Mitral valve prolapse morphofunctional features by cardiovascular magnetic resonance: more than just a valvular disease.

INTRODUCTION: Mitral valve (MV) prolapse (MVP) is a primary valvular abnormality. We hypothesized that additionally there are concomitant abnormalities of the left ventricle (LV) and MV apparatus in this entity even in the absence of significant mitral regurgitation (MR). OBJECTIVE: To characterize MV and LV anatomic and functional features in MVP with preserved LV ejection fraction, with and without significant MR, using cardiovascular magnetic resonance (CMR). METHODS: Consecutive MVP patients (n = 80, mean 52 years, 37% males) with preserved LV ejection fraction, and 44 controls (46 years, 52% males) by CMR were included, as well as 13 additional patients with "borderline" MVP. From cine images we quantified LV volumes, MV and LV anatomic measurements (including angle between diastolic and systolic annular planes, annular displacement, and basal inferolateral hypertrophy) and, using feature tracking, longitudinal and circumferential peak systolic strains. RESULTS: Significant MR was found in 46 (56%) MVP patients. Compared with controls, MVP patients had LV enlargement, basal inferolateral hypertrophy, higher posterior annular excursion, and reduced shortening of the papillary muscles. LV basal strains were significantly increased, particularly in several basal segments. These differences remained significant in patients without significant MR, and many persisted in "borderline" MVP. CONCLUSIONS: In patients with MVP and preserved LV ejection fraction there is LV dilatation, basal inferolateral hypertrophy, exaggerated posterior annular displacement and increased basal deformation, even in the absence of significant MR or overt MVP. These findings suggest that MVP is a disease not only of the MV but also of the adjacent myocardium.

Left ventricular apical aneurysm in hypertrophic cardiomyopathy as a risk factor for sudden death at any age.

In hypertrophic cardiomyopathy (HCM) aging has proved protective against sudden death (SD) risk and aggressive recommendations for prophylactic ICDs are uncommon in patients ≥60 years. Nevertheless, we present a patient with an unexpected but aborted sudden death event at the advanced age of 71 years due to a left ventricular apical aneurysm (LVAA) which has emerged as a novel SD marker. Subsequent reappraisal of the Tufts HCM database, specifically the 118 LVAA patients, showed that 36% of SD events occurred at ≥60 years. Of HCM patients ≥ 60 years, SD was 8-fold more common with aneurysm than without aneurysms (16% vs 2%; P < 0.001). Risk in HCM with LVAA persists throughout life and senior LVAA patients should also be considered for primary prevention of SD with the ICD.

Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure.

BACKGROUND: Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose use for ATP generation. We hypothesized that cardiac accumulation of toxic lipid intermediates inhibits insulin signaling in advanced heart failure and that mechanical unloading of the failing myocardium corrects impaired cardiac metabolism. METHODS AND RESULTS: We analyzed the myocardium and serum of 61 patients with heart failure (body mass index, 26.5±5.1 kg/m(2); age, 51±12 years) obtained during left ventricular assist device implantation and at explantation (mean duration, 185±156 days) and from 9 control subjects. Systemic insulin resistance in heart failure was accompanied by decreased myocardial triglyceride and overall fatty acid content but increased toxic lipid intermediates, diacylglycerol, and ceramide. Increased membrane localization of protein kinase C isoforms, inhibitors of insulin signaling, and decreased activity of insulin signaling molecules Akt and Foxo were detectable in heart failure compared with control subjects. Left ventricular assist device implantation improved whole-body insulin resistance (homeostatic model of analysis-insulin resistance, 4.5±0.6-3.2±0.5; P<0.05) and decreased myocardial levels of diacylglycerol and ceramide, whereas triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/phosphatidylinositol-3 kinase/Akt signaling cascade after left ventricular assist device implantation was confirmed by increased phosphorylation of Akt and Foxo, which was accompanied by decreased membrane localization of protein kinase C isoforms after left ventricular assist device implantation. CONCLUSIONS: Mechanical unloading after left ventricular assist device implantation corrects systemic and local metabolic derangements in advanced heart failure, leading to reduced myocardial levels of toxic lipid intermediates and improved cardiac insulin signaling.

Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function.

