bluuebunny/crossref_metadata_2025_split huggingface dataset:
1177Insights on mitochondrial energetics in obstructive hypertrophic cardiomyopathy
Authors: Lombardi M , Lazzeroni D , Rimoldi O , Girolami F , Pisano A , Benedetti G , Alfieri O , D'Amati G , Foglieni C , Camici P 
Published: October 2019

Abstract

Background
Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, heterogeneous in phenotype and clinical course. The genotype-phenotype relationship and associated molecular mechanisms are still incompletely understood. In the HCM milieu, increased energy cost of force production, impairing performance and mitochondrial function, may be associated to patients' genotype and/or phenotype.

Purpose
To determine abnormalities in mitochondrial energetics in HCM and their possible relationship with genotype and clinical phenotype of patients.

Methods
Septal myectomies from characterized patients with obstructive HCM (HOCM, n=18) and donor hearts discarded from transplantation (CTRL, n=8) have been compared. HOCM patients were screened and demographic, clinical and instrumental data (routine ECG, echocardiography and cardiac magnetic resonance-CMR) were collected.
Genetic analysis was performed on total DNA extracted from myectomies by NGS on MiSeq platform using the TruSight Cardio Sequencing kit and testing a panel of 26 genes.
Activity and amount of mitochondrial enzymes generating/scavenging reactive oxygen species were investigated.

Results
Within the HOCM cohort 30% of patients was bearing mutations in sarcomeric genes associated with HCM.
The amount and/or activity of mitochondrial Complex I NADH dehydrogenase, of SOD2 and (m)-aconitase were upregulated in HOCM vs. CTRL. NADH dehydrogenase level was inversely correlated with the degree of mitral valve regurgitation and mitral valve backward volume by CMR (Spearman R=−0.5 and −0.8, respectively).
The Complex V enzyme ATP synthase activity decreased, whilst its amount was comparable in HOCM vs. CTRL. Analogously the SOD1 activity was similar in HOCM and CTRL.
No difference in mitochondrial DNA (mtDNA) copy number was found.
Results were unrelated to HCM-associated mutations.

Conclusions
HOCM hearts are characterized by mitochondrial hyperactivity aimed at quenching reactive oxygen species, but decreased ATP synthase activity. Overall, these data suggest an abnormal mitochondrial activity in the myocardium of HOCM patients independent of the presence of HCM-associated mutations. Moreover, our results underpin the markedly abnormal cellular energetics of HOCM, identifying potential therapeutic targets.

Acknowledgement/Funding
NET-2011-02347173, Italian Minister of Health
1198Women and non-diabetic patients react more strongly to radiofrequency renal sympathetic denervation
Authors: Zweiker D , Lambert T , Steinwender T , Weber T , Niederl E , Koppelstaetter C , Hohenstein-Scheibenecker K , Rohla M , Reindl-Schwaighofer R , Kindslehner C , Gruener P , Auer J , Dechant C , Zirlik A , Zweiker R 
Published: October 2019

Abstract

Background/Introduction
Three recently published sham-controlled studies proved the efficacy of renal denervation (RDN) in hypertensive patients. However, there it is still unclear which patients should be selected for RDN.

Purpose
This study seeks to clarify which patient subgroups benefit most from radiofrequency RDN by analysing a nationwide multicentre registry database.

Methods
This is a post-hoc analysis from the multicentre Austrian Transcatheter Renal Denervation Registry hosted by the Austrian Society of Hypertension. We correlated change of systolic blood pressure (BP) after RDN to gender and presence/absence of comorbidities. Bivariate correlation and multiple linear regression analyses were performed.

Results
291 patients (43% female, median age 64 years) undergoing RDN between April 2011 and September 2014 were included in this analysis. Mean baseline ambulatory 24-hour BP (systolic/diastolic) was 150±18/89±14 mmHg and mean baseline office BP was 170±16/94±14 mmHg.
After RDN, mean ambulatory 24-hour BP reduction was 9±19/6±16 mmHg. The following features were associated with a good response to RDN: high baseline systolic ambulatory BP (ρ=0.53, p<0.001), high baseline diastolic office BP (ρ=0.40, p<0.001), female gender (ρ=0.10, p=0.049), absence of diabetes mellitus (DM, ρ=0.11, p=0.033), and absence of peripheral arterial disease (ρ=0.17, p=0.002). Multivariate analysis identified high baseline systolic ambulatory BP, female gender and absence of DM as independent predictors for systolic ambulatory BP reduction (systolic ambulatory BP: HR 5.83 [95% CI 4.83–6.83], p<0.001; absence of DM: HR 5.82 [2.04–9.60], p=0.003; female gender: HR 5.07 [1.46–8.68], p=0.006), although women and patients without DM had lowest baseline ambulatory BP. Furthermore, both women and patients without DM used significantly less antihypertensives after RDN (female vs male: 4.0±1.3 vs 4.4±1.3, p=0.002; no DM vs DM: 4.0±1.3 vs 4.6±1.3, p<0.001).
Figure 1

