[Show abstract][Hide abstract] ABSTRACT: Heart failure (HF) is associated with high morbidity and mortality and its incidence is increasing worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage HF before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small RNA sequencing. miRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNA– target-mRNA interactions, target mRNA levels were negatively correlated with changes in abundance for highly expressed miRNAs in HF and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced HF, which coincided with a similar increase in cardiac troponin I (cTnI) protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 mo following initiation of LVAD support. In stable HF, circulating miRNAs showed less than fivefold differences compared with normal, and myomir and cTnI levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers.
Proceedings of the National Academy of Sciences 08/2014; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peripheral vascular disease (PVD) portends increased morbidity and mortality in patients with heart failure. In those with advanced heart failure, heart transplantation (HT) is the only causative therapy to increase survival. However, little is known about the impact of symptomatic PVD on survival of HT recipients in large multicenter cohorts. The aim of this study was to investigate an association between recipient symptomatic PVD and survival after HT. We analyzed 20,297 patients from the United Network of Organ Sharing data set. Survival analysis using a control cohort established by propensity matching was performed. There was an increased prevalence of traditional cardiovascular risk factors in 711 patients with symptomatic PVD compared with 19,586 patients without PVD. Patients with pretransplant symptomatic PVD had increased post-transplant mortality compared with those without PVD (1-, 5- and 10-year survival rate 91.5% vs 94.9%, 74.8% vs 82.6%, 48.6% vs 54.7%, respectively, log-rank p <0.001). On multivariate analysis based on the propensity matching, factors associated with a lower survival rate were presence of PVD (hazard ratio 1.20, 95% confidential interval 1.02 to 1.42, p = 0.030), and female gender (hazard ratio 1.22, 95% confidence interval 1.02 to 1.47, p = 0.034). In conclusion, patients with symptomatic PVD have a lower survival rate after HT. Symptomatic PVD should be considered an independent risk factor for poor prognosis in patients undergoing HT evaluation.
[Show abstract][Hide abstract] ABSTRACT: Background and objectivePulmonary hypertension (PH) is a known complication in patients with interstitial lung disease (ILD). Cardiopulmonary exercise testing (CPET) is an essential tool for the assessment of patients with cardiac and pulmonary diseases due to its prognostic and therapeutic implications. Few studies have evaluated the relationship between CPET response and mean pulmonary artery pressures (mPAP) in ILD. The purpose of the present study was to determine and compare the potential correlations between CPET, 6-min walk test (6MWT), pulmonary function testing (PFT) and PH in patients with ILD being evaluated for lung transplantation.Methods
The present study reviewed patients with ILD who received lung transplantations and had CPETs within 2 years before transplantation, right heart catheterizations, PFTs and 6MWTs within 4 months of CPET.ResultsA total of 72 patients with ILD were analysed; 36% had PH. There were significant correlations between mPAP and CPET parameters in patients with PH; but mPAP had no impact on percent of predicted diffusion capacity of the lung for carbon monoxide or 6-min walk distance (6MWD). CPET parameters were able to detect differences between levels of severity of PH through the use of the ratio of minute ventilation to rate of carbon dioxide production () and the partial pressure of end-tidal carbon dioxide.Conclusions
This is the first study that analyses 6MWD, PFT and CPET in patients with ILD awaiting lung transplantation with and without PH. The present study demonstrates the significant impact of PH on exercise capacity and performance in patients with ILD awaiting lung transplantation.
[Show abstract][Hide abstract] ABSTRACT: Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function.
Systolic HF patients (left ventricular ejection fraction [LVEF] ≤40%) underwent skeletal muscle biopsies (non-dominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed using real-time polymerase chain reaction. Aerobic function was assessed using cardiopulmonary exercise and 6 minute walk tests. Strength capacity was assessed using pneumatic leg press (maximum strength and power). Serological inflammatory markers were also assessed.
54 male patients (66.6±10.0 years) were studied; 24 systolic HF patients (mean LVEF=28.9±7.8%) and 30 age-matched controls. Aerobic and strength parameters were diminished in HF vs. controls. FoxO1 and FoxO3 were increased in HF vs. controls (7.9+6.2 vs. 5.0±3.5, 6.5 ±4.3 vs. 4.3±2.8, respectively, p≤0.05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9±5.4 vs. 5.3±3.6, p<0.05). Muscle levels of IGF-1 as well as serum levels of TNF-α, CRP, IL-1β, and IL-6 were similar in HF and controls.
Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared to controls, but other atrophy gene expression patterns (atrogin-1 and MuRF-1) as well as growth promoting patterns (IGF-1) were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counter-regulatory role to offset ubiquitin pathway-mediated functional decrements.