Hearts utilize fatty acids as a primary source of energy. The sources of those lipids include free fatty acids and lipoprotein triglycerides. Deletion of the primary triglyceride-hydrolyzing enzyme lipoprotein lipase (LPL) leads to cardiac dysfunction. Whether heart LPL-knockout (hLPL0) mice are compromised due a deficiency in energetic substrates is unknown. To test whether alternative sources of energy will prevent cardiac dysfunction in hLPL0 mice, two different models were used to supply nonlipid energy. 1) hLPL0 mice were crossed with mice transgenically expressing GLUT1 in cardiomyocytes to increase glucose uptake into the heart; this cross-corrected cardiac dysfunction, reduced cardiac hypertrophy, and increased myocardial ATP. 2) Mice were randomly assigned to a sedentary or training group (swimming) at 3 mo of age, which leads to increased skeletal muscle production of lactate. hLPL0 mice had greater expression of the lactate transporter monocarboxylate transporter-1 (MCT-1) and increased cardiac lactate uptake. Compared with hearts from sedentary hLPL0 mice, hearts from trained hLPL0 mice had adaptive hypertrophy and improved cardiac function. We conclude that defective energy intake and not the reduced uptake of fat-soluble vitamins or cholesterol is responsible for cardiac dysfunction in hLPL0 mice. In addition, our studies suggest that adaptations in cardiac metabolism contribute to the beneficial effects of exercise on the myocardium of patients with heart failure.

Fish oil selectively improves heart function in a mouse model of lipid-induced cardiomyopathy.

Fish oil (FO) supplementation may improve cardiac function in some patients with heart failure, especially those with diabetes. To determine why this occurs, we studied the effects of FO in mice with heart failure either due to transgenic expression of the lipid uptake protein acyl CoA synthetase 1 (ACS1) or overexpression of the transcription factor peroxisomal proliferator-activated receptor (PPAR) γ via the cardiac-specific myosin heavy chain (MHC) promoter. ACS1 mice and control littermates were fed 3 diets containing low-dose or high-dose FO or nonpurified diet (NPD) for 6 weeks. MHC-PPARγ mice were fed low-dose FO or NPD. Compared with control mice fed with NPD, ACS1, and MHC-PPARγ, mice fed with NPD had reduced cardiac function and survival with cardiac fibrosis. In contrast, ACS1 mice fed with high-dose FO had better cardiac function, survival, and less myocardial fibrosis. FO increased eicosapentaenoic and docosahexaenoic acids and reduced saturated fatty acids in cardiac diacylglycerols. This was associated with reduced protein kinase C alpha and beta activation. In contrast, low-dose FO reduced MHC-PPARγ mice survival with no change in protein kinase C activation or cardiac function. Thus, dietary FO reverses fibrosis and improves cardiac function and survival of ACS1 mice but does not benefit all forms of lipid-mediated cardiomyopathy.

Increased levels of retinol binding protein 4 in patients with advanced heart failure correct after hemodynamic improvement through ventricular assist device placement.

BACKGROUND: Chronic heart failure is associated with higher risk for developing diabetes mellitus. Secretory products from adipocytes may contribute to the deterioration in glycemic control and increased insulin resistance (IR). Retinol binding protein 4 (RBP4) is an adipose tissue-derived protein with pro-diabetogenic effects. The aim of the present study was to investigate the relationship of RBP4 in patients with heart failure. METHODS AND RESULTS: Serum levels of RBP4, insulin, and fasting glucose were assessed in 58 patients with severe heart failure at the time of left ventricular assist device (LVAD) implantation and in 44 patients at the time of explantation, as well as in 10 normal control subjects. Serum RBP4 levels were measured by specific enzyme-linked immunosorbent assay, and IR was assessed using the homeostatic model of IR (HOMA-IR). Fasting glucose, insulin and HOMA-IR were significantly higher in patients at the time of LVAD implantation compared to controls (all P<0.01). RBP-4 and HOMA-IR significantly decreased after LVAD implantation (21.7 ± 8.8 mg/dl to 16.0 ± 3.8 mg/dl, P<0.05; 4.2 ± 2.7 to 2.5 ± 2.0, P<0.01). CONCLUSIONS: Patients with advanced heart failure have increased levels of RBP4, and LVAD implantation reduces RBP4. These findings implicate RBP4 in the cascade of reversible metabolic derangements in advanced heart failure.

