Serological evidence of early remodeling in high-risk non-ST elevation acute coronary syndromes

INTRODUCTION: Non-ST elevation acute coronary syndrome (ACS) represents a spectrum of risk, with electrocardiographic (ECG) changes and a positive troponin being associated with higher morbidity and mortality. Ischaemia produces alterations in the collagenous component of the heart, even in the absence of myocyte necrosis. Collagen turnover can be assessed biochemically with C-propeptide for type I collagen (PICP) and C-telopeptide for type I collagen (CITP) being markers of collagen synthesis and degradation respectively. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a marker of inhibition of degradation. METHODS: Fifty-two patients with non-ST elevation acute ACS were recruited and dichotomised into high- and low-risk groups based on ECG and troponin level. Sequential measurements of plasma PICP, CITP and TIMP-1 were performed over a 48 hour period. RESULTS: Twenty were classified as low-risk (negative troponin and normal ECG) and 32 as high-risk. PICP was within the normal range at all time points in both groups. However, admission CITP was higher in the high-risk group (3.7 vs. 2.6 ng/ml, p<0.001) and, unlike the low-risk group, demonstrated a further rise over 48 h. Similarly, mean TIMP-1 displayed a sequential change over time in the high-risk group only, and admission level was higher compared to the low-risk group (302 vs. 221 ng/ml, p<0.01). DISCUSSION: There is serological evidence of time-dependent altered collagen metabolism in high-risk ACS, which is not present in the low-risk group. This may reflect a degree of remodeling and may aid risk stratification of patients presenting with non-ST elevation ACS

Endothelial dysfunction and glycocalyx shedding in heart failure: insights from patients receiving cardiac resynchronisation therapy

To determine (a) whether chronic heart failure with reduced ejection fraction (HFrEF) is associated with increased glycocalyx shedding; (b) whether glycocalyx shedding in HFrEF with left ventricular dyssynchrony is related to inflammation, endothelial dysfunction and/or redox stress and is ameliorated by cardiac resynchronisation therapy. Glycocalyx shedding has been reported to be increased in heart failure and is a marker of increased mortality. Its role in dyssynchronous systolic heart failure and the effects of cardiac resynchronisation therapy (CRT) are largely unknown. Twenty-six patients with dyssynchronous HFrEF were evaluated before and 6 months after CRT insertion. Echocardiographic septal to posterior wall delay (SPWD) assessed intra-ventricular mechanical dyssynchrony, and quality of life, integrity of nitric oxide (NO) signalling, inflammatory and redox-related biomarkers were measured. Glycocalyx shedding was quantitated via plasma levels of the glycocalyx component, syndecan-1. Syndecan-1 levels pre-CRT were inversely correlated with LVEF (r = - 0.45, p = 0.02) and directly with SPWD (r = 0.44, p = 0.02), QOL (r = 0.39, p = 0.04), plasma NT-proBNP (r = 0.43, p = 0.02), and the inflammatory marker, symmetric dimethylarginine (SDMA) (r = 0.54, p = 0.003). On multivariate analysis, syndecan-1 levels were predicted by SPWD and SDMA (β = 0.42, p = 0.009 and β = 0.54, p = 0.001, respectively). No significant correlation was found between syndecan-1 levels and other markers of endothelial dysfunction/inflammatory activation. Following CRT there was no significant change in syndecan-1 levels. In patients with dyssynchronous HFrEF, markers of glycocalyx shedding are associated with the magnitude of mechanical dyssynchrony and elevation of SDMA levels and inversely with LVEF. However, CRT does not reverse this process.Chukwudiebube N. Ajaero, Nathan E.K. Procter, Yuliy Y. Chirkov, Tamila Heresztyn, Margaret A. Arstall, Andrew D. McGavigan, Michael P. Frenneaux, John D. Horowit

Renewal theory as a universal quantitative framework to characterize phase singularity regeneration in mammalian cardiac fibrillation

BACKGROUND: Despite a century of research, no clear quantitative framework exists to model the fundamental processes responsible for the continuous formation and destruction of phase singularities (PS) in cardiac fibrillation. We hypothesized PS formation/destruction in fibrillation could be modeled as self-regenerating Poisson renewal processes, producing exponential distributions of interevent times governed by constant rate parameters defined by the prevailing properties of each system. METHODS: PS formation/destruction were studied in 5 systems: (1) human persistent atrial fibrillation (n=20), (2) tachypaced sheep atrial fibrillation (n=5), (3) rat atrial fibrillation (n=4), (5) rat ventricular fibrillation (n=11), and (5) computer-simulated fibrillation. PS time-to-event data were fitted by exponential probability distribution functions computed using maximum entropy theory, and rates of PS formation and destruction (λf/λd) determined. A systematic review was conducted to cross-validate with source data from literature. RESULTS: In all systems, PS lifetime and interformation times were consistent with underlying Poisson renewal processes (human: λf, 4.2%/ms±1.1 [95% CI, 4.0-5.0], λd, 4.6%/ms±1.5 [95% CI, 4.3-4.9]; sheep: λf, 4.4%/ms [95% CI, 4.1-4.7], λd, 4.6%/ms±1.4 [95% CI, 4.3-4.8]; rat atrial fibrillation: λf, 33%/ms±8.8 [95% CI, 11-55], λd, 38%/ms [95% CI, 22-55]; rat ventricular fibrillation: λf, 38%/ms±24 [95% CI, 22-55], λf, 46%/ms±21 [95% CI, 31-60]; simulated fibrillation λd, 6.6-8.97%/ms [95% CI, 4.1-6.7]; R2 ≥0.90 in all cases). All PS distributions identified through systematic review were also consistent with an underlying Poisson renewal process. CONCLUSIONS: Poisson renewal theory provides an evolutionarily preserved universal framework to quantify formation and destruction of rotational events in cardiac fibrillation.Dhani Dharmaprani, Madeline Schopp, Pawel Kuklik, Darius Chapman, Anandaroop Lahiri ... Lewis Mitchell ... et al