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1.  Treatment Strategies for the Prevention of Heart Failure 
Current heart failure reports  2013;10(4):10.1007/s11897-013-0154-8.
With the astounding morbidity and mortality associated with heart failure (HF), preventive approaches have been explored. Controlling hypertension to prevent HF is well-established, especially with sodium restriction and thiazide-based antihypertensive therapies showing potential advantages. Control of dyslipidemia with aggressive statin therapy is particularly beneficial in preventing HF in the setting of acute coronary syndrome. The HOPE study also established the benefit of ACE inhibitors in the prevention of HF in high-risk subjects. Meanwhile old data supporting tight glycemic control in preventing HF have not been confirmed, suggesting the complexity of diabetic cardiomyopathy. Avoiding tobacco use and other known cardiotoxins are likely helpful. While there has been substantial development in identifying biomarkers predicting future development of HF, therapeutic interdiction guided by biomarker levels have yet to be established even though it offers hope in modulating the natural history of the development of HF in at risk individuals.
doi:10.1007/s11897-013-0154-8
PMCID: PMC3823759  PMID: 24014140
heart failure; prevention; beta-blocker; angiotensin converting enzyme inhibitor; angiotensin receptor blocker; thiazide diuretic; left ventricular hypertrophy; left bundle branch block; diabetes mellitus; troponin; brain natriuretic peptide; cardiomyopathy; statins; biomarkers; coronary artery disease; hypertension; obesity; hyperlipidemia; insulin resistance
2.  miRNA-548c: a specific signature in circulating PBMCs from dilated cardiomyopathy patients 
High fidelity genome-wide expression analysis has strengthened the idea that microRNA (miRNA) signatures in peripheral blood mononuclear cells (PBMCs) can be potentially used to predict the pathology when anatomical samples are inaccessible like heart. PBMCs from 48 non-failing controls and 44 patients with relatively stable chronic heart failure (ejection fraction of ≤ 40%) associated with dilated cardiomyopathy (DCM) were used for miRNA analysis. Genome-wide miRNA-microarray on PBMCs from chronic heart failure patients identified miRNA signature uniquely characterized by the downregulation of miRNA-548 family members. We have also independently validated downregulation of miRNA-548 family members (miRNA-548c & 548i) using real time-PCR in a large cohort of independent patient samples. Independent in silico Ingenuity Pathway Analysis (IPA) of miRNA-548 targets shows unique enrichment of signaling molecules and pathways associated with cardiovascular disease and hypertrophy. Consistent with specificity of miRNA changes with pathology, PBMCs from breast cancer patients showed no alterations in miRNA-548c expression compared to healthy controls. These studies suggest that miRNA-548 family signature in PBMCs can therefore be used as to detect early heart failure. Our studies show that cognate networking of predicted miRNA-548 targets in heart failure can be used as a powerful ancillary tool to predict the ongoing pathology.
doi:10.1016/j.yjmcc.2013.05.011
PMCID: PMC3735826  PMID: 23735785
Peripheral Blood Mononuclear Cells (PBMC); microRNA-548; dilated cardiomyopathy; canonical signaling networks; biomarker
3.  Novel Urinary Biomarkers in Detecting Acute Kidney Injury, Persistent Renal Impairment and All-cause Mortality following Decongestive Therapy in Acute Decompensated Heart Failure 
Journal of cardiac failure  2013;19(9):621-628.
Background
New urinary biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1) and interleukin-18 (IL-18) are proposed to allow a more reliable early diagnosis and prognosis of acute kidney injury (AKI) in acute decompensated heart failure (ADHF). Our aim was to compare the predictive value of urinary NGAL, KIM-1 and IL-18 for the occurrence of AKI, persistent renal impairment and mortality in ADHF.
Methods and Results
Eighty-three patients admitted for ADHF were analyzed. Urinary creatinine (Cr), NGAL, KIM-1 and IL-18 were measured at baseline. Serum Cr was measured daily during the next 4 days and again at outpatient follow-up after 6 months. Mortality data were prospectively collected. Urinary NGAL, KIM-1 and IL-18 were modestly correlated with each other (Spearman's ρ≤0.61) and poorly correlated to estimated glomerular filtration rate (eGFR; Spearman's ρ≤0.28). None predicted AKI defined as a 25% decrease in eGFR during index hospitalization, but urinary IL-18/Cr was the strongest predictor of persistently elevated serum Cr≥0.3 mg/dL after 6 months compared to baseline (AUC=0.674; p=0.013). Urinary IL-18 was also associated with all-cause mortality (HR 1.48, 95%CI 1.16–1.87; p=0.001).
