bluuebunny/crossref_metadata_2025 huggingface dataset:
P5335Effect of anthropometrics, serostatus, medication and cocaine use on quantified coronary plaque volumes in patients with human immunodeficiency virus
Authors: Kolossvary M , Lai H , Bluemke D , Mandler R N , Fishman E K , Gerstenblith G , Li J , Foster P , Bazr S , Chen S , Kickler T , Lai S
Published: October 2019

Introduction

The effect of human immunodeficiency virus (HIV) and its medications on coronary artery disease (CAD) is controversial. Furthermore, illicit drug use such as cocaine occurs more often in these populations, however its potential modulating impact on CAD poorly understood.

Purpose

We sought to assess the effect of anthropometrics, serostatus, HIV medications and cocaine use in HIV patients on coronary plaque volumes assessed using coronary CT angiography (CTA).

Methods

We randomly selected 100 HIV patients without known CAD, but with coronary CTA confirmed coronary stenosis. All major epicardial vessels were segmented. Total plaque volume, low-attenuation non-calcified plaque volume and calcified plaque volumes were quantified from vessel portions which contained coronary atherosclerosis. We used linear regression analysis to assess the association between anthropometric (age, sex, body mass index), traditional risk factors (hypertension, diabetes, positive family history, HDL, LDL, cholesterol, triglycerides levels, years of alcohol and smoking), HIV associated parameters (years of HIV infection, months of protease inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, antiretroviral therapy medication use, hepatitis virus C infection, endothelin 1 levels, CD4 levels and viral load), years of cocaine use and coronary plaque volumes.

Results

Among anthropometric and traditional risk factors age (β=10.35, p=0.006) and smoking years (β=2.72, p=0.044) showed a significant association with total plaque volume, while all other parameters did not. Among HIV related parameters non-showed a significant association with the total plaque volume. However, the years of cocaine use significantly increased the amount of plaque volume (β=4.51, p=0.024). The amount of low-attenuation non-calcified plaque volume was only associated with the years of cocaine use (β=0.30, p=0.031), while all other parameters were non-significant. The amount of calcified plaque volume was associated with age (β=2.82, p=0.047) and years of cocaine use (β=1.52=0.043).

Conclusions

Cocaine use significantly increases the amount of low-attenuation non-calcified plaque volume, calcified plaque volume and overall plaque volume in HIV patients. Our results suggest the importance of cocaine use prevention in HIV patients as it increases plaque volumes which have been shown to be associated with poor cardiovascular outcomes.

Acknowledgement/Funding

This study was supported by grants from the US National Institute on Drug Abuse, National Institutes of Health (U01DA040325).
P5337Neutrophil-lymphocyte ratio and peripheral arterial disease in HIV infection
Authors: Ortega-Zaragoza N Y , Bollo-Pazos J C , Alvarez-Mendoza J P , Mondaca-Figueroa J , Molina-Alvarado M , Escobedo De La Pena J
Published: October 2019

Background/Introduction

While antiretroviral therapy has increased survival in HIV-infected patients, cardiovascular mortality is now their leading cause of death. Together with a high prevalence of traditional cardiovascular risk factors in HIV infection, chronic inflammation may be also responsible of an increased risk of cardiovascular diseases.

Purpose

To determine the association between a systemic inflammation-based biomarker, the neutrophil-lymphocyte ratio, and the occurrence of peripheral arterial disease in HIV infected patients.

Methods

In a case-control design, 41 patients with peripheral arterial disease and HIV infection were compared to 119 patients with HIV infection but no peripheral arterial disease. All patients were recruited at a Regional Hospital. The ankle-brachial index was measured in all subjects and peripheral arterial disease was defined as an ankle-brachial index >0.9. The neutrophil-lymphocyte ratio was assessed using neutrophil and lymphocyte levels in the complete blood count measurement, from routine hemograms performed six to twelve months before measurement of the ankle-brachial index. The cut-off of neutrophil-lymphocyte ratio >2 was used to categorize patients into low- and high- neutrophil-lymphocyte ratio groups. Odds ratios (OR) with 95% confidence intervals were used to estimate the strength of association. In order to control for potential confounders, a multiple logistic regression model was used.

Results

There was a significant association between elevated neutrophil-lymphocyte ratio and the presence of peripheral arterial disease (OR 7.25 [3.32–15.85], after adjustment for age (OR 1.07 [1.04–1.11]), smoking index (OR 1.12 [1.02–1.24]. Other considered variables did not contribute to the model (HDL-cholesterol, LDL-cholesterol, triglycerides, sex, diabetes, obesity and treatment).

Conclusions

The ankle-brachial index is a simple, cost-effective and validated method to assess peripheral arterial disease, which its presence increases the risk of cardiovascular disease morbidity and mortality. The neutrophil-lymphocyte ratio is a simple, rapid and novel inflammation parameter, that may help to identify HIV-infected patients with a higher risk of peripheral arterial disease.
P5341Predictive factors of atherosclerotic cardiovascular diseases events in HIV-HVC co-infected patients: results from hepavih ANRS co13 cohort
Authors: Boccara F , Tan B K , Chalouni M , Salmon Ceron D , Cinaud A , Esterle L , Gilbert C , Bani-Sadr F , Dabis F , Sogni P , Wittkop L
Published: October 2019

Introduction

Several studies highlighted an increased risk of cardiovascular disease (CVD) in HIV-HCV co-infected patients without clearly identifying specific virologic factors associated with atherosclerotic CVD (ASCVD) events.

Purpose

Hence, we analyzed data collection from the French nationwide ANRS CO13 HEPAVIH cohort to determine the incidence of ASCVD events in HIV-HCV co-infected patients and the predictive factors associated with its occurrence.