Pyridoxine-Deficient Streptococcus: An Uncommon Virulent Cause of Subacute Destructive Aortic Valve Endocarditis.

Nutritional variant streptococcus (NVS) or pyridoxal-dependent streptococcus is a rare but significant cause of infective endocarditis (IE), which presents as a diagnostic dilemma due to difficulty in organism isolation, and high rates of treatment failure, recurrence, and mortality. We discuss a case of a 52-year-old male who presented with chronic fatigue, cyclic fever, night sweats, and weight loss. He was treated with culture-directed antibiotics and surgical aortic valve replacement due to disease severity and risk of embolization. This case highlights the clinical significance of NVS IE, and the importance of early recognition, and immediate, often invasive therapy to improve outcomes.

Clinical Spectrum and Management Implications of Left Ventricular Outflow Obstruction With Mild Ventricular Septal Thickness in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HC) has historically been characterized as a disease of substantial left ventricular hypertrophy, often associated with dynamic left ventricular outflow tract obstruction. However, we have recently encountered patients with subaortic obstruction and only minimal basal septal thickness, raising important management implications. Thereby, we sought to characterize the natural history and treatment strategies for this under-recognized subgroup of HC patients with dynamic obstruction. Of 1,591 consecutive patients with a HC diagnosis, 113 (7%) were identified with outflow obstruction due to elongated mitral valve leaflets producing systolic anterior motion and septal contact typical of HC (gradient, 84 ± 29 mm Hg at rest or with exercise), with maximal ventricular septal thickness ≤15 mm, including 14 patients with only 10 to 12 mm. In addition to the mechanism of outflow obstruction, other evidence supporting a HC diagnosis prominently included: positive HC family history and/or pathogenic sarcomere mutation, arrhythmic sudden death event, typical histopathology of septal muscle, and characteristic mitral valve and papillary muscle anomalies. Over 3.8 ± 3.5 years, 41 patients (36%) developed severe heart failure including 36 who have undergone myectomy associated with reconstruction of the outflow tract and mitral valve apparatus, resulting in relief of gradient without iatrogenic ventricular septal defect or mitral valve replacement. Postoperatively, all 36 patients have survived with symptom relief to New York Heart Association classes I/II. In conclusion, these observations expand the HC clinical profile and phenotype to include an under-appreciated subgroup in which disease expression includes outflow obstruction due primarily to an elongated mitral valve, associated with only minimal (or normal) ventricular septal thickness. Such HC patients can develop marked functional limitation amenable to an operative strategy that effectively relieved symptoms due to outflow obstruction, but without mitral valve replacement.

Aorto-left atrial fistula diagnosed with computed tomographic angiography: A case report.

Aorto-atrial fistulas are a rare diagnosis with limited reports in the clinical literature. These findings are often characterized by echocardiography alone; however, the advent and increased availability and use of CT angiography to diagnose cardiac abnormalities provides improved anatomic visibility of potential defects. We are reporting a case of a 76-year-old male with decompensated heart failure secondary to a fistula between the aorta and left atrium after remote history of bioprosthetic aortic valve replacement.

Supplementation of l-Alanyl-l-Glutamine and Fish Oil Improves Body Composition and Quality of Life in Patients With Chronic Heart Failure.

BACKGROUND: Skeletal muscle dysfunction and exercise intolerance are clinical hallmarks of patients with heart failure. These have been linked to a progressive catabolic state, skeletal muscle inflammation, and impaired oxidative metabolism. Previous studies suggest beneficial effects of ω-3 polyunsaturated fatty acids and glutamine on exercise performance and muscle protein balance. METHODS AND RESULTS: In a randomized double-blind, placebo-controlled trial, 31 patients with heart failure were randomized to either l-alanyl-l-glutamine (8 g/d) and polyunsaturated fatty acid (6.5 g/d) or placebo (safflower oil and milk powder) for 3 months. Cardiopulmonary exercise testing, dual-energy x-ray absorptiometry, 6-minute walk test, hand grip strength, functional muscle testing, echocardiography, and quality of life and lateral quadriceps muscle biopsy were performed at baseline and at follow-up. Oxidative capacity and metabolic gene expression were analyzed on muscle biopsies. No differences in muscle function, echocardiography, 6-minute walk test, or hand grip strength and a nonsignificant increase in peak VO2 in the treatment group were found. Lean body mass increased and quality of life improved in the active treatment group. Molecular analysis revealed no differences in muscle fiber composition, fiber cross-sectional area, gene expression of metabolic marker genes (PGC1α, CPT1, PDK4, and GLUT4), and skeletal muscle oxidative capacity. CONCLUSIONS: The combined supplementation of l-alanyl-l-glutamine and polyunsaturated fatty acid did not improve exercise performance or muscle function but increased lean body mass and quality of life in patients with chronic stable heart failure. These findings suggest potentially beneficial effects of high-dose nutritional polyunsaturated fatty acids and amino acid supplementations in patients with chronic stable heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01534663.

