125 research outputs found
Is the deficiency of the long isoform of cellular FLICE-inhibitory protein involved in myocardial remodeling?
Using high-resolution voltage maps to predict âredoâ in the treatment of atrial fibrillation (AF)
The aim of this work is to use biomarkers extracted from high-resolution voltage maps of atrial fibrillation (AF) patients in order to make predictions about future âredoâ procedures. We collected maps of the left atrium of 122 patients, prior of being treated for AF The bipolar voltage maps were extracted with the Rythmia system from Boston Scientific and subsequently analyzed in the MATLAB environment. The present study focuses on three biomarkers extracted from those maps. Two are associated with the bipolar voltage measurements on the map, i.e., the mean
voltage and the voltage dispersion on the map. The third indicator is the area of the atrium evaluated from the map.
The data are used for feeding a supervised classification algorithm. The output variable is a binary variable that is set to 1 if the patient will need a âredoâ procedure in the twelve months following the cardiac intervention and 0 otherwise. We show that the biomarkers have some statistical power in predicting future outcomes. Especially the mean voltage on the map is the best predictor of the future outcome. We determine the cutoff value for the mean voltage based on the best prediction accuracy of Vm=0.542 mV in agreement with previous studies. We discuss some
extensions of this study that could allow improvements in predictive power.Peer ReviewedPostprint (published version
Apoptosis in hypertensive heart disease: a clinical approach
PURPOSE OF REVIEW: It is widely accepted that there are two principal forms of cell death, namely, necrosis and apoptosis. According to the classical view, necrosis is the major mechanism of cardiomyocyte death in cardiac diseases.
RECENT DEVELOPMENTS: In the past few years observations have been made showing that cardiomyocyte apoptosis occurs in diverse conditions including hypertensive heart disease, and that apoptosis may be a contributing cause of loss and functional abnormalities of cardiomyocytes in this condition.
SUMMARY: This review will summarize recent evidence demonstrating the potential contribution of cardiomyocyte apoptosis to heart failure in hypertensive patients. In addition, some strategies aimed to detect and prevent apoptosis of cardiomyocytes will be considered
Cardiac Fibrosis in heart failure: Focus on non-invasive diagnosis and emerging therapeutic strategies
Heart failure is a leading cause of mortality and hospitalization worldwide. Cardiac fibrosis, resulting from the excessive deposition of collagen fibers, is a common feature across the spectrum of conditions converging in heart failure. Eventually, either reparative or reactive in nature, in the long-term cardiac fibrosis contributes to heart failure development and progression and is associated with poor clinical outcomes. Despite this, specific cardiac antifibrotic therapies are lacking, making cardiac fibrosis an urgent unmet medical need. In this context, a better patient phenotyping is needed to characterize the heterogenous features of cardiac fibrosis to advance toward its personalized management. In this review, we will describe the different phenotypes associated with cardiac fibrosis in heart failure and we will focus on the potential usefulness of imaging techniques and circulating biomarkers for the non-invasive characterization and phenotyping of this condition and for tracking its clinical impact. We will also recapitulate the cardiac antifibrotic effects of existing heart failure and non-heart failure drugs and we will discuss potential strategies under preclinical development targeting the activation of cardiac fibroblasts at different levels, as well as targeting additional extracardiac processes
Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats
Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension. Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered. In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)-induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats. Ang II-induced increases of intracellular free calcium concentration ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L) in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3). Isometric contraction induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L). Incubation of VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L) resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3). The stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L). Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro. This action can be related to the ability of torasemide to block the increase of [Ca(2+)](i) induced by Ang II in VSMCs. It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo
Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial
Background:
Myocardial fibrosis is characterized by excessive crossâlinking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen crossâlinking and/or deposition.
Methods and results:
We investigated 381 HFpEF patients from the multicentre, randomized, placeboâcontrolled AldoâDHF trial with measures of the E:e' ratio. The ratio of serum carboxyâterminal telopeptide of collagen type I to serum matrix metalloproteinaseâ1 (CITP:MMPâ1, an inverse index of myocardial collagen crossâlinking) and serum carboxyâterminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1âyear treatment with spironolactone 25âmg once daily or placebo. Patients were classified by CITP:MMPâ1 and PICP tertiles at baseline. While CITP:MMPâ1 tertiles at baseline interacted (Pâ<â0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMPâ1 levels, this ratio was significantly reduced in the remaining spironolactoneâtreated patients. In addition, PICP was unchanged in patients with lower CITP:MMPâ1 levels but was reduced in the remaining spironolactoneâtreated patients.