Journal of cardiac failure 04/2014; · 3.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examined the impact of the United Network for Organ Sharing (UNOS) policy changes for regional differences in waitlist time and mortality before and after heart transplantation.
The 2006 UNOS thoracic organ allocation policy change was implemented to allow for greater regional sharing of organs for heart transplantation.
We analyzed 36,789 patients who were listed for heart transplantation from January 1999 through April 2012. These patients were separated into 2 eras centered on the July 12, 2006 UNOS policy change. Pre- and post-transplantation characteristics were compared by UNOS regions.
Waitlist mortality decreased nationally (up to 180 days: 13.3% vs. 7.9% after the UNOS policy change, p < 0.001) and within each region. Similarly, 2-year post-transplant mortality decreased nationally (2-year mortality: 17.3% vs. 14.6%; p < 0.001) as well as regionally. Waitlist time for UNOS status 1A and 1B candidates increased nationally 17.8 days on average (p < 0.001) with variability between the regions. The greatest increases were in Region 9 (59.2-day increase, p < 0.001) and Region 4 (41.2-day increase, p < 0.001). Although the use of mechanical circulatory support increased nearly 2.3-fold nationally in Era 2, significant differences were present on a regional basis. In Regions 6, 7, and 10, nearly 40% of those transplanted required left ventricular assist device bridging, whereas only 19.6%, 22.3%, and 15.5% required a left ventricular assist device in regions 3, 4, and 5, respectively.
The 2006 UNOS policy change has resulted in significant regional heterogeneity with respect to waitlist time and reliance on mechanical circulatory support as a bridge to transplantation, although overall both waitlist mortality and post-transplant survival are improved.
[Show abstract][Hide abstract] ABSTRACT: The mammalian heart, the bodys largest energy consumer, has evolved robust mechanisms to tightly couple fuel supply with energy demand across a wide range of physiologic and pathophysiologic states. Yet, when compared to other organs, relatively little is known about the molecular machinery that directly governs metabolic plasticity in the heart. While previous studies have defined Kruppel like Factor 15 (KLF15) as a transcriptional repressor of path-ologic cardiac hypertrophy, a direct role for the KLF family in cardiac metabolism has not been previously established. We show in human heart samples that KLF15 is induced after birth and reduced in heart failure, a myocardial expression pattern that parallels reliance on lipid oxidation. Isolated working heart studies and unbiased transcriptomic profiling in Klf15 deficient hearts demonstrate that KLF15 is an essential regulator of lipid flux and metabolic homeostasis in the adult myocardium. An important mechanism by which KLF15 regulates its direct transcriptional targets is via interaction with p300 and recruitment of this critical co activator to promoters. This study establishes KLF15 as a key regulator of myocardial lipid utilization and is the first to implicate the KLF transcription factor family in cardiac metabo-lism.
Journal of Biological Chemistry 01/2014; · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Heart failure (HF) is associated with the derangement of muscle structure and metabolism, contributing to exercise intolerance, frailty and mortality. Reduced handgrip strength is associated with increased patient frailty and higher morbidity and mortality. We evaluated handgrip strength as a marker of muscle function and frailty for prediction of clinical outcomes after ventricular assist device (VAD) implantation in patients with advanced HF.
Methods and Results
Handgrip strength was measured in 72 patients with advanced HF before VAD implantation (2.3±4.9 days pre-VAD). We analyzed dynamics in handgrip strength, laboratory values, post-operative complications and mortality. Handgrip strength correlated with serum albumin levels (r=0.334, p=0.004). Compared to baseline, handgrip strength increased post-VAD implantation by 18.2±5.6% at 3 months (n=29) and 45.5±23.9% at 6 months (n=27). Patients with a handgrip strength <25% of body weight had an increased risk of mortality, increased postoperative complications and lower survival after VAD implantation.
Patients with advanced HF show impaired handgrip strength indicating a global myopathy. Handgrip strength <25% of body weight is associated with higher postoperative complication rates and increased mortality following VAD implantation. Thus, the addition of measures of skeletal muscle function underlying the frailty phenotype to traditional risk markers might have incremental prognostic value in patients undergoing evaluation for VAD placement.
Journal of cardiac failure 01/2014; · 3.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
We evaluated neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C in comparison to established markers of renal function in patients with heart failure (HF).
Patients with advanced HF develop progressive renal dysfunction. The renal biomarkers NGAL and cystatin C might improve prognostic assessment of patients with HF.
Serum samples were collected from 40 patients with stable HF (58±8 yrs, BMI 29.4±4.2 kg/m2), 40 HF patients undergoing ventricular assist device (VAD) implantation (53±11 yrs, BMI 26.8±5.5 kg/m2) and VAD removal at cardiac transplantation, and 24 controls (48±7 yrs, BMI 29.4±4.2 kg/m2). Clinical data were collected from institutional medical records. NGAL and cystatin C levels were measured by ELISA and eGFR calculated using MDRD formula.
