bluuebunny/crossref_metadata_2025 huggingface dataset:
P6286Old age significantly worsens stroke outcome in old mice through a mechanism of inflamm-aging successfully countered by the tumour necrosis factor alpha antibody infliximab
Authors: Bonetti N R , Liberale L , Pasterk L , Diaz-Canestro C , Akhmedov A , Gobbato S , Luescher T F , Beer J H , Camici G G
Published: October 2019

Background

Stroke is the second leading cause of death and the number one cause of adult disability worldwide. As a strongly age-dependant disease, its prevalence is expected to rise along with the average age in western populations. While the epidemiological evidence linking stroke to age is non-refutable, the specific and independent effects of age on stroke remain elusive.

This presents an important missing link for developing targeted treatments tailored to the growing elderly population.

A potential mechanism pertinent to stroke outcome in the elderly is a chronic low-grade inflammatory state, coined “inflamm-aging”. Such a phenomenon could not only increase the risk for stroke, but also negatively affect its outcome and thus offers both preventive and therapeutic value.

Purpose

To determine the specific effects of age on the outcome after stroke in mice and delineate culprit molecular pathways with a focus on inflammatory mediators and to assess the efficacy of specific anti-inflammatory treatment with the TNF-α antibody Infliximab in this setting.

Methods

Old (18–20 months) C57BL/6 wildtype mice were compared to young (12 weeks) controls. Baseline levels of inflammatory cytokines were assayed in plasma and brain homogenates by ELISA. Ischemic stroke was induced by transient middle cerebral artery occlusion (30 minutes/48 h). Neurological function was assessed by a Bederson based score and the RotaRod test. Anti-inflammatory treatment with Infliximab was administered to a subset of old mice via weekly intraperitoneal injections (10 mg/kg) for 4 weeks prior to stroke induction. Young and old control animals received vehicle.

Results

At baseline (prior to stroke), old animals showed significantly higher plasma levels of TNF-α compared to young (Fig. 1A), while IL-6 and IL-1β remained below detection level in both groups. In brain homogenates of healthy old and young animals, TNF-α and IL-1β did not differ, while IL-6 was below detection level.

Old mice showed significantly larger stroke sizes (Fig.1B), performed worse neurologically (Fig. 1C) and suffered from higher post-stroke mortality compared to young (Fig. 1D). Pre-treatment with the TNF-α inhibitor Infliximab significantly decreased stroke size, neurological impairment and mortality in old animals (Fig1B-D).

Figure 1

Conclusions

In a model lacking additional confounding factors, we demonstrate a direct adverse effect of age per se on stroke outcome and mortality. Elevated TNF-α plasma levels in old mice outline the mechanism of “inflamm-aging” as a possible culprit. This concept is strongly supported by the beneficial effect of Infliximab on stroke outcome in old animals. Further investigation of the downstream mediators of the observed effect could help in tailoring treatments to the particularly vulnerable and growing elderly population.
P6291Post-myocardial infarction activation of P2X7 dependent inflammasome is crucial to develop an appropriate scar integrity
Authors: Merz J , Van Garlen S , Ahmed I , Dimanski D , Rofa K , Hoppe N , Bode C , Zirlik A , Stachon P
Published: October 2019

Introduction

Cardiovascular diseases are the main cause of death worldwide. Acute ischemia results in cell death of cardiomyocytes accompanied with the release of so called damage associated molecular patterns (DAMPs) such as nucleotides. High concentration of ATP in the extracellular fluid leads to the opening of the ionotropic purinergic receptor P2X7. The following transmembranous ion flux triggers the assembly of the NLRP-3 inflammasome and proteolytic caspase-1 activation which cleaves pro-IL-1β and provokes the release of fully active pro-inflammatory IL-1β. Myocardial scar formation can be divided into an early remodelling IL-1β-dependent and a late scar forming TGFβ phase. Both phases negatively regulate each other. The current stuy aimed to investigate the role of this master regulator of NLRP3 inflammasome assembly P2Y7 in myocardial remodeling during prolonged ischemic conditions.

Methods

10 weeks old P2X7 knock-out and C57Bl6/J mice received a full ligation of the left anterior descending (LAD) artery. Mice three and seven days post-infarction underwent echocardiography. Myocardial scar formation was assessed by histological staining and flow cytometry. Furthermore caspase-1 activity was measured using FLICA in histology. Gene expression was assessed using TaqMan realtime PCR.

