Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype.

Ischemia caused by coronary artery disease and myocardial infarction leads to aberrant ventricular remodeling and cardiac fibrosis. This occurs partly through accumulation of gene expression changes in resident fibroblasts, resulting in an overactive fibrotic phenotype. Long-term adaptation to a hypoxic insult is likely to require significant modification of chromatin structure in order to maintain the fibrotic phenotype. Epigenetic changes may play an important role in modulating hypoxia-induced fibrosis within the heart. Therefore, the aim of the study was to investigate the potential pro-fibrotic impact of hypoxia on cardiac fibroblasts and determine whether alterations in DNA methylation could play a role in this process. This study found that within human cardiac tissue, the degree of hypoxia was associated with increased expression of collagen 1 and alpha-smooth muscle actin (ASMA). In addition, human cardiac fibroblast cells exposed to prolonged 1% hypoxia resulted in a pro-fibrotic state. These hypoxia-induced pro-fibrotic changes were associated with global DNA hypermethylation and increased expression of the DNA methyltransferase (DNMT) enzymes DNMT1 and DNMT3B. Expression of these methylating enzymes was shown to be regulated by hypoxia-inducible factor (HIF)-1α. Using siRNA to block DNMT3B expression significantly reduced collagen 1 and ASMA expression. In addition, application of the DNMT inhibitor 5-aza-2'-deoxycytidine suppressed the pro-fibrotic effects of TGFß. Epigenetic modifications and changes in the epigenetic machinery identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu. Targeting up-regulated expression of DNMTs in ischemic heart disease may prove to be a valuable therapeutic approach.

The role of renin angiotensin system intervention in stage B heart failure.

This article outlines the link between the renin angiotensin aldosterone system (RAAS) and various forms of cardiomyopathy, and also reviews the understanding of the effectiveness of RAAS intervention in this phase of ventricular dysfunction. The authors focus their discussion predominantly on patients who have had previous myocardial infarction or those who have left ventricular hypertrophy and also briefly discuss the role of RAAS activation and intervention in patients with alcoholic cardiomyopathy.

Can individualized weight monitoring using the HeartPhone algorithm improve sensitivity for clinical deterioration of heart failure?

AIMS: Previous studies have demonstrated poor sensitivity of guideline weight monitoring in predicting clinical deterioration of heart failure (HF). This study aimed to evaluate patterns of remotely transmitted daily weights in a high-risk HF population and also to compare guideline weight monitoring and an individualized weight monitoring algorithm. METHODS AND RESULTS: Consenting, consecutive, high-risk patients were provided with a mobile phone-based remote weight telemonitoring device. We aimed to evaluate population vs. individual weight variability, weight patterns pre- and post-events of clinical deterioration of HF, and to compare guideline weight thresholds with the HeartPhone algorithm in terms of sensitivity and specificity for such events. Of 87 patients recruited and followed for an average of 23.9 ± 12 weeks, 19 patients experienced 28 evaluable episodes of clinical deterioration of HF. Following a post-discharge decline, the population average weight remained stable for the follow-up period, yet the 7-day moving average of individual patients exceeded 2 kg in three-quarters of patients. Significant increases in weight were observed up to 4 days before HF events. The HeartPhone algorithm was significantly more sensitive (82%) in predicting HF events than guideline weight thresholds of 2 kg over 2-3 days (21%) and a 'rule of thumb' threshold of 1.36 kg over 1 day (46%). CONCLUSIONS: An individualized approach to weight monitoring in HF with the HeartPhone algorithm improved prediction of HF deterioration. Further evaluation of HeartPhone with and without other biomarkers of HF deterioration is warranted.

Screening to prevent heart failure (STOP-HF): expanding the focus beyond asymptomatic left ventricular systolic dysfunction.