Patients with stable HF showed elevated NGAL and cystatin C levels compared to controls (114.2±52.3 ng/mL vs. 72.0±36.1 ng/mL, p<0.0001; cystatin C: 1490.4±576.1 ng/mL vs. 986.3±347.5 ng/mL, p=0.0026). Unlike cystatin C, NGAL increased in advanced HF requiring VAD implantation (158.7±74.8 ng/mL, p<0.001). On VAD, 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) while cystatin C, creatinine and eGFR were not different. NGAL correlated with eGFR (r=-0.2188, p=0.01).
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.
The Journal of Heart and Lung Transplantation. 01/2014;
[Show abstract][Hide abstract] ABSTRACT: Although dobutamine stress echocardiography (DSE) is performed in heart transplant patients, the safety profile of atropine administration in DSE in this setting is unclear.
We identified heart transplant patients who received atropine during DSE from January 1984 to August 2011 at our institution and compared them with a propensity-scored matched control group of heart transplant patients who underwent DSE without atropine. Adverse events were defined as significant arrhythmias (sinus arrest, Mobitz type II heart block, complete heart block, ventricular tachycardia, or ventricular fibrillation), hypotension requiring hospitalization, syncope or presyncope, myocardial infarction, and death. Forty-five heart transplant patients (median age 62 years, 82% male) received 0.2-1 mg atropine during DSE. Of these, 1 patient (2.2%) developed temporary complete heart block. No adverse events were identified in the control group of 154 patients who received dobutamine without atropine.
Our findings suggest that complete heart block can occur infrequently with the administration of atropine in heart transplant patients undergoing DSE. Therefore, patients should be appropriately monitored for these adverse events during and after DSE.
Journal of cardiac failure 11/2013; 19(11):762-767. · 3.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 non-lipid 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 months 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 to 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.
AJP Endocrinology and Metabolism 10/2013; · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: X-linked Emery-Dreifuss muscular dystrophy is caused by loss of function of emerin, an integral protein of the inner nuclear membrane. Yet emerin null mice are essentially normal, suggesting the existence of a critical compensating factor. We show that the lamina-associated polypeptide1 (LAP1) interacts with emerin. Conditional deletion of LAP1 from striated muscle causes muscular dystrophy; this pathology is worsened in the absence of emerin. LAP1 levels are significantly higher in mouse than human skeletal muscle, and reducing LAP1 by approximately half in mice also induces muscle abnormalities in emerin null mice. Conditional deletion of LAP1 from hepatocytes yields mice that exhibit normal liver function and are indistinguishable from littermate controls. These results establish that LAP1 interacts physically and functionally with emerin and plays an essential and selective role in skeletal muscle maintenance. They also highlight how dissecting differences between mouse and human phenotypes can provide fundamental insights into disease mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Hypoalbuminemia has been recognized as a prognostic indicator in patients with heart failure. We aimed to investigate the association of hypoalbuminemia with postoperative mortality in patients undergoing left ventricular assist device (LVAD) implantation. We studied 272 consecutive patients undergoing LVAD implantation from 2000 to 2010 at our institution. Preoperative clinical characteristics and laboratory variables associated with mortality were analyzed. Postoperative survival of patients with preoperative hypoalbuminemia (<3.5 g/dl, n = 125) and those with normal albumin concentration (≥3.5 g/dl, n = 147) was compared. Survival after LVAD surgery was better in patients with normal albumin levels compared with those with hypoalbuminemia before surgery (3 and 12 months: 93.2% vs 82.4% and 88.4% vs 75.2%, respectively, p <0.001). Multivariate analysis revealed that preoperative albumin was independently associated with mortality after LVAD implantation (hazard ratio 0.521, 95% confidence interval 0.290 to 0.934; p = 0.029.) Furthermore, the impact of normalization of albumin levels during LVAD support on postoperative survival was analyzed in both groups. Subgroup analysis of patients with preoperative hypoalbuminemia and postoperative normalization of albumin levels (n = 81) showed improved survival compared with those who remained hypoalbuminemia (n = 44) or those who had decreasing albumin levels during LVAD support (n = 40; 3-month survival: 92.6% vs 63.6% and 65.0%; p <0.01). In conclusion, preoperative hypoalbuminemia is associated with poor prognosis after LVAD surgery. Postoperative normalization of albumin level is associated with improved survival. Attention to albumin levels by correcting nutrition, inflammation, and hepatic function could be an effective way to improve prognosis in patients evaluated for LVAD implantation.
The American journal of cardiology 07/2013; · 3.58 Impact Factor