Pam R. Taub

Primary Results of the HABIT Trial (Heart Failure Assessment With BNP in the Home)

OBJECTIVES This study was a multicenter, single-arm, double-blinded observational prospective clinical trial designed to monitor daily concentrations of B-type natriuretic peptide (BNP) and to determine how these concentrations correlate with acute clinical heart failure decompensation (ADHF) and related adverse clinical outcomes in at-risk HF patients. BACKGROUND Although BNP at discharge is predictive of 30-day outcomes, outpatient serial testing may improve the risk of detecting early decompensation. METHODS A total of 163 patients with HF signs and symptoms of ADHF discharged from the hospital or in an outpatient setting measured their weight and BNP levels daily for 60 days with a finger-stick test. Patients and physicians were blinded to BNP levels. The composite outcome was ADHF events: cardiovascular death, admission for decompensated HF, or clinical HF decompensation requiring either parenteral HF therapy or changes in oral HF medications. RESULTS A total of 6,934 daily BNP values were recorded, with a median of 46 measures per patient over a monitoring period of 65 days. Forty patients had 56 events. Correlations between BNP measures weakened over time, and the dispersion between BNP measures grew. During 10,035 patient-days, there were 494 (4.9%) days of weight gain (≥5 lbs). The hazard ratio per unit increase of ln BNP was 1.84, and the hazard ratio on a day of weight gain was 3.63. These effects retained significance when controlling for symptoms. When the monitoring period for each subject was broken into intervals based on ADHF events, there were 39 (18.4%) intervals of upward trending BNP corresponding to a risk increase of 59.8% and 64 (30.2%) downward trending intervals corresponding to a risk decrease of 39.0%. There were 94 (44.3%) intervals with 1 or more days of weight gain corresponding to a risk increase of 26.1%. CONCLUSIONS This pilot study demonstrates that home BNP testing is feasible and that trials using home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight monitoring is complementary to BNP, but BNP changes correspond to larger changes in risk, both upward and downward. (Heart Failure [HF] Assessment with B-type Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231).

Post-traumatic Stress Disorder A Fast Track to Premature Cardiovascular Disease?

An increasing body of evidence reported in the literature indicates a possible role for post-traumatic stress disorder (PTSD) as a cause for cardiovascular disease (CVD). However, mechanistic evidence on the progression of adverse cardiac outcomes in PTSD is lacking. In this review, we examine the potential paths by which CVD could occur in those with PTSD. Dysregulation of the hypothalamic-pituitary-adrenal axis and autonomic nervous dysfunction are commonly observed in PTSD, which in turn leads to a variety of physiological changes potentially damaging to the heart. Increased inflammation, dysfunction of the vascular endothelium, hypercoagulability, and cardiac hyperreactivity all have been noted in patients with PTSD. Altered neurochemistry, most notably increased arginine vasopressin, as well as an increased prevalence of the metabolic syndrome, may also contribute to adverse cardiac outcomes. Although the association between PTSD and physical disease is often complicated by health risk behaviors or comorbid psychiatric conditions, the evidence for a link between PTSD and CVD is substantial. In our examination, we attempt to identify potential cardiac biomarkers that may be useful in detecting increased cardiac risk in patients with PTSD. As research in this area is exceedingly limited, we hope to inspire further research, as there is great potential value in identifying prognostically useful cardiac biomarkers so as to predict and prevent the onset of CVD in patients with PTSD.

Effects of (-)-epicatechin on myocardial infarct size and left ventricular remodeling after permanent coronary occlusion.

OBJECTIVES We examined the effects of the flavanol (-)-epicatechin on short- and long-term infarct size and left ventricular (LV) structure and function after permanent coronary occlusion (PCO) and the potential involvement of the protective protein kinase B (AKT)/extracellular signal-related kinase (ERK) signaling pathways. BACKGROUND (-)-epicatechin reduces blood pressure in hypertensive patients and limits infarct size in animal models of myocardial ischemia-reperfusion injury. However, nothing is known about its effects on infarction after PCO. METHODS (-)-epicatechin (1 mg/kg daily) treatment was administered via oral gavage to 250 g male rats for 10 days before PCO and was continued afterward. The PCO controls received water. Sham animals underwent thoracotomy and treatment in the absence of PCO. Immunoblots assessed AKT/ERK involvement 2 h after PCO. The LV morphometric features and function were measured 48 h and 3 weeks after PCO. RESULTS In the 48-h group, treatment reduced infarct size by 52%. There were no differences in hemodynamics among the different groups (heart rate and aortic and LV pressures). Western blots revealed no differences in AKT or ERK phosphorylation levels. At 3 weeks, PCO control animals demonstrated significant increases in LV end-diastolic pressure, heart and body weight, and LV chamber diameter versus sham. The PCO plus (-)-epicatechin group values were comparable with those of the sham plus (-)-epicatechin group. Treatment resulted in a 33% decrease in myocardial infarction size. The LV pressure-volume curves demonstrated a right shift in control PCO animals, whereas the (-)-epicatechin curves were comparable with those of the sham group. The LV scar area strains were significantly improved with (-)-epicatechin. CONCLUSIONS These results demonstrate the unique capacity of (-)-epicatechin to confer cardioprotection in the setting of a severe form of myocardial ischemic injury. Protection is sustained over time and preserves LV structure and function. The cardioprotective mechanism(s) of (-)-epicatechin seem to be unrelated to AKT or ERK activation. (-)-epicatechin warrants further investigation as a cardioprotectant.