Methods

The French multicenter nationwide ANRS CO13 HEPAVIH clinic-based cohort collected prospective clinical and biological data from HIV-HCV co-infected patients followed-up in 28 different university hospitals between December 2005 to November 2016. Participants with at least one year of follow-up were included. Primary outcome was the occurrence of major ASCVD events (cardiovascular death, acute coronary syndrome, coronary revascularization and stroke). Secondary outcomes were total ASCVD events including major ASCVD events and minor ASCVD events (peripheral arterial disease [PAD]). Incidence rates were estimated using Aalen-Johansen method and factors associated with ASCVD identified with Cox proportional hazards models.

Results

A total of 1213 patients were included: median age 45.4 years [42.1–49.0], 70.3% men, current smoking 70.2%, overweight 19.5%, liver cirrhosis 18.9%, chronic alcohol consumption 7.8%, diabetes mellitus (5.9%), personal history of CVD 2.7%, and statins use 4.1%. After a median follow-up of 5.1 years [3.9–7.0], 44 participants experienced at least one ASCVD event (26 major ASCVD event, and 20 a minor event). Incidences for total, major and minor ASCVD events were of 6.98 [5.19; 9.38], 4.01 [2.78; 6.00], and 3.17 [2.05; 4.92] per 1000 person-years, respectively. Personal history of CVD (Hazard Ratio (HR)=13.94 [4.25–45.66]), high total cholesterol (HR=1.63 [1.24–2.15]), low HDL cholesterol (HR=0.08 [0.02–0.34]) and undetectable HIV viral load (HR=0.41 [0.18–0.96]) were identified as independent factors associated with major ASCVD events while cirrhosis status, liver fibrosis and HCV sustained viral response were not.

Cumulative incidence of CV events

Conclusion

HIV-HCV co-infected patients experience a high incidence of ASCVD events both coronary and peripheral artery diseases. Traditional CV risk factors are the main determinants of ASCVD whereas undetectable HIV viral load seems to be protective. Management of cholesterol abnormalities and controlling viral load are essential to modify this high cardiovascular risk.

Acknowledgement/Funding

Agence Natoinale de Recherche sur le SIDA et les Hépatites virales
P5344Paradigme shift to disequilibrium in the genesis of orthostatic intolerance in patients with chronic fatigue syndrome
Authors: Miwa K
Published: October 2019

Background

Chronic fatigue syndrome (CFS) characterized by severe disabling fatigue and prolonging post-exertional malaise. The dysfunction of the central nervous system associated with myalgic encephalomyelitis (ME) has been postulated as the main cause of CFS. Orthostatic intolerance (OI) causes a marked reduction in the activities of daily living and impairs the quality of life in patients with ME/CFS. OI has been surmised to be a cardiovascular symptom with cerebral hypo-perfusion and exaggerated sympathetic nervous activation.

Purpose

Postural instability or disequilibrium may be involved in the etiology of OI because postural stability is an essential element for static balance.

Methods

The study comprised 72 patients with ME/CFS (18 men and 54 women; mean age, 37±10 years), who underwent neurological examinations and the active 10-min standing test.

Results

Disequilibrium defined as instability on standing with their feet together and eyes shut, was detected in 23 (32%) patients while postural orthostatic tachycardia in 16 (22%). Compared with 49 patients without disequilibrium, patients with disequilibrium more prevalently failed to complete the 10-min standing test (74% vs. 4%, p<0.01) and body sway was significantly more prevalently observed during the test (100% vs. 12%, p<0.01). The performance status score was significantly higher in patients with disequilibrium than those without it (median: 7 vs. 5, p<0.01), suggesting more severely restricted activity of daily living in the former. The prevalence of postural orthostatic tachycardia during the standing test was comparable between the patients with disequilibrium (23%) and those without it (22%, p=1.00). The 19 (26%) patients who failed to complete the 10-min standing test had disequilibrium more prevalently than those who completed it (89% vs. 11%, p<0.01). Performance status score was significantly higher in patients who failed to complete it than those who completed it (median: 6 vs. 5, p<0.01), suggesting more severe restriction of activity of daily living in the former. Significantly higher rates of disequilibrium (89% vs. 11%, p<0.01), unstable standing on one leg (84% vs. 17%, p<0.01) as well as abnormal tandem gait (79% vs. 11%, p<0.01) were noted in patients who failed to complete it than those who completed it. Body sway during the standing test was significantly more prevalently observed in the patients who failed to complete it than those who completed it (89% vs. 23%, p<0.01). The prevalence of postural orthostatic tachycardia during the standing test was comparable between the patients who failed to complete it and those who completed it (21% vs. 23%, p=1.00). Among the patients who failed to complete it 8 had the previous study records which revealed that 6 of them had completed it 6–24 months before when all the 6 patients had had no disequilibrium.

Conclusion

Disequilibrium should be recognized as an important cause of OI in patients with ME/CFS.
P5346The effect of seizure type on ictal and early post-ictal Heart Rate Variability in patients with focal resistant epilepsy
Authors: Faria M T , Rodrigues S , Dias D , Rego R , Rocha H , Sa F , Oliveira A , Campelo M , Pereira J , Rocha-Goncalves F , Cunha J P S , Martins E
Published: October 2019

Background

Seizures commonly affect the heart rate and its variability. The increased interest in this area of research is related to the possible connection with sudden unexpected death in epilepsy (SUDEP). Generalized tonic-clonic seizures (GTCS) are reported as the most consistent risk factor for SUDEP. However, the general risk of seizures (and their type) on cardiac function still remains uncertain.

Purpose

To evaluate the influence of seizure type (GTCS vs non-GTCS) on ictal and early post-ictal Heart Rate Variability (HRV) in patients with refractory epilepsy.