Discussion
Ambulatory BP reductions after RDN were substantially more pronounced in female and in non-diabetic patients despite lower baseline BP. It is concluded that in terms of efficacy female patients and non-diabetics might be more suitable for RDN.

Acknowledgement/Funding
The Austrian Renal Denervation Registry was funded by the Austrian Society of Hypertension.
1337Myocardial extracellular volume in patients with aortic stenosis undergoing valve intervention - A multicentre T1 mapping study
Authors: Everett R , Treibel T , Fukui M , Lee H , Rigolli M , Singh A , Tastet L , Musa T A , Chin C , Om S Y , Captur G , Funk S , Clavel M A , Clavel M A , Cavalcante J , Cavalcante J , Dweck M R , Dweck M R 
Published: October 2019

Abstract

Background
The development of myocardial fibrosis is a key mechanism in the transition from compensated hypertrophy to heart failure in aortic stenosis (AS). Focal and diffuse fibrosis can be quantified using cardiac magnetic resonance (CMR) imaging late gadolinium-enhanced (LGE) and T1 mapping techniques.

Purpose
To assess T1 mapping measures of fibrosis in patients with severe AS referred for aortic valve intervention, and determine their associations with clinical characteristics, disease severity and long-term clinical outcome.

Methods
In this international prospective cohort study, patients with severe AS underwent contrast enhanced CMR with T1 mapping and LGE prior to aortic valve intervention. Image analysis was performed by a single core laboratory and the extracellular volume fraction [ECV%] calculated from T1 mapping images. The presence of LGE was determined visually and quantified using the full-width-at-half-maximum technique.

Results
Four-hundred and forty patients (70±10 years, 59% male) from ten international centres were enrolled. Aortic valve intervention was performed 15 [4 to 58] days following CMR. Within a follow-up of 3.8 [2.8 to 4.6] years, 52 patients died.
ECV% (mean 27.7±3.6%) correlated with increasing age, Society of Thoracic Surgeons Predicted Risk of Mortality score, known coronary artery disease, lower peak aortic-jet velocity, larger left ventricular (LV) mass, lower LV ejection fraction, and presence of LGE (P<0.05 for all). Following adjustment for all demographic and clinical variables, ECV% remained associated with age (P=0.028), LV ejection fraction (P<0.001) and presence of LGE (P=0.035).
Univariable predictors of all-cause mortality included age, male sex, impaired LV ejection fraction and presence of LGE (all P<0.05). A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6 and 52.7 deaths per 1000 patient-years; log-rank test, P=0.009). ECV% was independently associated with all-cause mortality following adjustment for age, sex, impaired LV ejection fraction and presence of LGE (HR per unit increase in ECV: 1.10, 95%, (1.02–1.19), P=0.013).
ECV440 abstract iamge

Conclusion
In patients with severe aortic stenosis scheduled for aortic valve intervention, extracellular volume-based T1 mapping correlates with LV decompensation. ECV% is a strong independent predictor of late all-cause mortality and is a potential therapeutic target.
2153The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease; a cohort study
Authors: Van 'T Klooster C C , Ridker P M , Hjortnaes J , Van Der Graaf Y , Asselbergs F W , Westerink J , Aerts J G J V , Visseren F L J 
Published: October 2019

Abstract

Background
Chronic systemic low-grade inflammation, measured by elevated plasma concentrations of high sensitive C-reactive Protein (CRP), is a risk factor for cardiovascular disease (CVD). There is evidence that systemic low-grade inflammation is also related to a higher risk of cancer.

Purpose
In the present prospective cohort study the relation between systemic low-grade inflammation and risk of cancer was evaluated in patients with clinically manifest vascular disease.

