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1.  Insufficient Natriuretic Response to Continuous Intravenous Furosemide Is Associated with Poor Long-Term Outcomes in Acute Decompensated Heart Failure 
Journal of cardiac failure  2014;20(6):392-399.
Treatment of acute decompensated heart failure with loop diuretics such as furosemide is frequently complicated by insufficient urine sodium excretion. We hypothesize that insufficient natriuretic response to diuretic therapy, characterized by lower urine sodium (UNa) and urine furosemide is associated with subsequent inadequate decongestion, worsening renal function, and adverse long-term events.
Methods and Results
We enrolled 52 consecutive patients with ADHF and measured serum and urine sodium (UNa), urine creatinine (UCr), and urine furosemide (UFurosemide) levels on a spot sample taken after treatment with continuous intravenous furosemide, and followed clinical and renal variables as well as adverse long-term clinical outcomes (death, rehospitalizations and cardiac transplant). We observed comparable correlations between UNa:UFurosemide ratio as well as UNa and fractional excretion of sodium (FENa) with 24-hour net urine output (r=0.52–0.64, all p<0.01) and 24-hour weight loss (r=0.44–0.56, all p<0.01). Interestingly, FENa (but not UNa or UNa:UFurosemide) were influenced by estimated glomerular filtration rate (eGFR). We observed an association between lower UNa:UFurosemide with greater likelihood of worsening renal function (HR 3.01, p=0.02) and poorer adverse clinical outcomes (HR 1.63, p=0.008) after adjusting for age and eGFR. Meanwhile, both diminished weight loss and net fluid output over 24 hours of continuous intravenous furosemide were observed when UNa:UFurosemide ratios were <2 mmol/mg or when UNa <50 mmol.
In patients with ADHF receiving continuous furosemide infusion, impaired natriuretic response to furosemide is associated with greater likelihood of worsening renal function and future adverse long-term outcomes that is independent and incremental to intrinsic glomerular filtration.
PMCID: PMC4067259  PMID: 24704538
Acute decompensated heart failure; furosemide; urine sodium; natriuresis
2.  Angiotensin-Converting Enzyme 2 as a Therapeutic Target for Heart Failure 
Current heart failure reports  2014;11(1):58-63.
The renin-angiotensin system (RAS) plays a major role in the pathophysiology of cardiovascular disorders. Angiotensin II (Ang-II), the final product of this pathway, is known for its vasoconstrictive and proliferative effects. Angiotensin-converting enzyme 2 (ACE2), a newly discovered homolog of ACE, plays a key role as the central negative regulator of the RAS. It diverts the generation of vasoactive Ang-II into the vasodilatory and growth inhibiting peptide angiotensin(1-7) [Ang(1-7)], thereby providing counter-regulatory responses to neurohormonal activation. There is substantial experimental evidence evaluating the role of ACE2/Ang(1-7) in hypertension, heart failure, and atherosclerosis. In this review, we aim to focus on the conceptual facts of the ACE2-Ang(1-7) axis with regards to clinical implications and therapeutic targets in cardiovascular disorders, with emphasis on the potential therapeutic role in cardiovascular diseases.
PMCID: PMC3944399  PMID: 24293035
renin angiotensin system; angiotensin converting enzyme 2; angiotensin (1-7); heart failure
3.  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.
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
4.  Prognostic Value of Estimated Functional Capacity Incremental to Cardiac Biomarkers in Stable Cardiac Patients 
Few studies have investigated functional capacity self‐assessment tools in either prediction of future major adverse cardiac outcomes beyond all‐cause mortality or direct comparisons with clinically available biomarkers.
Methods and Results
We estimated functional capacity using the Duke Activity Status Index (DASI) questionnaire in 8987 sequential stable patients without acute coronary syndrome who were undergoing elective diagnostic coronary angiography with 3‐year follow‐up of major adverse cardiac events (death, nonfatal myocardial infarction, or stroke). A low DASI score provided independent prediction of a 4.8‐fold increase in future risk of incident major adverse cardiac events at 3 years (quartiles 1 versus 4 hazard ratio [95% CI] 4.76 [4.03 to 5.61], P<0.001), and a 3.8‐fold increased risk after adjusting for traditional risk factors (3.77 [3.15 to 4.51], P<0.001). The prognostic value of the DASI score was evident in both primary and secondary prevention cohorts, with and without heart failure, as well as high and low C‐reactive protein and B‐type natriuretic peptide levels. The DASI score reclassified 15% of patients (P<0.001) beyond traditional risk factors in predicting future MACE.
A simple self‐assessment tool of functional capacity in stable patients undergoing elective diagnostic cardiac evaluation provides independent and incremental prognostic value for prediction of both significant coronary angiographic disease and long‐term adverse clinical events.