Results

Macrophages in the myocardial infarct area showed high P2X7 expression by Co-staining with fluorescent antibodies against F4/80, CD68 and P2X7. Intriguingyl P2X7 deficient animals showed a significantly worse survival rate in a Kaplan-Meier survival analysis compared to wt littermated with LAD ligation (Mortality after 21 days P2X7+/+ 50%; P2X7−/− 100%, p<0.05). Cause of death assessed by autopsy was myocardial rupture in P2X7−/− mice. Accordingly histological analysis revealed a less compact infarct area in P2X7 knock-out animals with abundant coagulation necrosis. In agreement with that we observed a thickened infarcted anterior wall by echocardiography in P2X7 animals. Furthermore whereas the infarcted area of P2X7 competent mice showed high signals for active caspase-1 in histology, we were not able to detect any signal of caspase-1 activity in P2X7 deficient mice. In coherence with this observation we detected a premature increased TGFβ gene transcript upregulation in infarct tissue of P2X7 deficient animals.

Conclusion

The knockout of the NLRP3 inflammasome activating P2X7 receptor impairs the outcome after myocardial infarction by reduced monocyte infiltration and deranged scar formation. Disruption of the fine-tuned IL-1β/TGFβ sequence with an early block of IL-1β signaling and premature TGFβ activation could explain the missing clean-up of necrotic debris and impaired scar formation. Taken together these findings highlight the importance of an early inflammasome phase during myocardial scar formation.
P6302GALNT4 enhances monocyte adherence and chemotaxis by regulating PSGL1 O-glycosylation in patients with acute coronary syndrome
Authors: Ye Z X , Huang H
Published: October 2019

Background

GalNAc-T4 (GALNT4), a member of N-acetylgalactosaminyltransferases family, which transfers GalNAc to Serine and Threonine residues in the initial step of O-linked protein glycosylation. Genome wide association studies (GWAS) have predicted that GALNT4 gene play a causal role in the susceptibility to cardiovascular diseases, whereas the precise mechanisms of it in acute coronary disease (ACS) is unknown.

Purpose

In this study, we sought to determine the role of GALNT4 in regulating monocytes with ACS and the underlying mechanisms.

Methods and results

The expression of GALNT4 mRNA was significantly elevated in patience with STEMI (n=50) compare with stable coronary heart disease (SCHD) (n=50) and controls (n=50) (Clinicaltrial.gov: NCT 03335514). Moreover, GALNT4 siRNA knockdown suppressed monocytes adherence under static and flow condition with P-selectin stimulation, as well as chemotaxis triggered by monocyte chemotactic protein-1 (MCP-1). In contrast, adenovirus mediated GALNT4 overexpression enhanced monocytes adherence and chemotaxis. Furthermore, vicia villosa lectin (VVL) pull down and PSGL1 immunoprecipitation assays showed that GALNT4 overexpression increased VVL binding to PSGL-1 and P-selectin induce phosphorylation of Akt and mTOR. Conversely, knockdown of GALNT4 decreased VVL binding and attenuated the activity of Akt /mTOR. Additionally, mTOR inhibitor rapamycin blocked these effects of GALNT4 overexpression on monocytes.

Conclusion

Expression of GALNT4 was increased in patience with ACS, GALNT4 overexpression enhances the adherence and chemotaxis of monocytes via modifying O-glycosylation of PSGL-1 and activity Akt/mTOR pathway. These findings suggest that GALNT4 may be a potential therapeutic target for ACS.

Acknowledgement/Funding

The National Natural Science Foundation of China (No. 81100220 and No. 81770340)
P6305Activation of invariant natural killer T cells ameliorates doxorubicin-induced cardiomyopathy
Authors: Sada M , Matsushima S , Ikeda S , Okabe K , Ishikita A , Tadokoro T , Enzan N , Yamamoto T , Deguchi Y , Ikeda M , Ide T , Tsutsui H
Published: October 2019

Background

Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions, especially strongly upregulating interferon (IFN)-γ. Activation of iNKT cells have been previously reported to exert protective effects against post-infarcted cardiac remodeling and cardiac ischemia/reperfusion injury. However, the role of iNKT cells has not been determined in doxorubicin (DOX)-induced cardiomyopathy.