Methods
In total 7178 patients from the SMART cohort with manifest cardiovascular disease and plasma CRP levels ≤10 mg/L were included. Data of the cohort were linked to the Dutch national cancer registry. Cox regression models were fitted to study the relation between CRP and incident cardiovascular disease as well as incident cancer. Cancer types were classified according to anatomical location of origin, as well as histopathological subtype, irrespective of their anatomical location of origin. To adjust for potential confounding, age, sex, smoking status, packyears of smoking, and body mass index were added to the models, and additional cardiovascular risk factors, including diabetes mellitus, and systolic blood pressure.

Results
After a median follow-up time of 8.3 years (interquartile range 4.6–12.3) 1289 recurrent cardiovascular events (myocardial infarction, stroke, or vascular mortality) and 1072 incident cancer diagnoses were observed. CRP level was related to recurrent cardiovascular disease risk (HR 1.57; 95% CI 1.35–1.82) (Figure 1A), as well as risk of CVD and/or cancer (HR 1.45; 95% CI 1.29–1.62) (Figure 1B) comparing the third tertile of CRP to the first tertile. CRP concentration was related to total cancer risk (HR 1.33; 95% CI 1.13–1.55 for the third tertile of CRP compared to the first tertile) (Figure 1C). Especially incident lung cancer, independent of histopathological subtype, was related to CRP level (HR 2.64; 95% CI 1.77–3.93 for the third tertile of CRP compared to the first) (Figure 1D). No effect modification by smoking status or years of smoking cessation was observed of the relation between CRP and lung cancer (p-values for interaction >0.05). Incidence of epithelial neoplasms and especially squamous cell neoplasms were related to CRP concentration, irrespective of their anatomical location of origin (HR 1.17; 95% CI 1.08–1.27, and HR 1.11; 95% CI 1.02–1.20 for 1 mg/L higher CRP level respectively). Sensitivity analyses accounting for reverse causality by excluding patients with a cancer diagnosis within 1 and within 2 years of follow up showed similar results.
Kaplan Meier curves per CRP tertile

Conclusion
Chronic systemic low-grade inflammation, measured by plasma CRP levels ≤10mg/L, is a risk factor for incident cancer, markedly lung cancer, independent of smoking status, in patients with stable cardiovascular disease.
2161Redox-mediated PKA-RIalpha localisation to the lysosome inhibits myocardial calcium release and robustly reduces myocardial injury
Authors: Simon J N , Vrellaku B , Monterisi S , Chu S , Rawlings N , Lomas O , Marchal G A , Waithe D , Gajendragadkar P , Jayaram R , Channon K , Swietach P , Zaccolo M , Eaton P , Casadei B 
Published: October 2019

Abstract

Background
Kinase oxidation is a critical signalling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, type-1 protein kinase A (PKARIα) can be reversibly oxidised, forming interprotein disulphide bonds within the holoenzyme complex. However, the effect of PKARIα oxidation on downstream signalling in the heart, particularly under states of oxidative stress, remains unexplored.

Purpose
To determine the direct functional consequences of PKARIα oxidation in the heart and investigate their impact on ischaemia/reperfusion (I/R) injury.

Methods and results
Experiments using the AKAR3ev FRET biosensor in murine left ventricular (LV) myocytes and Fluorescence Recovery After Photobleaching (FRAP) of GFP-tagged wild-type (WT) and mutant RIα proteins expressed in RIα-null fibroblasts showed that PKARIα oxidation does not increase the kinases' catalytic activity, but enhances its binding to A-kinase anchoring proteins (AKAP; n=30–39/N=3, p<0.01). Super-resolution microscopy revealed localisation of oxidised PKARIα to lysosomes in WT myocytes, which was completely absent in “redox dead” Cys17Ser PKARIα knock-in mice (KI; panel A; n=38–41/N=3, p<0.01) and reduced when AKAP binding was prevented using the RIAD disruptor peptide (30.6±5.1% reduction; n=35–37/N=3, p<0.01).
Displacement of PKARIα from lysosomes resulted in spontaneous sarcoplasmic reticulum calcium release and dramatic calcium oscillations in KI LV myocytes (panel B), which were preventable by ryanodine receptor blockade (1 mM tetracaine; n=14, p<0.01), acute depletion of endolysosomal calcium stores (100 nM bafilomycin; n=7; p<0.01), or lysosomal two-pore channel inhibition (5 μM Ned-19; n=9; p<0.05).
I/R (secondary to cardiopulmonary bypass) was found to induce PKARIα oxidation in the myocardium of patients undergoing cardiac surgery (panel C; n=18, p<0.05). Absence of this response in KI mouse hearts resulted in 2-fold larger infarcts (p<0.01) and a concomitant reduction in LV contractile recovery (final LVDP of 55.9±8.6 vs 82.5±7.1 mmHg in WT; n=7–8, p<0.05), both which were prevented by addition of Ned-19 at the time of reperfusion (panel D; n=4, p<0.01).