Conclusions
Like urinary NGAL, urinary KIM-1 and IL-18 are relatively modest predictors of AKI in ADHF. Among these novel renal biomarkers examined, further investigations regarding the prognostic value of urinary IL-18 are warranted.
doi:10.1016/j.cardfail.2013.07.004
PMCID: PMC3781948  PMID: 24054338
Acute decompensated heart failure; acute kidney injury; biomarkers; outcome
4.  Nitric Oxide Bioavailability and Adiponectin Production in Chronic Systolic Heart Failure: Relation to Severity of Cardiac Dysfunction 
Adiponectin is an anti-inflammatory, anti-atherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailablity. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association [NYHA] class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA) and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman’s r=0.41, p<0.001) and NT-proBNP levels (r=0.55, p<0.001), inversely correlated with GABR (r= −0.39, p<0.001), and were not associated with hsCRP (p=0.81) or MPO (p=0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r= 0.33, p=0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sums p=0.002), RV systolic dysfunction (rank sums p=0.002), and RV diastolic dysfunction (rank sums p=0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (HR [95% CI]: 1.45 [1.02–2.07], p=0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust in the setting of cardiac dysfunction or elevated natriuretic peptide levels.
doi:10.1016/j.trsl.2013.02.005
PMCID: PMC3691294  PMID: 23499315
Congestive heart failure; adiponectin; ADMA; natriuretic peptides; diastolic dysfunction
5.  Cardiotonic Modulation in Heart Failure 
Medicinal herbs have been used over the past centuries for restoring the body's homeostatic balance. Contemporary use of herbal supplements remains widespread in many cultures as treatment for specific ailments. Many possess cardiovascular actions, and some interact with cardiac medications. However, there is variable scientific evidence with respect to their safety and efficacy, and few have been subjected to the same rigorous evaluation processes and regulations as contemporary pharmaceuticals (1). In the field of heart failure, we have also witnessed the failure of promising naturopathic therapies like hawthorn extract in translating their potential benefits in rigorous clinical trials (2,3).
doi:10.1016/j.jacc.2013.05.028
PMCID: PMC4024708  PMID: 23747774
chronic heart failure; controlled clinical trial; qili qiangxin capsules
6.  Detectable Subclinical Myocardial Necrosis Is Associated With Cardiovascular Risk in Stable Patients With Diabetes 
Diabetes Care  2013;36(5):1126-1131.
OBJECTIVE
To investigate the relationship between different degrees of subclinical myocardial necrosis, glycemic control, and long-term adverse clinical outcomes within a stable patient population with diabetes mellitus.
RESEARCH DESIGN AND METHODS
We examined 1,275 stable patients with diabetes mellitus undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (MI) (<0.03 ng/mL). The relationship of subclinical myocardial necrosis (cTnI 0.009–0.029 ng/mL) with incident major adverse cardiovascular events (MACE; defined as any death, MI, or stroke) over 3 years of follow-up was examined.
RESULTS
Subclinical myocardial necrosis was observed in 22% of patients. A strong association was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident MACE (hazard ratio, 1.98; 95% confidence interval, 1.48–2.65; P < 0.001) and remained statistically significant even after adjustment for traditional risk factors, high-sensitivity C-reactive protein, and creatinine clearance. Only a weak correlation was observed between the presence of subclinical myocardial necrosis and either glycemic control (r = 0.06; P = 0.044 for hemoglobin A1c versus cTnI) or insulin resistance (r = 0.04; P = 0.094 for glucose-to-insulin ratio versus cTnI).
CONCLUSIONS
The presence of detectable subclinical myocardial necrosis in stable patients with diabetes mellitus is associated with heightened long-term risk for MACE, independent of traditional risk factors and glycemic control.
doi:10.2337/dc11-1969
PMCID: PMC3631842  PMID: 23393213
7.  Pharmacologic Management of Chronic Reno-Cardiac Syndrome 
Current heart failure reports  2013;10(1):54-62.
Chronic kidney disease (CKD) significantly increases cardiovascular morbidity and mortality. Chronic kidney disease remains an under-represented population in cardiovascular clinical trials, and cardiovascular disease is an under-treated entity in CKD. Traditional cardiovascular risk factors in conjunction with uremia-related complications often progress to myocardial dysfunction. Such uremic cardiomyopathy leads to over-activation of neurohormonal pathways with detrimental effects. Management of the reno-cardiac syndrome (RCS) requires the targeting of these multiple facets. In this article we discuss the relevant pathophysiology of RCS, and present the clinical data related to its management.
doi:10.1007/s11897-012-0122-8
PMCID: PMC3568213  PMID: 23143732
Cardiorenal syndrome; Renocardiac syndrome; management; renin-angiotensin-aldosterone system; sympathetic nervous system; hypervolemia
8.  Influence of Age-Related Versus Non-Age-Related Renal Dysfunctionon Survival in Patients with Left Ventricular Dysfunction 
The American journal of cardiology  2013;113(1):127-131.