Methods

From January 2015 to July 2018, we prospectively evaluated 121 patients admitted to our institution's Epilepsy Monitoring Unit with focal resistant epilepsy. All patients underwent a 48-hour Holter recording. We included only patients who had both GTCS and non-GTCS during the recording and selected the first seizure of each type to analyze. HRV (AVNN, SDNN, RMSSD, pNN50, and LF/HF) was evaluated by analyzing 5-min-ECG epochs, starting with the seizure onset (ictal and early post-ictal period). The study was approved by our Institution Ethics Committee and all patients gave informed consent.

Results

Fourteen patients were included (7 Females, 4 patients with Temporal Lobe Epilepsy). The median age was 39 years (min-max, 18–57). Thirty-six percent presented cardiovascular risk factors without known cardiac disease.

A significant statistical reduction was found for AVNN (p=0.013), RMSSD (p=0.008), pNN50 (p=0.005) and HF (p=0.003), during GTCS when compared with non-GTCS (Wilcoxon test, p<0.05; two tailed).

Conclusion

Our study shows a significant reduced vagal tone during GTCS when compared with non-GTCS. Hence, GTCS had a more pronounced impact on HRV changes than other seizure types, which can be associated with higher SUDEP risk after GTCS.
P5350Atrial fibrillation prediction using P wave signal-averaged ECG in patients with embolic stroke of undetermined source
Authors: Shin S , Jung M , Song J , Kim J , Park K , Kim J , Lim H , Cho I , Won H , Lee W , Kim S , Kim T , Kim C , Lip G Y H
Published: October 2019

Background

Approximately 10–25% of ischemic strokes are of unknown origin. Determining their potential association with subclinical atrial fibrillation (SCAF) is important for proper secondary prevention. We investigated whether SCAF can be predicted by assessing the atrial substrate with signal-averaged electrocardiography (SAECG).

Methods

Between April 2015 and February 2018, we recruited 125 consecutive patients with embolic stroke of undetermined source (ESUS) and 125 patients with paroxysmal atrial fibrillation (AF) patients as control. All participants underwent P wave SAECG at baseline and ESUS patients were followed up with ECG and Holter ECG, at baseline, 3, 6, and 12 months after discharge, and every 12 months thereafter.

Results

In the ESUS group (69 males, 68.4±12.1 years), 32 (25.6%) patients were diagnosed with SCAF during follow-up. There were no significant differences between both groups in terms of P wave duration [PWD] (ESUS vs. AF, P=0.321). PWD demonstrated a significant predictive efficacy for SCAF detection during follow-up (C-index of standard PWD=0.657, 95% confidence interval (CI) 0.552–0.761, P=0.008).

Stroke recurrence occurred in 22 patients (17.6%) and was significantly associated with PWD but not SCAF (odds ratio 2.756, 95% CI 1.061–7.161, P=0.037).

Conclusion

PWD, an ECG biomarker associated with atrial substrate directly contributes to AF and ESUS, is useful for predicting SCAF. The potential for using this simple ECG biomarker for screening for SCAF amongst ESUS patients merits further exploration.
P5353Pregnancy in congenital heart disease - risk stratificaton
Authors: Pataki S , Szegedi M , Temesvari A , Ablonczy L , Andreka P , Balint H
Published: October 2019

Introduction

Maternal congenital heart disease is a leading cause of peripartum maternal mortality, which is also associated with increased risk of fetal morbidity and mortality. We aimed to provide risk stratification for congenital heart disease patients using the recently introduced CARPREG (Cardiac Disease in Pregnancy) II score at our Institute.

Patients and methods

We enrolled 191 pregnant women with congenital heart disease (mean age at pregnancy 29.2±5,7 years). We recorded all foetal (premature birth, abortion, congenital heart abnormalities) and maternal (postpartum heart failure, stroke, hypertension) events in 276 pregnancies. High-risk pregnancy was defined as a CARPREG II score of 4≤.

Results

High-risk pregnancy was detected in 14.1%. We found fetal and maternal events in 13.8% and 14.5% of all pregnancies, respectively, which both were more prevalent in the high-risk group (p<0.001). No maternal death occurred, whereas premature birth and abortion was detected in 7.6 and 2.9%, respectively, both complications were more frequent in the high-risk patient population as compared to the lower risk patients (30.8 vs. 7.2%, p<0.001). In univariate analysis, CARPREG II of 4≤ was significantly associated with fetal (p<0.001, OR: 4.2) and maternal (p<0.001, OR: 5.3) events. Risk factors of the CARPREG II were further analyzed using multivariate logistic regression analysis: prior cardiac events or arrhythmias (p=0.027) and cyanosis (p=0.026) were independent predictors of fetal complications. Left ventricular outflow tract obstruction (p<0.001), cardiac interventions (p=0.024) and prior cardiac events or arrhythmias (p=0.001) demonstrated significant association with maternal events.

Conclusion

The CARPREG II could help in the identification of high-risk pregnancies and thus aids the selection of patients for strict monitoring and special therapies. In line with previous studies we detected higher rates of fetal and maternal events among patients with CARPREG II of 4≤ score.
P5362Impact of statin therapy on long-term clinical outcomes between STEMI and NSTEMI after stent implantation
Authors: Kim Y H , Her A.-Y , Jeong M H , Kim B.-K , Lee S.-Y , Hong S.-J , Shin D.-H , Ahn C.-M , Kim J.-S , Ko Y.-G , Choi D , Hong M.-K , Jang Y
Published: October 2019

Background

Although European guideline recommends that statin should be given to all patients with acute myocardial infarction (AMI), irrespective of cholesterol concentration, limited studies were focused on the long-term effects of statin therapy between ST-segment elevation MI (STEMI) and non-ST-segment elevation MI (NSTEMI).

Purpose

The authors conducted the study to compare the relative beneficial role of statin on 2-year major clinical outcomes between STEMI and NSTEMI in patients who underwent successful PCI with DES.