PMCID: PMC4323823  PMID: 25332177
functional capacity impairment; Duke activity status index; prognosis; coronary artery disease
5.  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.
PMCID: PMC3735826  PMID: 23735785
Peripheral Blood Mononuclear Cells (PBMC); microRNA-548; dilated cardiomyopathy; canonical signaling networks; biomarker
6.  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.
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).
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.
PMCID: PMC3781948  PMID: 24054338
Acute decompensated heart failure; acute kidney injury; biomarkers; outcome
7.  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.
PMCID: PMC3691294  PMID: 23499315
Congestive heart failure; adiponectin; ADMA; natriuretic peptides; diastolic dysfunction
8.  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).
PMCID: PMC4024708  PMID: 23747774
chronic heart failure; controlled clinical trial; qili qiangxin capsules
9.  Detectable Subclinical Myocardial Necrosis Is Associated With Cardiovascular Risk in Stable Patients With Diabetes 
Diabetes Care  2013;36(5):1126-1131.
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.
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.
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).
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.
PMCID: PMC3631842  PMID: 23393213
10.  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.
PMCID: PMC3568213  PMID: 23143732
Cardiorenal syndrome; Renocardiac syndrome; management; renin-angiotensin-aldosterone system; sympathetic nervous system; hypervolemia
11.  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.
PMCID: PMC3470750  PMID: 22835414
Cardio-renal; Heart failure; Neutrophil gelatinase-associated lipocalin; Natriuresis; Diuresis
12.  Prognostic Role of Pulmonary Arterial Capacitance in Advanced Heart Failure 
Circulation. Heart failure  2012;5(6):778-785.
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).
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.
PMCID: PMC3538355  PMID: 23087402
heart failure; hemodynamics; pulmonary arterial capacitance; pulmonary vascular resistance
13.  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.
PMCID: PMC3414418  PMID: 22824112
14.  Dysregulated Arginine Metabolism and Importance of Compensatory Dimethylarginine Dimethylaminohydrolase-1 in Pulmonary Hypertension Associated with Advanced Systolic Heart Failure 
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.
Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear.
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).
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).
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.
PMCID: PMC3565538  PMID: 22440215
Nitric oxide synthase; asymmetric dimethylarginine; heart failure; pulmonary hypertension
15.  Cellular Proliferative Response to Cardiac Troponin-I in Patients with Idiopathic Dilated Cardiomyopathy 
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.
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.
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).
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.
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.
PMCID: PMC3137764  PMID: 21600537
Heart failure; galectin-3; renal function; prognosis
American heart journal  2011;162(2):262-267.e3.
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.
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.
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.
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.
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.
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.
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.
PMCID: PMC3105247  PMID: 21624735
Congestive heart failure; NGAL; renal insufficiency; cardio-renal
19.  Polyunsaturated Fatty Acids in Heart Failure: Should We Give More and Give Earlier? 
PMCID: PMC3069620  PMID: 21215549
n-3 PUFAs; heart failure; nonischemic cardiomyopathy; functional capacity; NYHA class
20.  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.
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.
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.
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).
Elevated plasma sACE2 activity was associated with greater severity of myocardial dysfunction and was an independent predictor of adverse clinical events.
PMCID: PMC3179261  PMID: 19700132
Heart failure; ACE2; remodeling; angiotensin
21.  Tissue Doppler Imaging in the Estimation of Intracardiac Filling Pressure in Decompensated Patients with Advanced Systolic Heart Failure 
Circulation  2008;119(1):62-70.
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.
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.
PMCID: PMC3169300  PMID: 19075104
heart failure; hemodynamics; diastole; remodeling; echocardiography
22.  Right Ventricular Response to Intensive Medical Therapy in Advanced Decompensated Heart Failure 
Circulation. Heart failure  2010;3(3):340-346.
Right ventricular (RV) systolic dysfunction is a strong predictor of adverse outcomes in heart failure, yet quantitatively assessing the impact of therapy on this condition is difficult. Our objective was to compare the clinical significance of changes in RV echocardiographic indices in response to intensive medical treatment in patients admitted to the hospital with acute decompensated heart failure (ADHF).
Methods and Results
Serial comprehensive echocardiography was performed in 62 consecutive patients with ADHF, and adverse events (death, cardiac transplantation, assist device, heart failure rehospitalization) were prospectively documented. RV peak systolic strain was assessed using speckle-tracking longitudinal strain analysis as the average of the basal, mid-, and apical segment of the RV free wall. Other conventional parameters of RV function (RV fractional area change, RV myocardial performance index, tricuspid annular peak systolic excursion, and tissue Doppler peak tricuspid annular systolic velocity) were measured for comparison. In our study cohort [left ventricular ejection fraction, 26±10%; cardiac index, 2.0±0.6 L/(min · m2)], overall mean RV peak systolic strain was –14±4% at baseline and –15±4% at 48 to 72 hours (P=0.27). Among all the RV functional indices measured, only RV peak systolic strain at 48 to 72 hours was associated with adverse events (P=0.02). In particular, improvement in RV peak systolic strain after intensive medical treatment was associated with lower adverse events in this patient population (26% versus 78%; hazard ratio, 0.13; 95% CI, 0.02 to 0.84; P=0.02).