Normal aging results in a predictable decline in glomerular filtration rate (GFR) and low GFR is associated with worsened survival. If this survival disadvantage is directly caused by the low GFR, as opposed to the disease causing the low GFR, the risk should be similar regardless of the underlying mechanism. Our objective was to determine if age related declines in estimated GFR (eGFR) carry the same prognostic importance as disease attributable losses in patients with ventricular dysfunction. We analyzed the Studies Of Left Ventricular Dysfunction (SOLVD) limited data set (n=6337). The primary analysis focused on determining if the eGFR mortality relationship differed by the extent the eGFR was consistent with normal ageing. Mean eGFR was 65.7 ± 19.0ml/min/1.73m2. Across the range of age in the population (27 to 80 years), baseline eGFR decreased by 0.67 ml/min/1.73m2 per year (95% CI 0.63 to 0.71). The risk of death associated with eGFR was strongly modified by the degree to which the low eGFR could be explained by aging (p interaction <0.0001). For example, in a model incorporating the interaction, uncorrected eGFR was no longer significantly related to mortality (adjusted HR=1.0 per 10 ml/min/1.73m2, 95% CI 0.97–1.1, p=0.53) whereas a disease attributable decrease in eGFR above the median carried significant risk (adjusted HR=2.8, 95% CI 1.6–4.7, p<0.001). In conclusion, in the setting of LV dysfunction, renal dysfunction attributable to normal aging had a limited risk for mortality, suggesting that the mechanism underlying renal dysfunction is critical in determining prognosis.
doi:10.1016/j.amjcard.2013.09.029
PMCID: PMC3915785  PMID: 24216124
Cardio-renal syndrome; Age related renal dysfunction; Prognosis; Heart failure
9.  The contributory role of gut microbiota in cardiovascular disease 
The Journal of Clinical Investigation  2014;124(10):4204-4211.
Our group recently discovered that certain dietary nutrients possessing a trimethylamine (TMA) moiety, namely choline/phosphatidylcholine and L-carnitine, participate in the development of atherosclerotic heart disease. A meta-organismal pathway was elucidated involving gut microbiota–dependent formation of TMA and host hepatic flavin monooxygenase 3–dependent (FMO3-dependent) formation of TMA–N-oxide (TMAO), a metabolite shown to be both mechanistically linked to atherosclerosis and whose levels are strongly linked to cardiovascular disease (CVD) risks. Collectively, these studies reveal that nutrient precursors, gut microbiota, and host participants along the meta-organismal pathway elucidated may serve as new targets for the prevention and treatment of CVD.
doi:10.1172/JCI72331
PMCID: PMC4215189  PMID: 25271725
10.  Relation of Systemic and Urinary Neutrophil Gelatinase-Associated Lipocalin Levels to Different Aspects of Impaired Renal Function in Patients with Acute Decompensated Heart Failure 
The American journal of cardiology  2012;110(9):1329-1335.
Both urine and serum neutrophil gelatinase-associated lipocalin (NGAL) reflect active chronic kidney disease and predict acute kidney injury (AKI). However, direct comparison of these markers in acute decompensated heart failure (ADHF) has not been performed. We prospectively evaluated 93 patients admitted with ADHF and treated with intravenous furosemide, and measured both systemic (serum) and urine NGAL levels and their corresponding markers of estimated glomerular filtration rate (GFR), natriuresis (urine sodium) and diuretic response (net output, urine sodium to furosemide ratio). In our study cohort, median urine and serum NGAL levels were 34 [interquartile range 24–86] ng/mL and 252 [interquartile range 175–350] ng/mL, respectively. Urine and serum NGAL were modestly correlated (r=0.37, p<0.001). Higher urine (but not systemic) NGAL correlated with markers of impaired natriuresis and reduced diuresis (p<0.005 for all). In contrast, higher serum NGAL demonstrated a stronger relationship with reduced glomerular filtration function (p<0.0001). Both markers predicted AKI (urine NGAL: odds ratio 1.7, p=0.035; serum NGAL: odds ratio 1.9, p=0.009). In conclusion, in patients with ADHF, urine NGAL levels reflect renal distal tubular injury with impaired natriuresis and diuresis, while systemic NGAL levels demonstrate a stronger association with glomerular filtration function. Both systemic and urine NGAL predict worsening renal function.
doi:10.1016/j.amjcard.2012.06.035
PMCID: PMC3470750  PMID: 22835414
Cardio-renal; Heart failure; Neutrophil gelatinase-associated lipocalin; Natriuresis; Diuresis
11.  Prognostic Role of Pulmonary Arterial Capacitance in Advanced Heart Failure 
Circulation. Heart failure  2012;5(6):778-785.
Background
RV dysfunction frequently occurs and independently prognosticates in left-sided HF. It is not clear which right ventricular (RV) afterload measure has the greatest impact on RV function and prognosis. We examined the determinants, prognostic role and response to treatment of pulmonary arterial capacitance (PAC, ratio of stroke volume over pulmonary pulse pressure), in relation to pulmonary vascular resistance (PVR) in heart failure (HF).