Conclusions:
A biochemical phenotype of high collagen crossâlinking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen crossâlinking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients
Circulating biomarkers predicting longitudinal changes in left ventricular structure and function in a general population
Background
Serial imaging studies in the general population remain important to evaluate the usefulness of pathophysiologically relevant biomarkers in predicting progression of left ventricular (LV) remodeling and dysfunction. Here, we assessed in a general population whether these circulating biomarkers at baseline predict longitudinal changes in LV structure and function.
Methods and Results
In 592 participants (mean age, 50.8 years; 51.4% women; 40.5% hypertensive), we derived echocardiographic indexes reflecting LV structure and function at baseline and after 4.7 years. At baseline, we measured alkaline phosphatase, markers of collagen turnover (procollagen type I, Câterminal telopeptide, matrix metalloproteinaseâ1) and highâsensitivity cardiac troponin T. We regressed longitudinal changes in LV indexes on baseline biomarker levels and reported standardized effect sizes as a fraction of the standard deviation of LV change. After full adjustment, a decline in LV longitudinal strain (â14.2%) and increase in E/eâČ ratio over time (+18.9%; Pâ€0.019) was associated with higher alkaline phosphatase activity at baseline. Furthermore, longitudinal strain decreased with higher levels of collagen I production and degradation at baseline (procollagen type I, â14.2%; Câterminal telopeptide, â16.4%; Pâ€0.029). An increase in E/eâČ ratio over time was borderline associated with lower matrix metalloproteinaseâ1 (+9.8%) and lower matrix metalloproteinaseâ1/tissue inhibitor of metalloproteinaseâ1 ratio (+11.9%; Pâ€0.041). Higher highâsensitivity cardiac troponin T levels at baseline correlated significantly with an increase in relative wall thickness (+23.1%) and LV mass index (+18.3%) during followâup (Pâ€0.035).
Conclusions
We identified a set of biomarkers predicting adverse changes in LV structure and function over time. Circulating biomarkers reflecting LV stiffness, injury, and collagen composition might improve the identification of subjects at risk for subclinical cardiac maladaptation
A urinary fragment of mucin-1 subunit α is a novel biomarker associated with renal dysfunction in the general population
Introduction:
Sequencing peptides included in the urinary proteome identifies the parent proteins and may reveal mechanisms underlying the pathophysiology of chronic kidney disease.
Methods:
In 805 randomly recruited Flemish individuals (50.8% women; mean age, 51.1 years), we determined the estimated glomerular filtration rate (eGFR) from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We categorized eGFR according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guideline. We analyzed 74 sequenced urinary peptides with a detectable signal in more than 95% of participants. Follow-up measurements of eGFR were available in 597 participants.
Results:
In multivariable analyses, baseline eGFR decreased (P †0.022) with urinary fragments of mucin-1 (standardized association size expressed in ml/min/1.73 m2, â4.48), collagen III (â2.84), and fibrinogen (â1.70) and was bi-directionally associated (P †0.0006) with 2 urinary collagen I fragments (+2.28 and â3.20). The eGFR changes over 5 years (follow-up minus baseline) resulted in consistent estimates (P †0.025) for mucin-1 (â1.85), collagen (â1.37 to 1.43) and fibrinogen (â1.45) fragments. Relative risk of having or progressing to eGFR <60 ml/min/1.73 m2 was associated with mucin-1. Partial least-squares analysis confirmed mucin-1 as the strongest urinary marker associated with decreased eGFR, with a score of 2.47 compared with 1.80 for a collagen I fragment as the next contender. Mucin-1 predicted eGFR decline to <60 ml/min/1.73 m2 over and above microalbuminuria (P = 0.011) and retained borderline significance (P = 0.05) when baseline eGFR was accounted for.