Biomarkers of Heart Failure

Biomarkers can provide insights into underlying mechanisms and lead to better understanding of complex disease states. This enhanced understanding can then be integrated into disease management, which can lead to better therapies and ultimately to improved patient outcomes. The natriuretic peptides (NPs) are established cost-effective biomarkers in heart failure and have set the standard for how a well-validated biomarker can be useful in the diagnosis/prognosis, monitoring of response to therapy, and management of chronic disease. Newer biomarkers such as midregional pro-adrenomedullin, ST2, and neutrophil gelatinase-associated lipocalin are emerging as adjuncts to NPs in the management of heart failure patients.

Proenkephalin predicts acute kidney injury in cardiac surgery patients.

AIMS Acute kidney injury (AKI) occurs in up to 40% of patients undergoing cardiac surgery. Proenkephalin A 119-159 (pro-ENK) is a novel, stable surrogate biomarker for enkephalins, endogenous opioids involved in various physiological processes, including neurohormonal stress. MATERIAL AND METHODS 92 patients undergoing cardiac surgery at the Veterans Affairs San Diego Healthcare System had a post-hoc analysis performed to determine the ability of pro-ENK to predict AKI as well as to compare it against other risk factors for development of AKI. RESULTS Of 92 patients, 20 patients developed AKI post-operatively. Pro-ENK levels were significantly elevated in patients who develop AKI. Log pro-ENK value pre-operatively has an odds ratio of 23.8 (p = 0.011, 95% CI = 2 - 270) in its association with AKI. Pro-ENK performs similarly to baseline creatinine in its ability to predict post-operative AKI. Importantly, pro-ENK has a strong positive correlation with creatinine (r = 0.806). Additionally, changes in pro-ENK level, from pre-operatively to 12 hours post-operatively have greatest area under curve by ROC analysis for AKI after post-operative day 1. CONCLUSION Pro-ENK is associated with prediction of AKI in patients undergoing cardiac surgery. Pro-ENK likely has decreased clearance in the setting of AKI. However, future studies analyzing this novel biomarker should be considered to further elucidate its clinical utility and to better understand mechanisms of renal injury.

Simultaneous quantification of F2-isoprostanes and prostaglandins in human urine by liquid chromatography tandem-mass spectrometry

A specific and sensitive LC-MS/MS method for analysis of F(2)-isoprostanes (F(2)-IsoPs) and prostaglandins (PGs) in urine was developed and validated to examine the levels of F(2)-IsoPs and prostaglandin F(2α) (PGF(2α)), in human urine in patients undergoing cardiac surgery. The rapid extraction for F(2)-IsoPs and PGs from urine was achieved using a polymeric weak anion solid phase extraction cartridge. The base-line separation of 8-iso-PGF(2α), 8-iso-15(R)-PGF(2α), PGF(2α), and 15(R)-PGF(2α) was carried out on a Hydro-RP column (250mm×2.0mm i.d., Phenomenex, CA) using a linear gradient of methanol:acetonitrile (1:1, v/v) in 0.1% formic acid at a flow rate of 0.2mL/min. The method was proved to be accurate and precise for simultaneous quantification of each analyte over a linear dynamic range of 0.05-50ng/mL with correlation coefficients greater than 0.99. The intra-day and inter-day assay precision at the lowest quality control (0.07ng/mL) level were less than 17%. The mean extraction recoveries of F(2)-IsoPs and PGs were in a range of 79-100%. In applications of this method to patients undergoing cardiac surgery, post-surgery urinary concentrations of 8-iso-PGF(2α) increased significantly in patients (n=14) who did not develop acute kidney (AKI) (pre-surgery 0.344±0.039 vs. post-surgery 0.682±0.094ng/mg creatinine, p<0.01), whereas there was no significant change in this isoprostane in the patients (n=4) who developed AKI (pre-surgery 0.298±0.062 vs. post-surgery 0.383±0.117ng/mg creatinine, NS). Therefore, the method is suitable for the analysis of individual F(2)-IsoPs and PGF(2α)s in both clinical and research studies.