Methods and Results
We reviewed 724 consecutive patients with HF who underwent right heart catheterization between 2000 and 2005. Changes in PAC were explored in an independent cohort of 75 subjects treated for acute decompensated HF. PAC showed a strong inverse relation with PVR (r=−0.64) and wedge pressure (r=−0.73), and provides stronger prediction of significant RV failure than PVR (AUC ROC 0.74 vs 0.67 respectively, p = 0.003). During a mean follow-up of 3.2 ± 2.2 years, both lower PAC (p<0.0001) and higher PVR (p<0.0001) portend more adverse clinical events (all-cause mortality and cardiac transplantation). In multivariate analysis, PAC (but not PVR) remains an independent predictor (Hazard ratio =0.92 [95% confidence interval: 0.84–1.0, p=0.037]). Treatment of HF resulted in a decrease in PVR (270±165 to 211±88 dynes·sec·cm−5, p=0.002), a larger increase in PAC (1.65±0.64 to 2.61±1.42 ml/mmHg, p<0.0001), leading to an increase in pulmonary arterial time constant (PVR × PAC) (0.29±0.12 to 0.37±0.15 sec, p<0.0001).
Conclusions
PAC bundles the effects of PVR and left sided filling pressures on RV afterload, explaining its strong relation with RV dysfunction, poor long-term prognosis, and response to therapy.
doi:10.1161/CIRCHEARTFAILURE.112.968511
PMCID: PMC3538355  PMID: 23087402
heart failure; hemodynamics; pulmonary arterial capacitance; pulmonary vascular resistance
12.  Translating Metabolomics to Cardiovascular Biomarkers 
Metabolomics is the systematic study of the unique chemical fingerprints of small-molecules, or metabolite profiles, that are related to a variety of cellular metabolic processes in a cell, organ, or organism. While mRNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling provides direct and indirect physiologic insights that can potentially be detectable in a wide range of biospecimens. Although not specific to cardiac conditions, translating metabolomics to cardiovascular biomarkers has followed the traditional path of biomarker discovery from identification and confirmation to clinical validation and bedside testing. With technological advances in metabolomic tools (such as nuclear magnetic resonance spectroscopy and mass spectrometry) and more sophisticated bioinformatics and analytical techniques, the ability to measure low-molecular-weight metabolites in biospecimens provides a unique insight into established and novel metabolic pathways. Systemic metabolomics may provide physiologic understanding of cardiovascular disease states beyond traditional profiling, and may involve descriptions of metabolic responses of an individual or population to therapeutic interventions or environmental exposures.
doi:10.1016/j.pcad.2012.06.004
PMCID: PMC3414418  PMID: 22824112
13.  Dysregulated Arginine Metabolism and Importance of Compensatory Dimethylarginine Dimethylaminohydrolase-1 in Pulmonary Hypertension Associated with Advanced Systolic Heart Failure 
Objective
To examine the hemodynamic determinants of dysregulated arginine metabolism in patients with acute decompensated heart failure and explore possible mechanism of arginine dysregulation in human heart failure.
Background
Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear.
Methods
We prospectively determined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and global arginine bioavailability ratio [GABR=arginine/(ornithine+citrulline)] by tandem mass spectrometry in subjects with advanced decompensated heart failure in the intensive care unit (“ADHF”, n=68) and with stable chronic heart failure (“CHF”, n=57).
Results
Compared to CHF subjects, plasma ADMA was significantly higher (median[interquartile range]: 1.29 [1.04–1.77] versus 0.87 [0.72–1.05] μM, p<0.0001), and GABR significantly lower (0.90 [0.69–1.22] versus 1.13 [0.92–1.37], p=0.002) in ADHF subjects. Elevated ADMA and diminished GABR were associated with higher systolic pulmonary artery pressure (sPAP) and higher central venous pressure, but not with other clinical or hemodynamic indices. We further observed myocardial levels of dimethylarginine dimethylaminohydrolase-1 (DDAH-1) were increased in CHF without elevated sPAP (<50mmHg), but diminished with elevated sPAP (≥50mmHg, difference with sPAP<50 mmHg, p=0.02).
Conclusions
Dysregulated arginine metabolism was observed in advanced decompensated heart failure, particularly with pulmonary hypertension and elevated intracardiac filling pressures. Compared to control hearts, we observed higher amounts of ADMA-degradation enzyme DDAH-1 (but similar amounts of ADMA-producing enzyme, PRMT-1) in the human failing myocardium.
doi:10.1016/j.jacc.2011.12.022
PMCID: PMC3565538  PMID: 22440215
Nitric oxide synthase; asymmetric dimethylarginine; heart failure; pulmonary hypertension
14.  The Function and Distribution of Apolipoprotein A1 in the Artery Wall are Markedly Distinct from those in Plasma 
Circulation  2013;128(15):10.1161/CIRCULATIONAHA.113.002624.