Methods

Finally, a total of 26317 AMI patients who underwent stent implantation and who were prescribed the statin were enrolled and they were separated into two groups; the STEMI group (n=15002) and the NSTEMI group (n=11315). The clinical endpoint was the occurrence of major adverse cardiac events (MACE) defined as all-cause death, recurrent myocardial infarction (re-MI), total coronary revascularization (target lesion revascularization [TLR], target vessel revascularization [TVR], non-TVR) during 2-year follow-up period.

Results

After propensity score-matched (PSM) analysis, two PSM groups (7746 pairs, n=15492, C-statistic = 0.766) were generated. In the total study population, the cumulative incidences of MACE, all-cause death, and cardiac death were significantly higher in the NSTEMI group. However, after PSM, the cumulative incidence of all-cause death (Hazard ratio, 1.386; 95% CI, 1.133–1.696; p=0.002) was significantly higher in the NSTEMI group. The cumulative incidences of MACE, cardiac death, re-MI, total revascularization, TLR, TVR, and non-TVR were similar between the two groups (Table 1).

Outcomes Cumulative Events at 2-year (%) Hazard Ratio (95% CI) p value STEMI NSTEMI Log-rank Propensity score matched patients MACE 532 (7.2) 584 (8.1) 0.092 1.106 (0.984–1.244) 0.092 All-cause death 163 (2.2) 224 (3.1) 0.001 1.386 (1.133–1.696) 0.002 Cardiac death 121 (1.5) 148 (2.0) 0.088 1.232 (0.969–1.566) 0.089 Re-MI 117 (1.6) 107 (1.5) 0.545 0.922 (0.710–1.199) 0.545 Total revascularization 291 (4.1) 307 (4.4) 0.422 1.068 (0.910–1.254) 0.423 TLR 92 (1.3) 89 (1.2) 0.880 0.978 (0.731–1.309) 0.880 TVR 173 (2.4) 184 (2.6) 0.478 1.078 (0.876–1.327) 0.478 Non-TVR 123 (1.7) 130 (1.9) 0.593 1.070 (0.836–1.369) 0.539

Conclusion

The mortality reduction capability of statin was more prominent in the STEMI group compared with the NSTEMI group.
P5365Microsomal triglyceride transfer protein inhibitor (lomitapide) efficacy in the treatment of patients with homozygous familial hypercholesterolemia phenotype
Authors: Fountas E , Diakoumakou O , Kolovou V , Stratakis S , Zacharis E , Liberopoulos E , Matsouka F , Tsoutsinos A , Mastorakou I , Katsikas T , Mavrogeni S , Hatzigeorgiou G , Kolovou G
Published: October 2019

Introduction

The majority of patients with homozygous familial hypercholesterolemia (HoFH) phenotype are treated additionally to lipid lowering (LL) drugs (statin + ezetimibe ± colesevelam) with lipoprotein apheresis (LA) sessions. The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in HoFH patients.

Patients and methods

In 12 HoFH patients treated with LL drugs ± biweekly LA sessions (9 patients) the 5–40 mg daily of lomitapide was added. Lipid profile [total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C)] before (LL drugs ± LA) and after lomitapide treatment were evaluated.

Results

The follow-up period of lomitapide treatment for 12 patients was 3–24 months (13.8±7.9). The median baseline LDL-C levels was 1000 mg/dL (339–1150). During LL drug therapy, patients showed a median LDL-C level of 383.5 mg/dL (Range: 214–866 mg/dL) and with LL drugs + Time-averaged levels (CAVG) the median was 288.1 mg/dL (Range: 183.69–716.65 mg/dL). The addition of lomitapide at the average dosage of 21.4 mg/day lowered LDL-C levels by 56.8% comparing to LL drugs alone therapy [mean reduction 262.12, 95% CI (105.53, 418.71), p=0.005] and by 54% [mean reduction −182.89, 95% CI (−342.35, −23.43), p=0.031] comparing to LL drugs + LA (CAVG). The CAVG of LDL-C in LL drugs + LA patients compared with LL drugs + lomitapide was 54% in favour of lomitapide (p=0.031). After lomitapide administration to LL drugs + LA treatment, 78% patients discontinued LA and 2 patients reduced their LA frequency by 50%. During follow-up, 2 patients (16.6%) reported side effects (transient diarrhea, 1 patient had liver transaminase >5× ULN and had to decrease dose of lomitapide). Two patients stopped lomitapide due to diet and alcohol restrictions.

Median and ranges of lipid and lipoprotein values before any intervention, after LL drugs, LL drugs plus LA, LL drugs plus LA (CAVG) and LL drugs plus lomitapide Total Cholesterol LDL-C HDL-C Triglycerides Before any intervention 1000 (339–1150) 900 (245–1070) 34.5 (25–50) 125 (87–314) After LL drugs 434 (278–915) 383.5 (214–866) 36 (27–51) 113 (62–198) LL drugs + LA (CAVG) 336.13 (248.57–784.16) 288.07 (183.69–716.65) 42.81 (25.84–46.68) 105.09 (55.79–166.68) LL drugs + Lomitapide 228.5 (118–554) 173.5 (74–515) 37.5 (29–50) 83.5 (23–316)

LDL graph

Conclusions

Treatment with lomitapide in HoFH patients has beneficial effect with constant decrease of LDL-C by 57% compared with classical LL therapy and by 54% compared with classical LL therapy and CAVG and seems to be with good safety profile. Although, in some cases the hybrid (all availably drug treatment and LA) therapy may be needed.
P5374Genetic deletion of IL-22 increased cardiac rupture after myocardial infarction in mice
Authors: Yamamoto M , Yasukawa H , Takahashi J , Nohara S , Sasak T , Shimozono K , Shibata T , Yanai T , Okabe K , Mawatari K , Fukumoto Y
Published: October 2019

Background

Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, which mainly targets epithelial cells and does not target immune cells. Recently, it has been reported that IL-22 play roles in tissue repair in the skin and the liver; however, role of IL-22 in the process of tissue repair after myocardial infarction (MI) is unknown. Here, we investigated the role of IL-22 in tissue repair process after MI.

