Increased regional epicardial fat volume associated with reversible myocardial ischemia in patients with suspected coronary artery disease.

Epicardial adipose tissue is a source of pro-inflammatory cytokines and has been linked to the development of coronary artery disease. No study has systematically assessed the relationship between local epicardial fat volume (EFV) and myocardial perfusion defects. We analyzed EFV in patients undergoing SPECT myocardial perfusion imaging combined with computed tomography (CT) for attenuation correction. Low-dose CT without contrast was performed in 396 consecutive patients undergoing SPECT imaging for evaluation of coronary artery disease. Regional thickness, cross-sectional areas, and total EFV were assessed. 295 patients had normal myocardial perfusion scans and 101 had abnormal perfusion scans. Mean EFVs in normal, ischemic, and infarcted hearts were 99.8 ± 82.3 cm(3), 156.4 ± 121.9 cm(3), and 96.3 ± 102.1 cm(3), respectively (P < 0.001). Reversible perfusion defects were associated with increased local EFV compared to normal perfusion in the distribution of the right (69.2 ± 51.5 vs 46.6 ± 32.0 cm(3); P = 0.03) and left anterior descending coronary artery (87.1 ± 76.4 vs 46.7 ± 40.6 cm(3); P = 0.005). Our results demonstrate increased regional epicardial fat in patients with active myocardial ischemia compared to patients with myocardial scar or normal perfusion on nuclear perfusion scans. Our results suggest a potential role for cardiac CT to improve risk stratification in patients with suspected coronary artery disease.

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.

Neutrophil gelatinase-associated lipocalin and cystatin C for the prediction of clinical events in patients with advanced heart failure and after ventricular assist device placement.

BACKGROUND: Progressive renal dysfunction develops in patients with advanced HF. We evaluated neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C compared with established markers of renal function in patients with heart failure (HF) because they might improve prognostic assessment of patients with HF. METHODS: Serum samples were collected from 40 patients with stable HF (age: 58 ± 8 years, body mass index [BMI]: 28.4 ± 6.4 kg/m(2)), 40 HF patients undergoing ventricular assist device (VAD) implantation (age: 53 ± 11 years, BMI: 26.8 ± 5.5 kg/m(2)), 40 patients undergoing VAD removal at cardiac transplantation, and 24 controls (age: 48 ± 7 years, BMI: 29.4 ± 4.2 kg/m(2)). Clinical data were collected from institutional medical records. NGAL and cystatin C levels were measured by enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease formula. RESULTS: Patients with stable HF showed elevated NGAL and cystatin C levels compared with controls (NGAL: 114.9 ± 48.3 ng/mL vs 72.0 ± 36.6 ng/mL, p < 0.0001; cystatin C: 1490.4 ± 576.1 ng/mL vs 954.7 ± 414.2 ng/mL, p = 0.0026). Unlike cystatin C, NGAL increased in advanced HF patients requiring VAD implantation (158.7 ± 74.8 ng/mL, p < 0.001). On VAD support, NGAL levels decreased (127.1 ± 80.4 ng/mL, p = 0.034). NGAL was higher in patients who developed right ventricular failure (187.8 ± 66.0 vs 130.9 ± 67.0 ng/mL, p = 0.03) and irreversible renal dysfunction (190.0 ± 73.8 ng/mL vs 133.8 ± 54.2 ng/mL, p < 0.05), whereas cystatin C, creatinine, and eGFR were not different. NGAL correlated with eGFR (r = -0.2188, p = 0.01). CONCLUSIONS: NGAL levels correlate with HF severity and hemodynamic improvement after VAD placement. Our findings suggest a role of this novel biomarker as a marker of severity and prognosis in patients with HF.

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.

Value of peak exercise oxygen consumption combined with B-type natriuretic peptide levels for optimal timing of cardiac transplantation.

BACKGROUND: Peak exercise oxygen consumption (VO(2)) is widely used to select candidates for heart transplantation (HTx). However, the prognosis of patients with advanced heart failure and peak VO(2) of 10 to 14 mL/min per kg in the era of modern medical therapy for heart failure is not fully elucidated. B-type natriuretic peptide (BNP) is a useful prognostic marker in patients with heart failure. METHODS AND RESULTS: A total of 424 patients undergoing HTx evaluation were classified according to peak VO(2) during cardiopulmonary exercise testing (>14, 10-14, and <10 mL/min per kg). Survival after cardiopulmonary exercise testing without HTx or ventricular assist device (VAD) support was compared with survival of 743 de novo HTx recipients. Multivariable analysis revealed that high BNP and low peak VO(2) were independently associated with death, HTx, or VAD requirements (hazard ratio, 3.5 and 0.6; 95% CI, 1.24-9.23 and 0.03-0.71; P=0.02 and <0.0001, respectively). VAD-free or HTx-free survival of patients with peak VO(2) 10 to 14 mL/min per kg was identical to post-HTx survival. When patients with peak VO(2) 10 to 14 mL/min per kg were dichotomized by a cutoff value of BNP of 506 pg/mL, those with BNP<506 pg/mL was equivalent to post-HTx survival (1 year: 90.8% versus 87.2%; P=0.61), whereas those with BNP≥506 showed worse VAD-free or HTx-free survival (1 year: 79.7%; P<0.001 versus post-HTx). Patients with peak VO(2) <10 mL/min per kg showed worse survival compared with post-HTx survival, and there was a survival difference between those with BNP≥506 and <506 pg/mL (1 year: 77.2% versus 56.1%; P=0.01). CONCLUSIONS: Patients with peak VO(2) 10 to 14 mL/min per kg and low BNP levels have a VAD-free or HTx-free survival similar to post-HTx survival in heart recipients, whereas high BNP levels indicate worse outcome in this group of patients.

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.

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.

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.