Conclusions
Oxidised PKARIα acts as a potent inhibitor of intracellular calcium release in the heart through its redox-dependent interaction with the lysosome. In the setting of I/R, where PKARIα oxidation is induced, this regulatory mechanism is critical for protecting the heart from injury and offers a novel target for the design of cardioprotective therapeutics.

Acknowledgement/Funding
British Heart Foundation CH/12/3/29609, RG/16/12/32451; Garfield-Weston Foundation MPS/IVIMS-11/12-4032; Wellcome Trust Fellowship 0998981Z/12/Z
2179Clinical significance of device-derived activity in ICD and CRT-D patients - Data from MADIT-RIT
Authors: Kutyifa V , Jones P , Goldenberg I , Brown M , Zareba W , Stein K , McNitt S , Polonsky S , Rosero S 
Published: October 2019

Abstract

Background
The Multicenter Automatic Defibrillator Implantation Trial – Reduce Inappropriate Therapy (MADIT-RIT) enrolled 1500 patients and showed that novel ICD programming reduced inappropriate therapy and improved survival. However, the role of device-derived patient activity to predict mortality is not known.

Methods
In 1500 patients enrolled in MADIT-RIT, device-derived patient activity was captured daily. Device-derived activity was averaged for the first 30 days following randomization, and utilized in this study to predict mortality post-30 days. Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression models were used to evaluate all-cause mortality by 30-day device derived patient activity quintiles, and as a 3-level function of 30-day device derived patient activity (Q1, Q2–3, Q4–5).

Results
There were a total of 1463 patients with data available (98%), 66 of them died during the follow-up post-30 days. Patients in the lowest quintile (Q1: 4%∼1 hour daily activity) of device-derived activity were older, they were more often female, and they more often had diabetes and NYHA class III HF symptoms. Patients in the lowest quintile of 30-day device derived median activity (1 hour daily activity) had the highest risk of mortality, 15% in 2 years as compared to Q2–3 (1–2 hours daily activity, 8–7% 2-year mortality), and Q4–5 (>2 hours daily activity, 2–3% 2-year mortality) (Figure, p<0.001 for the overall duration). Each quintile decrease in device-derived 30-day median patient activity was associated with a significant, 41% increase in mortality (HR=1.41, 95% CI: 1.15–1.71, p=0.001). Patients with the lowest level of 30-day median patient activity (Q1) had 4.13-times higher risk of mortality as compared to the highest level of activity patients, Q4–5 (HR=4.13, 95% CI: 1.89–9.03, p<0.001). Patients with intermediate levels of activity (Q2–3) still had a 2.8-fold increase in death as compared to the highest activity level cohort of patients (HR=2.79, 95% CI: 1.31–5.91, p=0.008).
Figure 1

Conclusions
Device-derived 30-day median patient activity predicted subsequent all-cause mortality in ICD and CRT-D patients enrolled in MADIT-RIT. Patients with low and moderate levels of 30-day device-derived median patient activity (less than 2 hours daily activity) were at a significantly higher risk of death, and these cohorts warrant further investigation and management to improve outcomes.

Acknowledgement/Funding
MADIT-RIT was funded by an unrestricted research grant from Boston Scientific to the University of Rochester.
2182Sirtuin 5 regulates arterial thrombosis by modulating endothelial plasminogen activator inhibitor-1
Authors: Liberale L , Akhmedov A , Nageswaran V , Bonetti N , Miranda M X , Montecucco F , Beer J H , Luscher T F , Camici G G 
Published: October 2019

Abstract

Introduction
Arterial thrombosis as a result of plaque rupture or erosion is a crucial event in myocardial infarction and stroke. Oxidative stress and inflammation promote endothelial dysfunction and play a pivotal role in destabilization of the atherosclerotic plaque. Sirtuin 5 (SIRT5) is a member of the sirtuin protein family with function as a NAD+-dependent protein desuccinylase and demalonylase. Being implicated in the regulation of different pathophysiological processes among which production of reactive oxygen species and transcription of inflammatory mediators, SIRT5 plays a role in the development of several cardiovascular diseases such as myocardial infarction and stroke. To date, the possible involvement of SIRT5 as a mediator of arterial thrombosis remains to be investigated.