Purpose

The purpose of this study was to examine whether the activation of iNKT cells by α-galactosylceramide (αGC), which specifically activates iNKT cells, could affect DOX-induced cardiomyopathy, and if so, to elucidate its downstream target.

Methods

C57BL/6J mice were received the intraperitoneal injection of either αGC (0.1μg/g, n=11) or vehicle (n=13). After 1 week, these mice were treated with a low dose of DOX (18mg/kg via intravenous 3 injections over 1 week), and were followed during 14 days.

Results

DOX mice (DOX+vehicle) showed left ventricular (LV) dysfunction and dilatation, which were significantly ameliorated in DOX mice receiving αGC (DOX+αGC) (LV fractional shortening: 27.4±4.31 vs. 31.5±4.62%, p<0.05, LV end-diastolic diameter: 3.70±0.16 vs. 3.32±0.23mm, p<0.05), with no significant changes in arterial pressure, body weight, and food consumption, 14 days after DOX injection. DOX+vehicle demonstrated a significant decrease in myocardial gene expression of Vα14Jα18, a specific marker of iNKT cells, and IFN-γ compared with control mice. Vα14Jα18 expression levels were higher in DOX+αGC than DOX+vehicle by 9.2 folds (p<0.05). Consistent with this change, IFN-γ was higher in DOX+αGC than DOX+vehicle by 4.4 folds (p<0.05), whereas interleukin (IL)-1, IL-4, IL-6, IL-10, IL-17, IL-23, and tumor necrosis factor (TNF)-α were not altered in both groups. Phosphorylation of Akt, its active form, in the heart was significantly increased in DOX+αGC compared with DOX+vehicle by 1.8 folds (p<0.05).

Conclusions

Activation of iNKT cells by αGC play a protective role against DOX-induced cardiac dysfunction, which was associated with enhancing expression of IFN-γ and activating Akt. Therapies designed to activate iNKT cells might be beneficial to protect the heart from DOX injury.
P6306Hyperlipidemia inhibits the protective effect of lisinopril after myocardial infarction via activation of dendritic cells
Authors: Ma Y , Ma L , Ge J , Zou Y
Published: October 2019

Background

In clinical situation, patients with myocardial infarction (MI) usually suffered from hyperlipidemia, hypertension, renal dysfunction or diabetes as well and the interaction of those risk factors may affect the effectiveness of ACEI. Dendritic cell (DC) is a potent central immunoregulator that orchestrates various types of inflammatory cells in innate and adoptive immunity. The role of DCs in the inflammation of cardiovascular disease is a hotspot of international research.

Purpose

To investigate the improvement of cardiac remodeling and inflammatory immune response after MI via ACEI regulating DCs and explore that whether the protective effect of ACEI is under the circumstance of hyperlipidemia.

Methods

In vivo, MI mice models were created via coronary artery ligation. We detected the survival and left ventricular function on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were obtained and assessed for Ang2 concentration, inflammatory cytokines and DCs expression via immunohistochemistry, ELISA, flow cytometry and western blot. In vitro, we treated DCs with ox-LDL+AngIIfor 48 hours simulating the internal environment of MI in ApoE−/− mice to explore the mechanism involved in the DCs maturation and inflammation.

Results

Under the circumstance of hyperlipidemia, the cardioprotective effect of ACEI is attenuated through regulating DCs maturation and inflammation after MI, including survival rate (Figure 1) and left ventricular function. The number of DCs in cardiac tissue were increased in MI mice with hyperlipidemia (Figure 2), when compared with the WT group. The expression of the maturity phenotype related molecules, such as CD83, on the DCs in spleen were also increased in the ApoE−/− mice. Then, the expressions of inflammatory cytokines, such as IL-6 and TNF-α. In vitro, it was found that the immune maturation and inflammation of DCs could be further induced by ox-LDL on the basis of AngIItreatment, as indicated by the upregulation of CD83 and CD86, the expressions of cytokines and chemokines. Furthermore, ox-LDL could activate the toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88) signaling pathway, promoting the phosphorylation of interleukin-1 receptor associated kinase (IRAK)-4 and the nuclear transferring of nuclear factor-kappaB (NF-κB).