Ventricular assist device implantation improves skeletal muscle function, oxidative capacity, and growth hormone/insulin-like growth factor-1 axis signaling in patients with advanced heart failure.

BACKGROUND: Skeletal muscle dysfunction in patients with heart failure (HF) has been linked to impaired growth hormone (GH)/insulin-like growth factor (IGF)-1 signaling. We hypothesized that ventricular assist device (VAD) implantation reverses GH/IGF-1 axis dysfunction and improves muscle metabolism in HF. METHODS: Blood and rectus abdominis muscle samples were collected during VAD implantation and explantation from patients with HF and controls. Clinical data were obtained from medical records, biomarkers measured by enzyme-linked immunosorbent assay (ELISA), and gene expression analyzed by reverse transcription and real-time polymerase chain reaction (RT-PCR). Grip strength was assessed by dynamometry. Oxidative capacity was measured using oleate oxidation rates. Muscle fiber type and size were assessed by histology. RESULTS: Elevated GH (0.27 ± 0.27 versus 3.6 ± 7.7 ng/ml in HF; p = 0.0002) and lower IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 were found in HF (IGF-1, 144 ± 41 versus 74 ± 45 ng/ml in HF, p < 0.05; and IGFBP-3, 3,880 ± 934 versus 1,935 ± 862 ng/ml in HF, p = 0.05). The GH/IGF-1 ratio, a marker of GH resistance, was elevated in HF (0.002 ± 0.002 versus 0.048 ± 0.1 pre-VAD; p < 0.0039). After VAD support, skeletal muscle expression of IGF-1 and IGFBP-3 increased (10-fold and 5-fold, respectively; p < 0.05) accompanied by enhanced oxidative gene expression (CD36, CPT1, and PGC1α) and increased oxidation rates (+1.37-fold; p < 0.05). Further, VAD implantation increased the oxidative muscle fiber proportion (38 versus 54 %, p = 0.031), fiber cross-sectional area (CSA) (1,005 ± 668 versus 1,240 ± 670 µm(2), p < 0.001), and Akt phosphorylation state in skeletal muscle. Finally, hand grip strength increased 26.5 ± 27.5 % at 180 days on-VAD (p < 0.05 versus baseline). CONCLUSION: Our data demonstrate that VAD implantation corrects GH/IGF-1 signaling, improves muscle structure and function, and enhances oxidative muscle metabolism in patients with advanced HF.

Hepatic dysfunction and survival after orthotopic heart transplantation: application of the MELD scoring system for outcome prediction.

BACKGROUND: The prevalence of heart failure (HF) is rising and the only corrective treatment is cardiac transplantation. Advanced HF is associated with congestive hepatopathy and progressive functional and ultrastructural changes of the liver. We hypothesized that hepatic dysfunction is associated with impaired clinical outcome after heart transplantation. METHODS: Data of 617 adult patients (75% men, mean age 53 ± 12 years, mean BMI 25 ± 4, mean ejection fraction 19 ± 9%) undergoing orthotopic heart transplantation (OHT) were analyzed retrospectively. Deviation from institutional normal ranges was used to define abnormal liver function. Standard Model for End-stage Liver Disease (MELD) scores were calculated and a modified MELD score with albumin replacing INR (modMELD) was created to eliminate the confounding effects of anti-coagulation. RESULTS: Before OHT, AST, ALT and total bilirubin were elevated in 20%, 18% and 29% of the population, respectively. Total protein and albumin were decreased in 25% and 52% of the population, respectively. By 2 months post-transplantation, percentages of individuals with pathologic values decreased significantly, except for ALT, total protein and albumin, all of which took longer to normalize. Individuals with a higher pre-transplantation MELD or modMELD score had worse outcome 30 days post-transplant and reduced long-term survival over a 10-year follow-up. CONCLUSIONS: In this large, single-center retrospective study, we demonstrated the dynamics of liver dysfunction after cardiac transplantation and that elevated MELD scores indicating impaired liver function are associated with poor clinical outcome after OHT. Thus, pre-operative liver dysfunction has a significant impact on survival of patients after cardiac transplantation.