Background
Prior studies show apolipoprotein A1 (apoA1) recovered from human atherosclerotic lesions is highly oxidized. Ex vivo oxidation of apoA1 or high density lipoprotein (HDL) cross-links apoA1 and impairs lipid binding, cholesterol efflux and lecithin cholesterol acyltransferase (LCAT) activities of the lipoprotein. Remarkably, no studies to date directly quantify either the function or HDL particle distribution of apoA1 recovered from the human artery wall.
Methods and Results
A monoclonal antibody (mAb 10G1.5) was developed that equally recognizes lipid-free and HDL-associated apoA1 in both native and oxidized forms. Examination of homogenates of atherosclerotic plaque-laden aorta showed >100-fold enrichment of apoA1 compared to normal aorta (P<0.001). Surprisingly, buoyant density fractionation revealed only a minority (<3% of total) of apoA1 recovered from either lesions or normal aorta resides within an HDL-like particle (1.063 ≤ d ≤ 1.21). In contrast, the majority (>90%) of apoA1 within aortic tissue (normal and lesions) was recovered within the lipoprotein-depleted fraction (d>1.21). Moreover, both lesion and normal artery wall apoA1 is highly cross-linked (50–70% of total), and functional characterization of apoA1 quantitatively recovered from aorta using mAb 10G1.5 showed ~80% lower cholesterol efflux activity and ~90% lower LCAT activity relative to circulating apoA1.
Conclusions
The function and distribution of apoA1 in human aorta are quite distinct from those found in plasma. The lipoprotein is markedly enriched within atherosclerotic-plaque, predominantly lipid-poor, not associated with HDL, extensively oxidatively cross-linked, and functionally impaired.
doi:10.1161/CIRCULATIONAHA.113.002624
PMCID: PMC3882895  PMID: 23969698
plaque; apolipoproteins; arteriosclerosis; cardiovascular diseases
15.  Cellular Proliferative Response to Cardiac Troponin-I in Patients with Idiopathic Dilated Cardiomyopathy 
Background
Approximately 20% of patients with idiopathic dilated cardiomyopathy (iDCM) have autoantibodies (AAbs) specific to cardiac troponin-I (cTnI). However, there has been no work evaluating active cellular autoimmunity. We aimed to identify a cTnI-stimulated cellular autoimmune response and to correlate our findings with cTnI AAb production.
Methods
Samples were obtained from stable ambulatory iDCM patients and healthy controls. Peripheral blood monocytes were incubated with cTnI, and cellular proliferation was measured using flow cytometry. AAbs against cTnI were detected by ELISA.
Results
A positive cellular proliferative response to cTnI was identified in 20.5% (9/44) patients with iDCM and 5.7% (2/35) of healthy controls (p < 0.05). Positive cTnI AAbs were identified in 20% (7/35) of healthy controls and 13.6% (6/44) of patients with iDCM (p = NS). The presence of cTnI AAbs did not correlate with a positive cellular proliferative response. However, patients with iDCM who had an AAb response to cTnI were less likely to be taking a statin (p < 0.05).
Conclusions
A cellular autoimmune response to cTnI is demonstrated in a subset of patients with iDCM. However, the presence of a cellular response did not correlate with the presence of AAbs to the same antigen.
doi:10.1111/j.1752-8062.2011.00313.x
PMCID: PMC3205470  PMID: 22029801
16.  Usefulness of Plasma Galectin-3 Levels in Systolic Heart Failure to Predict Renal Insufficiency and Survival 
The American journal of cardiology  2011;108(3):385-390.
Galectin-3 plays an important role in fibroblast activation and fibrosis in animal models. Elevated galectin-3 levels are associated with poor long-term survival in heart failure (HF). We examined the relation between plasma galectin-3 levels and myocardial indices of systolic HF. We measured plasma galectin-3 in 133 chronic HF and 45 advanced decompensated HF subjects with echocardiographic and hemodynamic evaluation. In our chronic HF cohort, median plasma galectin-3 level was 13.9ng/mL [interquartile range: 12.1–16.9ng/mL]. Higher galectin-3 was associated with more advanced age (r=0.22, p=0.010) and poor renal function (estimated glomerular filtration rate [eGFR]: r= −0.24, p=0.007; cystatin C: r= 0.38, p<0.0001), and predicted all-cause mortality (Hazard ratio [HR] 1.86 [95% confidence interval: 1.36–2.54], p<0.001). In multivariate analysis, galectin-3 remained an independent predictor of all-cause mortality after adjusting for age, eGFR, left ventricular (LV) ejection fraction (EF), and mitral E/septal Ea (HR 1.94 [1.30–2.91], p=0.001). However, galectin-3 did not predict the combined endpoint of all-cause mortality, cardiac transplantation, or HF hospitalization (p>0.05). Furthermore, there were no relations between galectin-3 and LV end-diastolic volume index (r= −0.05, p=0.61), LVEF (r= 0.10, p=0.25), or LV diastolic function (mitral E/septal Ea: r= 0.06, p=0.52; left atrial volume index: r= 0.08, p=0.41). In our advanced decompensated HF cohort, we did not observe any relation between galectin-3 and echocardiographic or hemodynamic indices. In conclusion, high plasma galectin-3 levels were associated with renal insufficiency and poorer survival in patients with chronic systolic HF. However, we did not observe a relation between galectin-3 and echocardiographic or hemodynamic indices.