Effects of (−)-epicatechin on molecular modulators of skeletal muscle growth and differentiation

Sarcopenia is a notable and debilitating age-associated condition. Flavonoids are known for their healthy effects and limited toxicity. The flavanol (-)-epicatechin (Epi) enhances exercise capacity in mice, and Epi-rich cocoa improves skeletal muscle structure in heart failure patients. (-)-Epicatechin may thus hold promise as treatment for sarcopenia. We examined changes in protein levels of molecular modulators of growth and differentiation in young vs. old, human and mouse skeletal muscle. We report the effects of Epi in mice and the results of an initial proof-of-concept trial in humans, where muscle strength and levels of modulators of muscle growth were measured. In mice, myostatin and senescence-associated β-galactosidase levels increase with aging, while those of follistatin and Myf5 decrease. (-)-Epicatechin decreases myostatin and β-galactosidase and increases levels of markers of muscle growth. In humans, myostatin and β-galactosidase increase with aging while follistatin, MyoD and myogenin decrease. Treatment for 7 days with (-)-epicatechin increases hand grip strength and the ratio of plasma follistatin/myostatin. In conclusion, aging has deleterious effects on modulators of muscle growth/differentiation, and the consumption of modest amounts of the flavanol (-)-epicatechin can partially reverse these changes. This flavanol warrants its comprehensive evaluation for the treatment of sarcopenia.

Cardiac biomarkers, mortality, and post-traumatic stress disorder in military veterans.

Post-traumatic stress disorder (PTSD) is gaining increasing recognition as a risk factor for morbidity and mortality. The aim of this study was to examine the impact of PTSD and abnormal cardiovascular biomarkers on mortality in military veterans. Eight hundred ninety-one patients presenting for routine echocardiography were enrolled. Baseline clinical data and serum samples for biomarker measurement were obtained and echocardiography was performed at the time of enrollment. Patients were followed for up to 7.5 years for the end point of all-cause mortality. Ninety-one patients had PTSD at the time of enrollment. There were 33 deaths in patients with PTSD and 221 deaths in those without PTSD. Patients with PTSD had a trend toward worse survival on Kaplan-Meier analysis (p = 0.057). Among patients with elevated B-type natriuretic peptide (>60 pg/ml), those with PTSD had significantly increased mortality (p = 0.024). Among patients with PTSD, midregional proadrenomedullin (MR-proADM), creatinine, and C-terminal proendothelin-1 were significant univariate predictors of mortality (p = 0.006, p = 0.024, and p = 0.003, respectively). In a multivariate model, PTSD, B-type natriuretic peptide, and MR-proADM were independent predictors of mortality. In patients with PTSD, MR-proADM was a significant independent predictor of mortality after adjusting for B-type natriuretic peptide, cardiovascular risk factors, cancer, and sleep apnea. Adding MR-proADM to clinical predictors of mortality increased the C-statistic from 0.572 to 0.697 (p = 0.007). In conclusion, this study demonstrates an association among PTSD, abnormal cardiac biomarker levels, and increased mortality.

Usefulness of B-type Natriuretic Peptide Levels in Predicting Hemodynamic and Clinical Decompensation

Pulmonary congestion can be challenging to diagnose because of nonspecific symptoms and the blunt nature of physical examination and radiographic findings. Assessing for euvolemia following treatment of congestion also can be difficult but can improve both the inpatient and outpatient care of patients who have heart failure. Tools such as the natriuretic peptides are important adjuncts to the physical examination and chest radiographs and often obviate the need for invasive hemodynamic assessment.

Perturbations in skeletal muscle sarcomere structure in patients with heart failure and Type 2 diabetes: restorative effects of ( − )-epicatechin- rich cocoa

HF (heart failure) and T2D (Type 2 diabetes) associate with detrimental alterations in SkM (skeletal muscle) structure/function. We have demonstrated recently that (-)-ERC (epicatechin-rich cocoa) improves SkM mitochondrial structure [Taub, Ramirez-Sanchez, Ciaraldi, Perkins, Murphy, Naviaux, Hogan, Ceballos, Maisel, Henry et al. (2012) Clin. Trans. Sci. 5, 43-47]. We hypothesized that an improved mitochondrial structure may facilitate the reversal of detrimental alterations in sarcomeric microstructure. In a pilot study, five patients with HF and T2D consumed ERC for 3 months; treadmill testing [VO2max (maximum oxygen consumption)] and SkM biopsies were performed. Western blot analysis, immunohistochemistry and electron microscopy were used. We report severe perturbations in components of the DAPC (dystrophin-associated protein complex) as well as sarcomeric microstructure at baseline. ERC induced recovery/enhancement of DAPC protein levels, sarcomeric microstructure and, in a co-ordinated fashion, alterations in markers of SkM growth/differentiation consistent with myofibre regeneration. VO2max increased (~24%) but did not reach statistical significance. These initial results warrant further rigorous investigation, since the use of ERC (or pure epicatechin) may represent a safe and novel means of improving muscle function.