Methods and results

First, we examined the expression of IL-22 and its receptor IL-22RA1 in the wild type (WT) mice by real-time PCR. The expression of IL-22 and IL-22RA1 in the hearts were significantly increased 3 days after MI (p<0.05). To clarify the role of IL-22 in the heart after MI, we produced MI model in the WT mice and IL-22 knockout (KO) mice. We found that the IL-22 KO mice had significantly higher mortality than the WT mice after MI (p<0.05). Approximately 80% of the IL-22 KO mice died with cardiac rupture after MI. The infarct size which was estimated by evans blue dye and triphenyltetrazolium chloride staining at 3 days after MI was comparable between the IL-22 KO mice and the WT mice. Next, we performed real time PCR and PCR array analysis for tissue fibrosis and repair genes. We found that alpha-smooth muscle actin (aSMA), NF-kB, TNF-a and MMP13 (also known as collagenase-3) were significantly increased in the infarct area of IL-22 KO mice compared to WT mice. Immunostaining showed that the myofibroblast marker aSMA positive cells in the border area after MI were markedly higher in the IL-22 KO mice compared with the WT mice (p<0.05). Approximately 70% of cardiac rupture after MI in the IL-22 KO mice were occurred in the infarct area adjacent to the border area. Furthermore, we found aSMA positive cells and MMP13 positive cells around the ruptured site of the heart.

Conclusion

Thus, IL-22 KO mice exhibit high mortality and increased cardiac rupture after MI. And expression of aSMA and MMP13 were highly expressed in the ruptured site after MI in the IL-22 KO mice. These results suggest that IL-22 may play an important role in the tissue repair process after MI.
P5388N-cadherin promotes cardiac regeneration by stabilizing beta-catenin
Authors: Tseng Y S , You M Y , Hsu Y C , Yang K C
Published: October 2019

Background

Although the adult mammalian heart fails to regenerate after injury, it is known that newborn mice within a week have full cardiac regenerative capacity. The molecular determinants underlying the disparate regenerative capacity between neonatal and adult mice, however, remain incompletely understood. Exploiting RNA sequencing in isolated cardiomyocytes from neonatal and adult mouse heart, we identified Cdh2, which encodes the adherence junction protein N-cadherin, as a potential novel mediator of cardiac regeneration. Cdh2 expression levels were much higher in neonatal, compared with adult, cardiomyocytes and showed a strong positive correlation with that of multiple cell cycle genes. N-cadherin has been reported to be essential for embryonic cardiac development; its role in cardiac regeneration, however, remains unknown.

Purpose

To determine the role of Cdh2 (N-cadherin) in cardiac regeneration and to investigate the underlying molecular mechanisms.

Methods

Apical resection in postnatal day 1 mice was used as a cardiac regenerative model. The in vitro gain/loss-of function studies of Cdh2/N-cadherin was performed in postnatal day 1 neonatal mouse cardiomyocytes (P1CM) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM). N-cadherin inhibitor exherin was used to study the effects of N-cadherin in vivo.

Results

Comparing to sham-operated control, Cdh2 was significantly upregulated in mouse cardiac apex and border zone following apical resection, which was accompanied with increased cardiomyocyte proliferation activity. In vitro, knocking down Cdh2 or inhibition of N-cadherin activity with exherin in P1CM significantly reduced the proliferative activity of cardiomyocytes, whereas overexpression of Cdh2 markedly increased the proliferation of P1CM. In addition, forced expression of Cdh2 resulted in significant upregulation of multiple cell cycle genes, including Ccnd1 (Cyclin D1) and Pcna (proliferating cell nuclear antigen), in P1CM. In vivo inhibition of N-cadherin in P1 neonatal mice with exherin following apical resection impaired cardiac regeneration and increased scar formation (Figure). Knocking down CDH2 in human iPSC-CMs significantly reduced the proliferative activity and the expression levels of cell cycle gene CCND1 in iPSC-CMs. Mechanistically, we demonstrated that the pro-mitotic effects of N-cadherin in cardiomyocytes were mediated, at least partially, by stabilizing β-catenin, a pro-mitotic transcription factor, through direct interaction with its cytoplasmic domain and/or inactivation of GSK3β, a critical component of β-catenin destruction complex.

N-Cad blocker impairs heart regeneration

Conclusion

Our study uncovered a previously unrecognized role of Cdh2 (N-cadherin) in cardiomyocyte proliferation and cardiac regeneration. Enhancing cardiac expression or activity of N-cadherin, therefore, could be a potential novel therapeutic approach to promote cardiac regeneration and restore cardiac function in adult heart following injury.
P5410Combination assessment of renal and hepatic dysfunction improves the predictability of prognosis in patients with acute decompensated heart failure
Authors: Shibata N , Sumi T , Umemoto N , Kajiura H , Inoue S , Iio Y , Sugiura T , Taniguchi T , Asai T , Yamada M , Shimizu K , Murohara T
Published: October 2019

Background

Renal dysfunction is associated with poor mortality in patients with heart failure (HF). Hepatic dysfunction, assessed by Fibrosis-4 (FIB4) index, has also prediction ability in acute decompensated HF (ADHF) patients. We investigated whether the assessment of the combination of FIB4 index and renal dysfunction improves predictability in patients with ADHF.