doi:10.1016/j.amjcard.2011.03.056
PMCID: PMC3137764  PMID: 21600537
Heart failure; galectin-3; renal function; prognosis
17.  SUBCLINICAL ECHOCARDIOGRAPHIC ABNORMALITIES IN PHENOTYPE-NEGATIVE CARRIERS OF MYBPC3 GENE MUTATION FOR HYERTROPHIC CARDIOMYOPATHY 
American heart journal  2011;162(2):262-267.e3.
Background
Early diastolic myocardial tissue Doppler (TD) velocities have reported to be reduced in mutation-positive patients with HCM in some studies even in the absence of left ventricular hypertrophy (LVH). Strain is a sensitive tool in detecting early systolic abnormalities in patients with hypertrophic cardiomyopathy (HCM). Our goal is to examine novel echocardiographic characteristics of phenotype-negative carriers for a known sarcomeric gene mutation for HCM.
Methods
We evaluated 41 consecutive subjects with a known myosin binding protein C3 (MYBPC3) mutation (c.3330+2T>G). Subjects who were mutation-positive without LVH (G+/LVH−, n=35) were compared to healthy controls (n=30) regarding tissue Doppler and segmental longitudinal strain measures.
Results
The G+/LVH− group was similar to the normal controls with respect to chamber size, LV mass index, and most diastolic filling parameters, including tissue Doppler derived Ea. Global longitudinal strain was similar for both groups (20.3 ± 2.1 vs. 19.8 ± 1.8; p=0.36) although regional segment analysis showed a notable reduction in the basal septum (16.8 ± 3.1 vs. 19.0 ± 4.0%, p=0.02) and increase in the basal posterior (22.5 ± 5.2 vs. 17.9 ± 5.2, p=0.001) as well as mid posterior (21.8 ± 4.7 vs. 18.2 ± 3.0, p=0.001) walls.
Conclusions
In our cohort of phenotype-negative carriers of a specific MYBPC3 mutation, there were minimal differences in conventional 2-dimensional, Doppler, and speckle-tracking derived parameters of systolic and diastolic function compared to that of normal subjects. The presence of regional alterations in strain indicative of the presence of underlying subclinical disease requires further validation.
doi:10.1016/j.ahj.2011.05.018
PMCID: PMC3155874  PMID: 21835286
hypertrophic cardiomyopathy; genetic heart disease; echocardiography; longitudinal strain
18.  Renal Dysfunction is a Stronger Determinant of Systemic Neutrophil Gelatinase-Associated Lipocalin Levels Than Myocardial Dysfunction in Systolic Heart Failure 
Journal of cardiac failure  2011;17(6):472-478.
Background
Neutrophil gelatinase-associated lipocalin (NGAL) is released by renal tubular cells in response to inflammation and injury. Recent studies have demonstrated that NGAL is upregulated in cardiomyocytes within the failing myocardium. However, the overall relationship between systemic NGAL levels and myocardial structure and performance has not been established.
Methods and Results
We measured systemic NGAL levels in 130 subjects with chronic systolic heart failure (HF) and comprehensive echocardiographic evaluation, as well as 69 subjects with acute decompensated systolic HF and hemodynamic evaluation. In the chronic HF cohort, higher plasma NGAL levels were modestly associated with increasing age (r= 0.18, p=0.035), higher NYHA class (rank sums, p=0.022) and impaired renal function (eGFR: r= −0.53, p<0.0001; cystatin C: r= 0.60, p<0.0001). Plasma NGAL levels were modestly associated with indices of diastolic dysfunction (mitral E/Ea: r= 0.27, p=0.002; LAVi, r= 0.25, p=0.011; tricuspid E/Ea: r= 0.20, p=0.029), but not after adjustment for renal function (p>0.10 for all). In Cox proportional hazards analysis, plasma NGAL predicted cardiac death or transplantation after adjustment for age, gender, LVEF, and mitral E/Ea (Hazard ratio 1.68, 95% confidence interval 1.08 – 2.57, p=0.022), but not after adjustment for renal function (p=0.83). In the acute HF cohort, we did not observe any relationship between NGAL and hemodynamic indices, but NGAL strongly correlated with renal function.