AIMS: We evaluated the extent to which left ventricular diastolic dysfunction (LVDD) contributes to the high false-positive rates observed when natriuretic peptides (NPs) are used to screen for left ventricular systolic dysfunction (LVSD), and the use of NPs in combination with electrocardiogram (ECG) to screen for pre-clinical ventricular dysfunction (PCVD). METHODS AND RESULTS: Eight hundred and fourteen patients over 40 years of age and with at least one cardiovascular risk factor were recruited. Screening strategies for LVSD included brain natriuretic peptide (BNP) alone at cut-offs of 20, 50, and 100 pg/mL, and BNP and abnormal ECG combined. Systolic and diastolic function was assessed by Doppler echocardiography. A left ventricular ejection fraction (LVEF) of <50% was present in 33 (4.1%) of subjects, while 11 (1.4%) had LVEF <40%. At a cut-off of 20, 50, and 100 pg/mL, sensitivity for BNP alone when screening for LVSD was 88, 70, and 45%, and specificity 46, 77, and 90%, respectively. Of those labelled 'false positive' in the 20, 50, and 100 pg/mL cut-off groups, 26, 46, and 65%, respectively, were found to have significant LVDD (left atrial volume index >34 mL/m(2)). Optimal sensitivity (80%) and specificity (72%) for PCVD was obtained when BNP at a cut-off of 50 pg/mL or an abnormal ECG were defined as a positive screen so that only this group would be sent for Doppler echocardiography. CONCLUSIONS: A significant number of patients at risk for LVSD and labelled false positive with screening were found to have LVDD. Identifying this at-risk cohort may improve outcomes, but the clinical and economic benefit of this screening strategy requires formal assessment.

Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure?

AIMS: Hypertension is one of the main drivers of the heart failure (HF) epidemic. The aims of this study were to profile fibro-inflammatory biomarkers across stages of the hypertensive heart disease (HHD) spectrum and to examine whether particular biochemical profiles in asymptomatic patients identify a higher risk of evolution to HF. METHODS AND RESULTS: This was a cross-sectional observational study involving a population of 275 stable hypertensive patients divided into two different cohorts: Group 1, asymptomatic hypertension (AH) (n= 94); Group 2, HF with preserved ejection fraction  (n= 181). Asymptomatic hypertension patients were further subdivided according to left atrial volume index ≥34 mL/m(2) (n= 30) and <34 mL/m(2) (n= 64). Study assays involved inflammatory markers [interleukin 6 (IL6), interleukin 8 (IL8), monocyte chemoattractant protein 1 (MCP1), and tumour necrosis factor α], collagen 1 and 3 metabolic markers [carboxy-terminal propeptide of collagen 1, amino-terminal propeptide of collagen 1, amino-terminal propeptide of collagen 3 (PIIINP), and carboxy-terminal telopeptide of collagen 1 (CITP)], extra-cellular matrix turnover markers [matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and tissue inhibitor of metalloproteinase 1 (TIMP1)], and the brain natriuretic peptide. Data were adjusted for age, sex, systolic blood pressure, and creatinine. Heart failure with preserved ejection fraction  was associated with an increased inflammatory signal (IL6, IL8, and MCP1), an increased fibrotic signal (PIIINP and CITP), and an increased matrix turnover signal (MMP2 and MMP9). Alterations in MMP and TIMP enzymes were found to be significant indicators of greater degrees of asymptomatic left ventricular diastolic dysfunction. CONCLUSION: These data define varying fibro-inflammatory profiles throughout different stages of HHD. In particular, the observations on MMP9 and TIMP1 raise the possibility of earlier detection of those at risk of evolution to HF which may help focus effective preventative strategies.

Proteomic analysis of coronary sinus serum reveals leucine-rich α2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure.

BACKGROUND: Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF. METHODS AND RESULTS: Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich α2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P≤0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-α (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-ßR1 (P<0.001) and α-smooth muscle actin (P=0.025) expression. CONCLUSIONS: LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, ß-blocker therapy, and BNP.

Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone.

OBJECTIVES: This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF). BACKGROUND: Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown. METHODS: We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained. RESULTS: The mean age of the patients was 80 +/- 7.8 years; 46% were male; 64% were receiving an angiotensin-converting enzyme inhibitor, 34% an angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide. CONCLUSIONS: This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).

Ocular volume change per cardiac cycle.

Ocular pneumoplethysmograph (OPG) tests were performed in 499 employees of an industrial firm. The ocular volume change (OVC), in microliters per cardiac cycle, was calculated from each of OPG tests. In the 195 females, the OVC was 294 +/- 81 microl. In the 304 males, the OVC was 269 +/- 86 microl. The female-male OVC difference was significant, p = 0.001.