Methods

We retrospectively enrolled consecutive 758 patients who admitted due to ADHF from January 2011 to February 2018 and followed up for one year. FIB4 index on admission was calculated by the formula: age (yrs) × AST[U/L] / (platelets [103/μL] × (ALT[U/L])1/2). Study subjects were divided into high FIB4 index (>3.25) and low FIB4 index (≤3.25), furthermore each group were classified by the presence/absence of CKD (estimated glomerular filtration rate <60 ml/min/1.73m). We have generated four groups; low FIB4/without CKD (n=154), low FIB4/with CKD (n=294), high FIB4/without CKD (n=56), and high FIB4/with CKD (n=254). The primary outcome was defined as all-cause mortality in one year. We performed Kaplan-Meyer analysis and multivariable Cox regression models. Furthermore, we evaluated the incremental value with C-index, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) when FIB4 index and renal dysfunction added to a baseline model.

Results

In total, 106 patients died in one year. High FIB4 index and CKD showed significantly higher 1-year mortality (high FIB4 index: 19.7% vs 10.3%, p<0.001, CKD: 17.0% vs 6.7%, p<0.001, respectively). Kaplan-Meyer analysis shows that high FIB4 index with CKD showed statistically higher mortality than the others (vs low FIB4/without CKD, p<0.001, vs high FIB4/without CKD, p=0.031, vs low FIB4/with CKD, p<0.001, respectively).

Multivariate Cox regression model revealed that both high FIB4 index and CKD were an independent risk predictor of 1-year mortality (FIB4 index: p<0.001, HR 1.06, 95% CI 1.035–1.087, CKD: p=0.004, HR 1.834, 95% CI 1.213–2.773, respectively) in patients with ADHF.

A baseline model for prediction of 1-year mortality was determined by multivariable logistic regression including age, body mass index, systolic blood pressure, and serum albumin (C-index: 0.688). Adding high FIB4 index and CKD to the baseline model, all of C-index (0.738, p=0.04), NRI (0.122, p=0.067), and IDI (0.024, p=0.004) were improved.

Receiver operating characteristic curves

Conclusions

Combination assessment of renal and hepatic dysfunction could improve the predictability of prognosis in patients with ADHF.

Acknowledgement/Funding

None
P5411Prognostic communication with hospitalized heart failure patients; the patients' perspective
Authors: Kitakata H , Kohno T , Kohsaka S , Fujisawa D , Nakano N , Shiraishi Y , Katsumata Y , Yuasa S , Fukuda K
Published: October 2019

Background

Informing heart failure (HF) patients about their prognosis is an important part of clinical management, particularly at the time of hospitalization. Current European Society of Cardiology guidelines recommend communicating this information to HF patients at the time of hospitalization and with any change in clinical status. However, little is known about actual patient preferences, understanding, and attitudes towards prognostic communication with their treating physicians.

Methods

We surveyed 113 consecutive hospitalized HF patients in a single university hospital. We assessed patient understanding of prognosis (likelihood of survival beyond 2 years), and compared patient expectations to model predictions. Model-predicted 2-year survival rate was calculated by the Seattle Heart Failure Model (SHFM). We also assessed patient preferences for information disclosure using the Prognosis and Treatment Perception Questionnaire (PTPQ). The PTPQ assesses patient beliefs regarding 1) the importance of knowing about prognosis, 2) the importance of knowing about treatment option, and 3) frequency of having a conversation about prognosis during the hospital stay.

Results

Enrolled patients were predominantly male (65.5%), with a mean age of 73.6±9.6 years and mean left ventricular ejection fraction was 46.2±15.4%. Median SHFM-estimated 2-year survival rate was 89.2% (interquartile range: 83.8–92.9%). Overall, patient understanding about prognosis was suboptimal. Among patients with a guarded 2-year survival (SHFM <90%: N=60), 44% reported that their likelihood of 2-year survival was >90% (Figure; red box). However, among patients with favorable 2-year survival (>90%: N=53), 38% reported a likelihood of <90% (Figure; blue box). Regarding treatment options, most patients (98%) desired to learn as many details as possible. Responses varied with regard to information on individual prognosis; whereas 51% wanted to know more about prognosis than their present status alone, a significant number (28%) of subjects answered “never” or “less often” to a query on the frequency of discussion about prognosis. Patient preference for more information about prognosis was associated with female sex (odds ratio [OR]: 2.52; 95% confidence interval [CI]: 1.12–5.69), fewer symptoms of depression (1-point increase on Patient Health Questionnaire-2, OR: 0.66; 95% CI: 0.49–0.87), and previous stroke (OR: 2.92; 95% CI: 1.04–8.19), but not other social/demographic or clinical factors (e.g., age, education, caregiver support, HF phenotype and severity, and other comorbid conditions).

Figure 1

Conclusions

There were substantial discrepancies in patient understanding of prognosis and in desire for more information from physicians. Interventions to improve prognostic understanding are warranted for HF patients, and hospitalization for HF could represent an opportunity for optimization.
P5429Mechanical dyssynchrony has a higher predictive value for CRT response than different ECG-based definitions of LBBB
Authors: Beela A , Duchenne J , Voigt J U
Published: October 2019

Background/Aim

To investigate the value of baseline assessment of mechanical dyssynchrony (Dyss) in predicting response to cardiac resynchronization therapy (CRT) in comparison to the classic ECG definition of left bundle branch block (LBBB) (Classic-def) as well as the recently proposed Sex- based definition (Sex-def.).

Methods

The baseline ECGs of 194 patients (31% females, 39% with ischemic cardiomyopathy, mean QRS width 159±25 ms and mean LVEF 29±8%) were investigated for identifying the criteria of LBBB before CRT implantation. Classic-def., defined as notched or slurred QRS complex in at least two of the leads I, aVL, V1, V2, V5 and V6 with a total width of at least 120 ms in addition to the absence of Q wave in lead I, V5 and V6 was identified in 74% of the study population. Sex-def. was identified in 69%, which is a QRS duration of at least 140 and 130 ms for men and women respectively with otherwise the same criteria of the Classic definition. Dyss was defined as the presence of either apical rocking and/or septal flash in 2D echocardiography prior to implantation. Volumetric response to CRT was defined as a reduction of at least 15% of the LV-end systolic volume (ESV) at follow up echocardiography (12±6 months after device implantation).