Conclusions
Systemic NGAL levels are largely determined by underlying impairment of renal rather than myocardial function. Our findings did not support any relationship or prognostic significance between systemic NGAL levels and indices of cardiac structure and function after adjustment for underlying renal function.
doi:10.1016/j.cardfail.2011.02.003
PMCID: PMC3105247  PMID: 21624735
Congestive heart failure; NGAL; renal insufficiency; cardio-renal
19.  Ceruloplasmin and Heart Failure in the Atherosclerosis Risk in Communities (ARIC) Study 
Circulation. Heart failure  2013;6(5):936-943.
Background
Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the association between Cp and incident heart failure (HF), death and CVD in the Atherosclerosis Risk in Communities (ARIC) Study.
Methods and Results
Cp was measured at ARIC visit 4 (1996–1998). We studied 9,240 individuals without HF or CVD at ARIC visit 4, and followed them for a mean of 10.5 years. Genome-wide association study was performed to identify genetic determinants of Cp levels and evaluate their association with incident HF. Cp levels (mean±standard deviation) were higher in women vs men (335±79 vs 258±44 mg/L, p<0.0001), women on vs not on hormone-replacement therapy (398±89 vs 291±60 mg/L, p<0.0001) and African Americans vs Caucasians (299±63 vs 293±74 mg/L, p=0.0005). After adjusting for traditional risk factors, high-sensitivity C-reactive protein, N-terminal pro–B-type natriuretic peptide, and high-sensitivity cardiac troponin T, higher levels of Cp were associated with HF (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.13–1.83) and mortality (HR 1.38, 95% CI 1.11–1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56±77.60mg/L, heterozygote 316.72±88.02mg/L; homozygote 331.04±85.40mg/L, p=8.3×10−) but not with incident HF. After adjustment for traditional risk factors Cp levels were also weekly associated with CVD.
Conclusions
Cp was associated with incident, HF mortality and CVD in the ARIC population. A single locus on chromosome 3 was associated with Cp levels but not with HF.
doi:10.1161/CIRCHEARTFAILURE.113.000270
PMCID: PMC3908901  PMID: 23861484
ceruloplasmin; heart failure; cardiovascular disease; single nucleotide polymorphism
20.  Polyunsaturated Fatty Acids in Heart Failure: Should We Give More and Give Earlier? 
doi:10.1016/j.jacc.2010.11.014
PMCID: PMC3069620  PMID: 21215549
n-3 PUFAs; heart failure; nonischemic cardiomyopathy; functional capacity; NYHA class
21.  Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia 
Human Molecular Genetics  2013;22(16):3381-3393.
Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10−41) and in 1690 AA subjects (rs505102; P = 1.05 × 10−8). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10−12; rs35897051, P = 3.32 × 10−8). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10−12), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case–control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
doi:10.1093/hmg/ddt189
PMCID: PMC3723315  PMID: 23620142
22.  An abundant dysfunctional apolipoprotein A1 in human atheroma 
Nature medicine  2014;20(2):193-203.
Recent studies indicate high density lipoproteins (HDL) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma, are dysfunctional and extensively oxidized by myeloperoxidase (MPO), while in vitro oxidation of apoA1/HDL by MPO impairs its cholesterol acceptor function. We developed a high affinity monoclonal antibody (mAb) that specifically recognizes apoA1/HDL modified by the MPO/H2O2/Cl-system using phage display affinity maturation. An oxindolyl alanine (2-OH-Trp) moiety at tryptophan 72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirm a critical role for apoA1 Trp72 in MPO-mediated inhibition of ABCA1-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation, but accounts for 20% of the apoA1 in atherosclerotic plaque. OxTrp72-apoA1 recovered from human atheroma or plasma was lipid-poor, virtually devoid of cholesterol acceptor activity, and demonstrated both potent pro-inflammatory activities on endothelial cells and impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n=627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a pro-atherogenic process in the artery wall.
doi:10.1038/nm.3459
PMCID: PMC3923163  PMID: 24464187
23.  Coenzyme Q supplementation in pulmonary arterial hypertension 
Redox Biology  2014;2:884-891.