Adipose tissue inflammation and adiponectin resistance in patients with advanced heart failure: correction after ventricular assist device implantation.

BACKGROUND: Heart failure (HF) is characterized by inflammation, insulin resistance, and progressive catabolism. We hypothesized that patients with advanced HF also develop adipose tissue inflammation associated with impaired adipokine signaling and that hemodynamic correction through implantation of ventricular assist devices (VADs) would reverse adipocyte activation and correct adipokine signaling in advanced HF. METHODS AND RESULTS: Circulating insulin, adiponectin, leptin, and resistin levels were measured in 36 patients with advanced HF before and after VAD implantation and 10 healthy control subjects. Serum adiponectin was higher in HF patients before VAD implantation compared with control subjects (13.3±4.9 versus 6.4±2.1 µg/mL, P=0.02). VAD implantation (mean, 129±99 days) reduced serum adiponectin (7.4±3.4 µg/mL, P<0.05) and improved insulin resistance (Homeostasis Assessment Model of insulin resistance: 7.6±7.7-4.5±3.6; P=0.012). [corrected] Adiponectin expression in adipose tissue decreased after VAD implantation (-65%; P<0.03). Adiponectin receptor expression was suppressed in the failing myocardium compared with control subjects and increased after mechanical unloading. Histomorphometric analysis of adipose tissue specimens revealed reduced adipocyte size in patients with advanced HF compared with control subjects (2105±585 µm(2) [corrected] versus 5583±142 µm(2) in control subjects; P<0.05), which increased after VAD placement. Of note, macrophage infiltration in adipose tissue was higher in advanced HF patients compared with control subjects (+25%; P<0.01), which normalized after VAD implantation. CONCLUSIONS: Adipose tissue inflammation and adiponectin resistance develop in advanced HF. Mechanical unloading of the failing myocardium reverses adipose tissue macrophage infiltration, inflammation, and adiponectin resistance in patients with advanced HF.

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

BACKGROUND: Cardiac 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. METHODS: Circulating 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. RESULTS: All 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%). CONCLUSIONS: Marked 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.

Supplementation of glutamine and omega-3 polyunsaturated fatty acids as a novel therapeutic intervention targeting metabolic dysfunction and exercise intolerance in patients with heart failure.

With its increasing prevalence throughout the world, heart failure continues to be associated with high morbidity and mortality. Patients with heart failure develop progressive metabolic abnormalities, inflammation, and atrophy in the myocardium and skeletal muscle. Improvement in functional capacity as defined by exercise tolerance is essential for better quality of life and potentially survival of these patients. Therapeutic management options aimed at improving peripheral organ function are limited. Nutritional approaches with dietary supplementation in addition to current therapies are particularly appealing as they are novel and mechanistically different. In this article, we review the role of glutamine and omega-3 polyunsaturated fatty acids on metabolism and functional capacity in heart failure. These two compounds are of particular interest due to their synergistic role on oxidative metabolism, lipolysis and inflammation.

Epicardial fat volume in patients with left ventricular systolic dysfunction.