Results

Patient with baseline Dyss showed the highest response rates (76%) with a sensitivity of 88%, a specificity of 63% and an area under the curve (AUC) of 0.76 (P<0.001) compared to 70% (sensitivity 82%, specificity 47%, AUC 0.65, P<0.01) in patients with Sex-def. and 65% (sensitivity 84%, specificity 40%, AUC 0.62, P=0.01) in patients with Classic-def. (Figure A).

Pairwise comparisons showed that the accuracy of the Sex-def. did not differ significantly from the Classic-def. in response prediction (AUC=0.65 vs. 0.62 for Sex-def. vs. Classic-def. respectively, P=0.27). Alternatively, Dyss showed a significantly higher accuracy in predicting response to therapy (AUC=0.76) as compared to Sex-def. and Classic-def. (P=0.02 and <0.01 respectively, Figure B).

Mech. dyssynchrony vs. ECG-based LBBB

Conclusion

The presence of Apical rocking and/or septal flash before CRT is associated with better response to CRT as compared to various ECG definitions of LBBB. Although a Sex-based definition of LBBB showed a trend of better response to CRT as compared to the Classic definition, it was not statistically significant.
P5436Angiotensin receptor-neprilysin inhibitor preserved cardiac function via improving angiogenetic ability in mice model of atherosclerosis
Authors: Suematsu Y S , Ideishi A I , Tashiro K T , Kuwano T K , Miura S M
Published: October 2019

Introduction

Angiotensin receptor-neprilysin inhibitor (ARNI) increases natriuretic peptide and improves heart failure. We previously reported that ARNI has the effects of suppression of myocardial hypertrophy and fibrosis in addition to reduction of afterload by natriuretic effect. We investigated the effects of ARNI against mice model of atherosclerosis and heart failure.

Method and results

Apolipoprotein E knockout mice fed high cholesterol diet for 4 weeks were divided into four groups: no treatment (CTL), valsartan 30 mg/kg (VAL), sacubitril (neprilysin inhibitor) 30 mg/kg (SAC), and ARNI 60mg/kg for additional 13 weeks. Body weight and systolic blood pressure in the VAL, SAC and ARNI groups did not show significant differences compared to those in the CTL group. Serum brain natriuretic peptide (BNP) in ARNI group (605±221 pg/ml) was significantly increased than that in VAL (391±57 pg/ml) and SAC (357±91 pg/ml) groups, but not CTL group (393±192 pg/ml). Although the rate of atherosclerotic area in aorta was 16.3±5.8% after treatment, there were no significant differences between the groups. In the CTL group, left ventricular ejection fraction (LVEF, 81.6±4.8%) and fractional shortening (FS, 44.8±5.8%) at baseline were significantly reduced after treatment (67.8±8.2% and 33.3±6.1%). Interestingly, LVEF (76.6±6.7%) and FS (40.1±6.1%) after treatment in the ARNI group were significantly preserved compared to those in the CTL group. In real time polymerase chain reaction analysis of LV after treatment, relative mRNA expression of BNP and angiogenetic factors including ATPase sarcoplasmic/endoplasmic reticulum Ca transporting 2, vascular endothelial growth factor A, cluster of differentiation 34 in ARNI group were significantly increased than those in the CTL group. Transforming growth factor-β in ARNI group was significantly reduced than that in the CTL group.

Conclusion

Although ARNI did not suppress atherosclerosis in mice, it preserved LVEF via improving angiogenetic ability.
P5445PCSK9 and 6-month Left Ventricular Ejection Fraction after ST-segment Elevation Myocardial Infarction. A Pilot Study
Authors: Nunez Villota J , Minana G , Bayes-Genis A , Nunez E , Revuelta-Lopez E , Sanchis J , Rios-Navarro C , Lopez-Lereu M , Monmeneu J V , Chorro F J , Lupon J , Bodi V
Published: October 2019

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma LDL. Beyond lipid control, recent findings suggest a deleterious effect of this protein in the pathogenesis of post-myocardial infarction left ventricle remodeling and heart failure-related complications. The aim of this work was to assess the relationship between circulating PCSK9 and 6-month cardiac magnetic resonance (CMR) imaging-derived left ventricle ejection fraction (LVEF) after a first ST-segment elevation myocardial infarction (STEMI).

Methods

We prospectively evaluated 40 patients with a first STEMI treated with primary percutaneous coronary intervention (PPCI) and LVEF<50% in which PCSK9 was measured 24h post-reperfusion. All patients underwent CMR imaging 1 week and 6 months after STEMI. The association between serum PCSK9 and 6-month LVEF was evaluated by ANCOVA. The following covariates were included in the final model; 1-week CMR-derived LVEF, age, gender, 1-week CMR-infarct size, plasma suppression of tumorigenicity-2 (ST2), low density lipoprotein-cholesterol, ante treatment with statins.

Results

The mean age of the sample was 60±12 years and 33 patients (82.5%) were male. Mean 1-week and 6-month LVEF were 41±7% and 48±10%, respectively. The mean±SD of PCSK9 was 1.93±0.38 U/mL. PCSK9 values were inversely related with 6-month LVEF (r=−0.35, p=0.028). The mean values of PCSK9 were significantly higher in patients with LVEF<50% at 6 months (2.06±0.29 vs. 1.80±0.41 U/mL, p=0.028). After a multivariate adjustment, circulating PCSK9 remained significant and inversely associated with 6-month LVEF (p=0.001).