Mitochondrial dysfunction is a fundamental abnormality in the vascular endothelium and smooth muscle of patients with pulmonary arterial hypertension (PAH). Because coenzyme Q (CoQ) is essential for mitochondrial function and efficient oxygen utilization as the electron carrier in the inner mitochondrial membrane, we hypothesized that CoQ would improve mitochondrial function and benefit PAH patients. To test this, oxidized and reduced levels of CoQ, cardiac function by echocardiogram, mitochondrial functions of heme synthesis and cellular metabolism were evaluated in PAH patients (N=8) in comparison to healthy controls (N=7), at baseline and after 12 weeks oral CoQ supplementation. CoQ levels were similar among PAH and control individuals, and increased in all subjects with CoQ supplementation. PAH patients had higher CoQ levels than controls with supplementation, and a tendency to a higher reduced-to-oxidized CoQ ratio. Cardiac parameters improved with CoQ supplementation, although 6-minute walk distances and BNP levels did not significantly change. Consistent with improved mitochondrial synthetic function, hemoglobin increased and red cell distribution width (RDW) decreased in PAH patients with CoQ, while hemoglobin declined slightly and RDW did not change in healthy controls. In contrast, metabolic and redox parameters, including lactate, pyruvate and reduced or oxidized gluthathione, did not change in PAH patients with CoQ. In summary, CoQ improved hemoglobin and red cell maturation in PAH, but longer studies and/or higher doses with a randomized placebo-controlled controlled design are necessary to evaluate the clinical benefit of this simple nutritional supplement.
Graphical abstract
Highlights
•Pulmonary arterial hypertension (PAH) is characterized by mitochondrial dysfunction.•Co-enzymeQ (CoQ) is important for mitochondria function.•CoQ supplementation improved heart function and red cell production in PAH.•The findings support the concept of mitochondrial-targeted therapies for PAH.
doi:10.1016/j.redox.2014.06.010
PMCID: PMC4143816  PMID: 25180165
Pulmonary hypertension; Mitochondria; Coenzyme Q; Hemoglobin; Heart failure; Metabolism
24.  Soluble Angiotensin Converting Enzyme 2 in Human Heart Failure: Relation with Myocardial Function and Clinical Outcomes 
Journal of cardiac failure  2009;15(7):565-571.
Objective
Angiotensin converting enzyme 2 (ACE2) is an endogenous counter-regulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established.
Methods
We measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF] ≤ 35%, NYHA class II-IV). Comprehensive echocardiography was performed at the time of blood sampling. We prospectively examined adverse clinical events (death, cardiac transplant, and heart failure hospitalizations) over 34 ± 17 months.
Results
Patients who had higher sACE2 plasma activity were more likely to have a lower LVEF (Spearman’s r= −0.36, p <0.001), greater RV systolic dysfunction (r=0.33, p<0.001), higher estimated pulmonary artery systolic pressure (r=0.35, p=0.002), larger LV end diastolic diameter (r=0.23, p=0.02), and higher plasma NT-proBNP levels (r=0.35, p<0.001). sACE2 was less associated with diastolic dysfunction (r=0.19, p=0.05), and was similar between patients with ischemic and non-ischemic cardiomyopathies. There was no relationship between sACE2 activity and markers of systemic inflammation. After adjusting for NT-proBNP and LVEF, sACE2 activity remained an independent predictor of adverse clinical events (HR=1.7 [95% CI: 1.1 – 2.6], p=0.018).
Conclusions
Elevated plasma sACE2 activity was associated with greater severity of myocardial dysfunction and was an independent predictor of adverse clinical events.
doi:10.1016/j.cardfail.2009.01.014
PMCID: PMC3179261  PMID: 19700132
Heart failure; ACE2; remodeling; angiotensin
25.  Tissue Doppler Imaging in the Estimation of Intracardiac Filling Pressure in Decompensated Patients with Advanced Systolic Heart Failure 
Circulation  2008;119(1):62-70.
Background
Early transmitral velocity / tissue Doppler mitral annular early diastolic velocity (E/Ea) has been correlated with pulmonary capillary wedge pressure (PCWP) in a wide variety of cardiac conditions. The objective of this study was to determine the reliability of mitral E/Ea for predicting PCWP in patients admitted for advanced decompensated heart failure (ADHF).
Methods and Results
Prospective consecutive patients with ADHF (ejection fraction [EF] ≤30%, NYHA class III-IV symptoms) underwent simultaneous echocardiographic and hemodynamic evaluation on admission and after 48 hours of intensive medical therapy. A total of 106 patients were included (mean age 57 ±12 years, EF 24 ±8%, PCWP 21 ±7 mmHg, mitral E/Ea 20 ±12). There was a lack of correlation between mitral E/Ea and PCWP, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy. Overall, mitral E/Ea was similar among patients with PCWP > and ≤ 18 mmHg, and sensitivity and specificity for mitral E/Ea > 15 to identify a PCWP > 18 mmHg was 66% and 50%, respectively. Contrary to prior reports, we did not observe any direct association between changes in PCWP and changes in mitral E/Ea.
Conclusion
In decompensated patients with advanced systolic heart failure, tissue Doppler derived mitral E/Ea may not be as reliable in predicting intracardiac filling pressures, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy.
doi:10.1161/CIRCULATIONAHA.108.779223
PMCID: PMC3169300  PMID: 19075104
heart failure; hemodynamics; diastole; remodeling; echocardiography

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