) took slightly longer: controls VDT90 2.4 (2.1-3.9) seconds vs patients VDT90 3.1 (2.7-3.5) seconds (P 1⁄4 .037). This was because the patients had more venous volume to drain. Adjusted to a standard mean for each leg, the reproducibility limits ( 3) of the VDI were 40.5 (95% confidence interval, 36.9-44.1) mL/s in controls and 51.8 (95% confidence interval, 48.5-55) mL/s in patients. Conclusions: Sequential orthostatic maneuvers using APG are able to measure the contributions of reflux and obstruction (filling and drainage) in patients with chronic venous disorder. This is the first study to evaluate venous drainage using the VDI. It was significantly faster in patients with chronic venous insufficiency. The responsiveness of a reduced VDI in patients with chronic venous obstruction to stenting has yet to be determined.