Conclusion

We proved ACEI reduces the recruitment of DCs to the infarct, leading to a higher survival rate and improved function and remodeling through decreased inflammation resulting from immune response after MI. However, this effect was inhibited under the circumstance of hyperlipidemia. TLR4-MyD88 signaling pathway might be the possible molecular mechanism involved in the immune maturation and inflammation of DCs induced by ox-LDL on the basis of AngII.

Acknowledgement/Funding

the Youth fund of the National Natural Science Foundation of China, Grant 81600280
P6311Is the new PH classification useful to assess the need for heart transplantation? Looking for harder markers for hard patients
Authors: Moretta A , Masetti M , Russo A , Dardi F , Palazzini M , Martin Suarez S , Galie' N , Potena L
Published: October 2019

Background

Pulmonary hypertension (PH) is an important prognostic marker among patients (pts) with heart failure. Recent ESC guidelines have introduced the concept of diastolic transpulmonary gradient (DPG) to differentiate combined (CpC) and isolated (IpC) post-capillary PH. However, its validation in a setting of patients evaluated for heart transplantation (HT) has been poorly explored; moreover, it doesn't incorporate right ventricular (RV) function.

Purpose

To analyze the prognostic role of current classification of PH and its interplay with RV function and diuretic therapy in pts with advanced heart failure referred for HT.

Methods

We included all pts evaluated for HT in our Center (2002–16) undergoing to a right heart cath (RHC), collecting data at first evaluation. Patients were divided into three groups: no PH (mPAP<25 mmHg), IpC-PH (mean PAP >25 mmHg, PVR<3 WU), CpC-PH (mean PAP>25 mmHg, PVR ≥3 WU and/or DPG ≥7 mmHg). Pulmonary artery pulsatility index (PAPi) was analyzed as a marker of RV function; oral furosemide>125 mg/day (median value) or i.v. diuretics/dialysis were considered as high-dose diuretics (HDD). The study endpoint was the combined incidence of death or need for high urgent HT, expressed as 2-yrs survival rate.

Results

Among the overall cohort of 458 pts (53.1±10.9 yrs, 82,6% males, 40.3% CAD, 9.3% on IABP), 57.9% had PH: 30.8% IpC-PH, 27.1% CpC-PH. Only 8 pts (0.2%) had DPG≥7, one with PVR<3. The use of HDD differed significantly according to PH classes (44.6% vs 56.3% vs 68.3%, no PH vs IpC vs CpC-PH respectively, p<0.01) and was associated with a worse outcome (p<0.01). The incidence of the primary endpoint in the overall cohort was 74.1±2.5%. While pts with CpC-PH had the worst prognosis, DPG≥7 did not predict the primary endpoint. At multivariate analysis, PVR ≥3 WU (HR: 16.7), PAPi <3.8 (median value, HR: 4.1), HDD (HR: 5.6) were independent predictors of the primary endpoint, (p<0.04 for all) as well as need for IABP (HR: 19.0, p<0.01), even adjusting for clinical variables. Lower PAPi values carried an higher risk at 2 years both in IpC and CpC PH groups, thus allowing to better stratify the need for urgent HT (81.6±6.6% vs 78.6±5.7% vs 67.3±6.7% vs 49.1±7.9% respectively, p<0.001) (Fig.1).

Figure 1

Conclusion

Our results suggest that, even if current definition of type 2 PH predicts the need of urgent HT, the incorporation of DPG ≥7 is epidemiologically irrelevant and doesn't increase accuracy, whereas combining an indirect marker of RV function (PAPi) with PVR assessment, even correcting for diuretic therapy, could help to better stratify the need of a rare resource like HT in patients with advanced heart failure and pulmonary hypertension.
P6315Effects of chronic heart failure unconventional therapies on endothelial function
Authors: Maloberti A , Piccinelli E , Zannoni J , Castelnuovo S , Vallerio P , Bassi I , Pansera G , Occhi L , Varrenti M , Masciocco G , Perna E , Cipriani M , Frigerio M , Giannattasio C
Published: October 2019

Introduction

Endothelial Dysfunction (ED) of peripheral arteries in Chronic Heart Failure (CHF) subjects has been demonstrated.