Discussion:
In the general population, mucin-1 subunit α, an extracellular protein that is shed from renal tubular epithelium, is a novel biomarker associated with renal dysfunction
Cardioprotective effect of the mitochondrial unfolded protein response during chronic pressure overload
Background
The mitochondrial unfolded protein response (UPRmt) is activated when misfolded proteins accumulate within mitochondria and leads to increased expression of mitochondrial chaperones and proteases to maintain protein quality and mitochondrial function. Cardiac mitochondria are essential for contractile function and regulation of cell viability, while mitochondrial dysfunction characterizes heart failure. The role of the UPRmt in the heart is unclear.
Objectives
The purpose of this study was to: 1) identify conditions that activate the UPRmt in the heart; and 2) study the relationship among the UPRmt, mitochondrial function, and cardiac contractile function.
Methods
Cultured cardiac myocytes were subjected to different stresses in vitro. Mice were subjected to chronic pressure overload. Tissues and blood biomarkers were studied in patients with aortic stenosis.
Results
Diverse neurohumoral or mitochondrial stresses transiently induced the UPRmt in cultured cardiomyocytes. The UPRmt was also induced in the hearts of mice subjected to chronic hemodynamic overload. Boosting the UPRmt with nicotinamide riboside (which augments NAD+ pools) in cardiomyocytes in vitro or hearts in vivo significantly mitigated the reductions in mitochondrial oxygen consumption induced by these stresses. In mice subjected to pressure overload, nicotinamide riboside reduced cardiomyocyte death and contractile dysfunction. Myocardial tissue from patients with aortic stenosis also showed evidence of UPRmt activation, which correlated with reduced tissue cardiomyocyte death and fibrosis and lower plasma levels of biomarkers of cardiac damage (high-sensitivity troponin T) and dysfunction (N-terminal proâB-type natriuretic peptide).
Conclusions
These results identify the induction of the UPRmt in the mammalian (including human) heart exposed to pathological stresses. Enhancement of the UPRmt ameliorates mitochondrial and contractile dysfunction, suggesting that it may serve an important protective role in the stressed heart
The activity of circulating dipeptidyl peptidase-4 is associated with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus
Background: Patients with type 2 diabetes mellitus (T2DM) present subclinical left ventricular systolic and/or
diastolic dysfunction (LVD). Dipeptidyl peptidase-4 (DPP4) inactivates peptides that possess cardioprotective actions.
Our aim was to analyze whether the activity of circulating DPP4 is associated with echocardiographically defined
LVD in asymptomatic patients with T2DM.
Methods: In this cross-sectional study, we examined 83 T2DM patients with no coronary or valve heart disease and
59 age and gender-matched non-diabetic subjects. Plasma DPP4 activity (DPP4a) was measured by enzymatic assay
and serum amino-terminal pro-brain natriuretic peptide (NT-proBNP) was measured by enzyme-linked
immunosorbent assay. LV function was assessed by two-dimensional echocardiographic imaging, targeted M-mode
recordings and Doppler ultrasound measurements. Differences in means were assessed by t-tests and one-way
ANOVA. Associations were assessed by adjusted multiple linear regression and logistic regression analyses.
Results: DPP4a was increased in T2DM patients as compared with non-diabetic subjects (5855 ± 1632 vs 5208 ± 957
pmol/min/mL, p < 0.05). Clinical characteristics and echocardiographic parameters assessing LV morphology were
similar across DPP4a tertiles in T2DM patients. However, prevalence of LVD progressively increased across
incremental DPP4a tertiles (13%, 39% and 71%, all p < 0.001). Multivariate regression analysis confirmed the
independent associations of DPP4a with LVD in T2DM patients (p < 0.05). Similarly, multiple logistic regression
analysis showed that an increase of 100 pmol/min/min plasma DPP4a was independently associated with an
increased frequency of LVD with an adjusted odds ratio of 1.10 (95% CI, 1.04 to 1.15, p = 0.001).
Conclusions: An excessive activity of circulating DPP4 is independently associated with subclinical LVD in T2DM
patients. Albeit descriptive, these findings suggest that DPP4 may be involved in the mechanisms of LVD in T2DM
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