Purpose
In this study we investigate the putative role of this protein in arterial thrombosis by using an established in vivo mouse model. The translational value of animal findings as well as the molecular mechanism underlying the observed effect will be investigated also in primary human aortic endothelial cells (HAECs).

Methods
SIRT5 knockout (KO) as well as SIRT5 transgenic (TG) animals were used for in vivo experiments. HAECs treated with SIRT5 silencing RNA (si-SIRT5) and stimulated with tumor necrosis factor (TNF)-α were used for in vitro assays.

Results
When compared to WT animals, SIRT5 KO mice display blunted carotid artery thrombus formation as underlined by delayed time to occlusion in a photochemical injury model. Oppositely, in SIRT5 TG mice the formation of an occlusive thrombus is accelerated (Fig 1). Mechanistically, SIRT5 KO and WT animals show no difference in terms of vascular tissue factor (TF) activity, TF concentration in plasma and expression of TF pathway inhibitor (TFPI) in the aorta. In line with the observed reduced thrombogenicity, SIRT5 KO animal express reduced level of the pro-thrombotic plasminogen activator-1 (PAI-1), as assessed by western blot in aorta lysate. Of interest, SIRT5 genetic deletion does not affect platelet aggregation, as assessed by ex-vivo collagen-induced aggregometry. In HAECs, SIRT5-silencing inhibits PAI-1 expression in response to TNF-α. Real-time polymerase chain reaction revealed that inhibition of PAI-1 expression occurs at the mRNA level. This effect is mediated by reduced activation of the MAP kinase Erk 1/2, but not JNK (Fig 1).

Conclusions
SIRT5 mediates arterial thrombosis by increasing endothelial PAI-1 expression. Hence, SIRT5 may be an effective therapeutic target in the context of atherothrombosis.
2199Cardiovascular risk behaviour is an emerging health issue in developing countries
Authors: Negesa L , Magarey J , Rasmussen P , Hendriks J 
Published: October 2019

Abstract

Background
Previously, cardiovascular disease (CVD) was considered the “Disease of the Rich”, however nowadays also populations with low socioeconomic status have been identified at increased risk of developing CVD. The global progress in CVD prevention is scarce particularly in developing countries, which are facing a high burden of CVD whilst there is limited availability of resources and evidence to educate and modify lifestyle behaviours in the population. Moreover, there is a lack of infrastructure and policy making in these countries.

Purpose
The goal of the study was to quantify the prevalence of different cardiovascular risk behaviours among patients with known cardiovascular conditions in a developing countries.

Methods
A hospital based cross-sectional survey was conducted in two referral hospitals in Ethiopia. Outpatient unit patients who had a confirmed diagnosis of CVD were eligible for participation in the study. Data were collected through face-to-face interviews with patients using validated tools; WHO STEPs instrument and international physical activity questionnaire.

Results
A total of 287 CVD patients were recruited, 56% were females and 90% were urban residents. All patients had inadequate consumption of fruit and vegetables, 20% were current khat chewers, 19% were current alcohol drinkers and only 1% were current smokers. The prevalence of low physical activity (defined as less than 600 MET-minutes per week) in the total population was 51.6% for both sexes; more than half of the total population were physically inactive. Moreover, females had a significantly higher prevalence of physical inactivity as compared to males, 58% vs 43.2%, P=0.017. Approximately one-third (30%) of patients had only one of these risk behaviours, more than half (52%) had two, 18% had three or more risk behaviours. The majority (70%) of the patients had multiple risk behaviours (Table 1), the prevalence of these did not significantly vary with sex, residence and educational level (p>0.05).

Conclusion
Patients with CVD maintain unhealthy lifestyles even though attending follow up care with a specific focus on risk management. The findings of this study demonstrate a high prevalence of physical inactivity, alcohol consumption and inadequate fruit and vegetable consumption in developing countries. The emerging increase of CVD and the continuation of unhealthy lifestyle in patients is somewhat comparable with western countries, demonstrating an emerging global problem. Moreover, this study shows the existing follow-up care is ineffective and provides evidence for policy makers that health services reform is required. Implementation of lifestyle support programs should be considered for the disease prevention policy agenda in developing countries.