Purpose

We assessed endothelial function in subjects undergoing unconventional treatments for CHF, namely Heart Transplantation (HTX), continuous-flow Left Ventricular Assist Device implantation (LVAD), and repeated levosimendan infusions (r-LEVO).

Methods

Twenty HTX recipients (median time from HTX 21 months), 20 patients supported with LVAD (median time from implant 39 months), and 20 patients receiving monthly Levosimendan infusions (median time on treatment 28 months) were enrolled and compared to a group of 20 healthy subjects. ED was evaluated with ultrasound assessment of the diameter before and after ischemic stress at the brachial artery level. The difference between the two diameters normalized for the baseline value (Flow Mediated Dilation – FMD) has been used for the analysis. All the patients were stable at the time of FMD assessment, with those on r-LEVO being evaluated prior to infusion.

Results

FMD was significantly lower in HTX and LVAD groups with respect to controls (9.8±7.4, 9.3±5.7, and 15.6±6.4% respectively, p=0.01), but not in r-LEVO group (12.5±6.9%).

When patients were analyzed according to time from the operation or on treatment, (< versus > of the median value), no differences were seen in HTX and r-LEVO group, while in LVAD group FMD was borderline significantly higher in patients with longer follow-up (8.4±6.4% versus 10.2±5.2%, p=0.05).

Conclusions

Based on this preliminary data we can inference the following: 1- FMD is abnormal in HTX recipients, despite their good functional status, probably due to factors unrelated to CHF (e.g. hypertension, renal insufficiency, denervation, and drug effects); 2- LVAD patients also show ED, with possible better adaptation in very long-term survivors; 3- Near-normal FMD values in CHF patients who remain stable with r-LEVO suggest that pulsed treatment may obtain favorable effects at peripheral level, persisting after clearance of the drug and its metabolites.

Acknowledgement/Funding

None
P6331Influence of dynapenia and obesity on prognoses of elderly heart failure patients
Authors: Uchida S , Kamiya K , Hamazaki N , Matsuzawa R , Nozaki K , Ichikawa T , Nakamura T , Yamashita M , Kootaka Y , Maekawa E , Yamaoka-Tojo M , Matsunaga A , Masuda T , Ako J
Published: October 2019

Background

In elderly people, a decline in activities of daily living is more closely associated with low muscle strength (dynapenia) than with low muscle mass. Moreover, the combination of low muscle strength and obesity (dynapenic obesity) is associated with a higher risk of mortality than dynapenia or obesity alone, but its influence on prognosis is still unknown in elderly heart failure (HF) patients. To clarify these relationships may contribute to the development of rehabilitation programs for elderly HF patients and the improvement their prognoses in the future.

Purpose

We aimed to investigate the influence of dynapenia and obesity on prognoses of elderly HF patients.

Methods

We evaluated 1006 elderly HF patients aged ≥65 years (76.5±6.9 years, 579 males) who were admitted to our hospital and participated in an inpatient cardiac rehabilitation program. We assessed patients' characteristics, including body mass index (BMI) and handgrip strength during hospitalization. Patients with low handgrip strength (<26 kg and <18 kg in males and females, respectively) and high BMI (≥25 kg/m2) were considered to have dynapenia and obesity, respectively. Moreover, patients fulfilling the above two criteria (dynapenia, obesity) were considered to have dynapenic obesity. Patients were divided into four groups: normal, dynapenia only, obesity only, and dynapenic obesity. We compared survival rates among the four groups using the Kaplan-Meier method and log-rank test. To identify predictors for all-cause mortality, we performed Cox regression analysis.

Results

During the 8-year follow-up period, 228 patients (21.2%) died. Eight-year cumulative incidences of mortality were 35.4%, 26.0%, 62.6%, and 33.1% in the normal, obesity only, dynapenia only, and dynapenic obesity groups, respectively. Significantly lower survival rates were observed in the dynapenia only group than in the other 3 groups (log-rank: 28.893, P<0.001). Cox regression analysis, after adjusting for age and sex, showed significantly poor prognosis in the dyanapenia only group than in the other 3 groups (normal group, hazard ratio [HR] = 0.684, 95% confidence interval [CI] = 0.488–0.959, P=0.028; obesity only group, HR = 0.330, 95% CI = 0.182–0.598, P<0.001; dynapenic obesity group, HR = 0.390, 95% CI = 0.206–0.739, P=0.004).