Figure 1

Conclusions

In patients with a first STEMI treated with PCCI and reduced ejection fraction, circulating PCSK9 was associated with lower LVEF at 6 months.
P5459Comparison of the predictive role of changes in left ventricular mass and arterial stiffness for coronary artery disease in essential hypertension: Data from a 8-year-follow-up study
Authors: Leontsinis I , Tsioufis C , Dimitriadis K , Kasiakogias A , Liatakis I , Koutra E , Kouremeti M , Iliakis P , Vogiatzakis N , Karaminas N , Asimaki E , Tousoulis D
Published: October 2019

Background/Introduction

Although arterial stiffening is related to atherosclerosis progression, its prognostic role in hypertension is not fully elucidated, while augmented left ventricular mass index (LVMI) is linked to adverse outcome.

Purpose

The aim of the present study was to compare the predictive role of changes in arterial stiffness and LVMI for the incidence of coronary artery disease (CAD) in a cohort of essential hypertensive patients.

Methods

We followed up 1082 essential hypertensives (mean age 55.9 years, 562 males, office blood pressure (BP)=145/91 mmHg) free of cardiovascular disease for a mean period of 8 years. All subjects had at least one annual visit and at baseline and last visit underwent complete echocardiographic study for estimation of LVMI and measurements of arterial stiffness on the basis of carotid to femoral pulse wave velocity (PWV), by means of a computerized method. The distribution of PWV was split by the median (8.2 m/sec) and accordingly subjects were classified into those with high (n=546) and low values (n=536). Moreover, LV hypertrophy (LVH) was defined as LVMI ≥125 g/m2 in males and LVMI ≥110 g/m2 in females, while CAD was defined as the history of myocardial infarction or significant coronary artery stenosis revealed by angiography or coronary revascularization procedure.

Results

The incidence of CAD over the follow-up period was 3.5%. Hypertensives who developed CAD (n=38) compared to those without CAD at follow-up (n=1044) had at baseline higher waist circumference (101.7±10.1 vs 96.2±11.6 cm, p=0.004), LVMI (123.9±22.1 vs 105.8±21.3 g/m2, p=0.026), prevalence of LVH (46% vs 25%, p=0.018) and prevalence of high PWV levels (67% vs 40%, p=0.021). No difference was observed between hypertensives with CAD and those without CAD with respect to baseline office BP, serum creatinine and lipid levels (p=NS for all). By univariate Cox regression analysis, it was revealed that changes in PWV levels between baseline and last visit predicted CAD (hazard ratio=1.243, p=0.014). However, in multivariate Cox regression model baseline glomerular filtration rate (hazard ratio=1.029, p=0.015) and changes in LVMI (hazard ratio=1.036, p<0.0001) but not alterations of PWV turned out to be independent predictors of CAD.

Conclusions

In essential hypertensive patients changes in LVMI predict future development of CAD, whereas PWV alterations exhibit no independent prognostic value. These findings support that LVMI constitutes a superior prognosticator of events than PWV and its estimation is essential in order to improve overall risk stratification in hypertension.
P5472Social economic deprivation and adverse clinical outcomes after acute coronary syndrome
Authors: Lau Y C , Latter J , Jong A , Weir R
Published: October 2019

Background

NHS was created in 1948 to redress the healthcare inequality through provision of universal healthcare service in the UK. However even of late, significant health inequality persists. Socioeconomic deprivation is known to result in increased overall morbidity and mortality.

Aim

To assess the impact of socioeconomic deprivation (as categorised by Scottish Index of Multiple Deprivation, SIMD) on the medical management and clinical outcomes of patients with ACS (NSTEMI/STEMI) who were treated with PCI

Methods

A retrospective study of NSTEMI/NSTEMI patients after inpatient treatment with coronary angiogram and PCI. The parameters include basic demographics, risk factors, LV EF on echocardiogram, lipid profile and discharge medication. Individual's socioeconomic deprivation index, as described SIMD was also recorded (1 – most deprived and 10 – least deprived), and accordingly placed into quintile (SIMD 1–2, 3–4, 5–6,7 –8, 9–10). Follow-up for 24 months. Clinical outcome assessed was composite endpoint event of MACE.

Results

357 from the lowest quintile (SIMD 1–2), 319 from SIMD 3–4, 191 from SIMD 5–6, 120 from SIMD 7–8, and 99 from the highest quintile (SIMD 9–10) were included. No statistical difference exists between age or gender. No difference in past medical history (inclusive of hypertension, diabetes, dyslipidemia, family history. No difference in incidence of nicotine use.

Prescription of aspirin, P2Y12 inhibitors (clopidogrel, ticagrelor or prasugrel) as well as secondary prevention medications (such as ace inhibitor/angiotensin II receptor blocker, beta blocker, statin and GTN) were good and not statistically different between all groups.

No statistical difference exists between all groups relating to pre-discharge LV ejection fraction on echocardiogram or random cholesterol level check on admission.

24 months follow-up demonstrated composite endpoint of MACE was statistically higher among patients of lowest socioeconomic quintile (Kaplan Meier plot, p<0.001). Step-wise multiple regression analysis also confirmed multiple socioeconomic deprivation as an independent predictor for more adverse clinical outcomes (p<0.001, R2=14.5%).

Patients from the least deprived quintile possess survival advantage almost 14-folds as compared to those of most deprived group (Odd-ratio 13.8 (95% CI: 39.4–48.5)).

After an ACS event, despite initial coronary intervention and subsequent optimal prescription of prognostically beneficial secondary prevention medications, patients from the lower socioeconomic group (as described by SIMD) are still more likely to experience readmission for cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Socioeconomic deprivation has been shown to be an independent predictor of adverse clinical outcome for those who survived initial ACS.

Acknowledgement/Funding

None