Dynamic improvement in RV mechanics in response to intensive medical therapy was associated with lower long-term adverse events in patients with ADHF than in patients not showing improvement.
PMCID: PMC3060051  PMID: 20176715
echocardiography; heart failure; hemodynamics; prognosis; right ventricle
23.  Measuring impedance in congestive heart failure: Current options and clinical applications 
American heart journal  2008;157(3):402-411.
Measurement of impedance is becoming increasingly available in the clinical setting as a tool for assessing hemodynamics and volume status in patients with heart failure. The 2 major categories of impedance assessment are the band electrode method and the implanted device lead method. The exact sources of the impedance signal are complex and can be influenced by physiologic effects such as blood volume, fluid, and positioning. This article provides a critical review of our current understanding and promises of impedance measurements, the techniques that have evolved, as well as the evidence and limitations regarding their clinical applications in the setting of heart failure management.
PMCID: PMC3058607  PMID: 19249408
24.  Recent Insights Into the Role of Autoimmunity in Idiopathic Dilated Cardiomyopathy 
Journal of cardiac failure  2008;14(6):521-530.
Dilated cardiomyopathy is a devastating disease associated with poor outcomes. Although the etiology of this disease remains largely unknown, so-called “idiopathic” dilated cardiomyopathy (iDCM) is associated with evidence of an autoimmune process that may be contributing to the pathophysiology of this disease. Indeed, iDCM shares many characteristics with other autoimmune diseases, including an association with systemic and organ-specific inflammation, an association with viral infections, a genetic predisposition, and a correlation with specific human leukocyte antigen subtypes.
Additionally, numerous pathologic cardiac-specific autoantibodies have been associated with iDCM, including those against α-myosin, the β1-adrenoceptor, and cardiac troponin I.
This review highlights the emerging evidence regarding autoimmune characteristics of iDCM, and summarizes the data of specific immunomodulatory therapies used to target autoimmune mechanisms in the treatment of patients with this devastating disease.
PMCID: PMC3050556  PMID: 18672201
Autoimmune; heart failure; immunoadsorption; intravenous immunoglobulin; inflammation
25.  Subclinical Myocardial Necrosis and Cardiovascular Risk in Stable Patients Undergoing Elective Cardiac Evaluation 
The presence of subclinical myocardial necrosis as a prodrome to longer term adverse cardiac event risk has been debated. The debate has focused predominantly within patients with acute coronary syndrome, and on issues of troponin assay variability and accuracy of detection, rather than the clinical significance of the presence of subclinical myocardial necrosis (i.e. “troponin leak”) within stable cardiac patients. Herein we examine the relationship between different degrees of subclinical myocardial necrosis and long-term adverse clinical outcomes within a stable cardiac patient population with essentially normal renal function.
Methods and Results
Sequential consenting patients (N=3,828; median creatinine clearance 100 ml/min/1.73m2) undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cutoff for defining myocardial infarction (<0.03 ng/mL) were evaluated. The relationship of subclinical myocardial necrosis with incident major adverse cardiovascular events (MACE, defined as any death, myocardial infarction, or stroke) over 3-year follow-up was examined. “Probable” (cTnI 0.001–0.008 ng/mL) and “definite” (cTnI 0.009 –0.029 ng/mL) subclinical myocardial necrosis were observed frequently within the cohort (34% and 18%, respectively). A linear relationship was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident MACE, particularly in those with cTnI 0.009 ng/mL or higher (Hazard Ratio 3.00, 95% confidence interval 2.4–3.8), even following adjustment for traditional risk factors, C-reactive protein (CRP), and creatinine clearance. The presence of subclinical myocardial necrosis was associated with elevations in acute phase proteins (CRP, ceruloplasmin, p<0.01 each) and reduction in systemic anti-oxidant enzyme activities (arylesterase, p<0.01), but showed no significant associations with multiple specific measures of oxidant stress, and borderline associations with myeloperoxidase, a marker of leukocyte activation.
In stable cardiology patients, prodromal subclinical myocardial necrosis is associated with substantially higher long-term risk for MACE. The underlying mechanisms contributing to this minimal troponin leak phenomenon warrants further investigation.
PMCID: PMC3045838  PMID: 20032289
Coronary artery disease; myocardium; ischemia; troponin; atherosclerosis

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