Epicardial adipose tissue has been linked to cardiovascular metabolism and inflammation and has been shown to predict prevalence and progression of coronary artery disease. Only limited data are available on the role of epicardial fat in patients with heart failure (HF). We analyzed cardiac adiposity and its relation to markers of morbidity and clinical outcome in patients with normal and impaired left ventricular (LV) function. Epicardial fat volume (EFV) and coronary artery calcium were measured in 381 patients (210 women and 171 men, mean age 55 ± 10 years) who underwent low-dose computed tomography. HF was defined by LV ejection fraction (EF) <55%. Three hundred twenty-one patients had an EF >55% (mean 63 ± 6) and 60 patients had an EF <55% (mean 41 ± 12). Subgroup analysis was performed according to degree of LV dysfunction in patients with HF (LVEF 35% to 55% or <35%). Mean EFVs were 114.5 ± 98.5 cm(3) in patients with normal EF and 83.5 ± 67.1 cm(3) in those with decreased EF (p <0.05). Mean EFVs were 96.1 ± 73.9 cm(3) in patients with moderate HF and 52.2 ± 29.7 cm(3) in patients with severe HF (p <0.05). Subgroup analysis revealed a persistently smaller EFV in patients with HF regardless of coronary artery calcium scores, markers of renal function, lipid metabolism, fasting blood glucose, or body mass index. In conclusion, our data demonstrate a stepwise decrease in EFV in patients with impaired cardiac function.

Effects of continuous-flow versus pulsatile-flow left ventricular assist devices on myocardial unloading and remodeling.

BACKGROUND: Continuous-flow left ventricular assist devices (LVAD) are increasingly used for patients with end-stage heart failure (HF). We analyzed the effects of ventricular decompression by continuous-flow versus pulsatile-flow LVADs on myocardial structure and function in this population. METHODS AND RESULTS: Sixty-one patients who underwent LVAD implantation as bridge-to-transplant were analyzed (pulsatile-flow LVAD: group P, n=31; continuous-flow LVAD: group C, n=30). Serial echocardiograms, serum levels of brain natriuretic peptide (BNP), and extracellular matrix biomarkers (ECM) were compared between the groups. Myocardial BNP and ECM gene expression were evaluated in a subset of 18 patients. Postoperative LV ejection fraction was greater (33.2±12.6% versus 17.6±8.8%, P<0.0001) and the mitral E/E' was lower (9.9±2.6 versus 13.2±3.8, P=0.0002) in group P versus group C. Postoperative serum levels of BNP, metalloproteinases (MMP)-9, and tissue inhibitor of MMP (TIMP)-4 were significantly lower in group P compared with group C (BNP: 552.6±340.6 versus 965.4±805.7 pg/mL, P<0.01; MMP9: 309.0±220.2 versus 475.2±336.9 ng/dL, P<0.05; TIMP4: 1490.9±622.4 versus 2014.3±452.4 ng/dL, P<0.001). Myocardial gene expression of ECM markers and BNP decreased in both groups; however, expression of TIMP-4 decreased only in group P (P=0.024). CONCLUSIONS: Mechanical unloading of the failing myocardium using pulsatile devices is more effective as indicated by echocardiographic parameters of systolic and diastolic LV function as well as dynamics of BNP and ECM markers. Therefore, specific effects of pulsatile mechanical unloading on the failing myocardium may have important implications for device selection especially for the purpose of bridge-to-recovery in patients with advanced HF.

Identification and characterization of small compound inhibitors of human FATP2.

Fatty acid transport proteins (FATPs) are bifunctional proteins, which transport long chain fatty acids into cells and activate very long chain fatty acids by esterification with coenzyme A. In an effort to understand the linkage between cellular fatty acid transport and the pathology associated with excessive accumulation of exogenous fatty acids, we targeted FATP-mediated fatty acid transport in a high throughput screen of more than 100,000 small diverse chemical compounds in yeast expressing human FATP2 (hsFATP2). Compounds were selected for their ability to depress the transport of the fluorescent long chain fatty acid analogue, C(1)-BODIPY-C(12). Among 234 hits identified in the primary screen, 5 compounds, each representative of a structural class, were further characterized in the human Caco-2 and HepG2 cell lines, each of which normally expresses FATP2, and in 3T3-L1 adipocytes, which do not. These compounds were effective in inhibiting uptake with IC(50)s in the low micromolar range in both Caco-2 and HepG2 cells. Inhibition of transport was highly specific for fatty acids and there were no effects of these compounds on cell viability, trans-epithelial electrical resistance, glucose transport, or long chain acyl-CoA synthetase activity. The compounds were less effective when tested in 3T3-L1 adipocytes suggesting selectivity of inhibition. These results suggest fatty acid transport can be inhibited in a FATP-specific manner without causing cellular toxicity.