Conclusion

Elderly HF patients with dynapenia alone had poor prognoses. Obesity may have protective effects on the survival of dynapenia patients with HF.
P6335The impact of patient's adherence to maintenance of euvolaemia on all-cause mortality and heart failure re-hospitalization: insights from the Optimize Heart Failure Care Program
Authors: Lopatin Y , Grebennikova A , Pagava Z , Berkinbayev S , Glezer M , Rakisheva A , Abdullaev A , Kurlyanskaya A , Dadashova G , Voronkov L , Chesnikova A , Tarlovskaya E , Sisakian H , Koziolova N , Hayrapetyan H
Published: October 2019

Background

Four recommended self-care behaviors (low salt diet, avoidance of excessive fluid intake, weight control, and flexible diuretic regimen) play an important role in the management of heart failure (HF) patients. However, little is known about the impact of patients' adherence to these self-care behaviors on prognosis and rate of HF re-hospitalizations. The aim of our study was to analyze the impact of HF patients' adherence to maintenance of euvolaemia on all-cause mortality and HF re-hospitalizations.

Methods

The analysis included data from the international prospective multicenter Optimize Heart Failure Care Program which was collected over 12 months from 628 patients (mean age 62.6±12.3 years, 70% male) hospitalized with decompensated HF, NYHA II-IV (mean 2.7±0.6), mean left ventricular ejection fraction 33.8±9.4%. The underlying etiology of HF was ischemic in 64% of cases. Before discharge from the hospital all HF patients were educated in self-care skills to maintain the euvolaemia. To assess patients' adherence to low salt diet, avoidance of excessive fluid intake, weight control and flexible diuretic regimen, an indirect method (patient-reported compliance, which was measured using a special questionnaire) was used. Three types of adherence were determined: good (patients always maintained euvolaemia), moderate (patients sometimes maintained euvolaemia) and poor adherence (patients did not maintain euvolaemia).

Results

After discharge from the hospital the overall adherence rates were 66.4% for low sodium diet, 58% for fluid intake, 69.9% for weight control, and 87.2% for the flexible diuretic regimen. However, the adherence to diet and the flexible diuretic regimen significantly decreased (p<0.01) by the 12 months of follow-up. Good, moderate and poor adherence to maintain euvolaemia were noted in 40%, 31.5% and 28.5% patients, respectively. After 12 months of follow-up all-cause mortality and rate of HF re-hospitalizations and were significantly lower in the group of good patients' adherence in comparison with moderate and poor patients' adherence (HR 0.72, 95% CI 0.61–0.84, p<0.0001) (Figure).

Conclusion

Less than half of HF patients demonstrated good adherence to the guideline-recommended control of euvolaemia. The rates of all-cause mortality and HF re-hospitalizations in the group of good patient's adherence were significantly lower compared with the groups of moderate and poor adherence to maintenance of euvolaemia. Constant efforts to promote the maintenance of euvolaemia in HF patients are needed.
P6336Plasma proteomic profile predicts survival in heart failure with reduced ejection fraction
Authors: Gui H , She R C , Li J , Sabbah H , Williams L K , Lanfear D
Published: October 2019

Background

Whether the plasma proteome can predict the course of heart failure (HF) and has incremental value to established predictors is uncertain.

Methods

Patients meeting Framingham HF criteria with history of reduced ejection fraction (n=1017) were prospectively enrolled in a registry and donated fasting blood samples. Plasma underwent analysis on the SOMAscan proteomic discovery platform, quantifying 4789 proteins using standard assay and quality controls. Patients were randomly divided into derivation (n=681) and validation (n=336) cohorts. We derived a proteomic risk score (PRS) in the derivation cohort using Lasso-penalized Cox regression and then tested it in the validation cohort. Both models were adjusted for an establish HF clinical risk score (MAGGIC) and NTproBNP. We assessed risk stratification improvement in the validation cohort by comparing models with and without PRS using the model C statistic, continuous net reclassification index (NRI), integrated discrimination index (IDI), and the median improvement in risk score (MIRS).

Results

Overall 47.5% of patients were African American, 35.2% were female, mean ejection fraction was 34.8%, and average age was 67.9 years. After median follow-up of 3.6 years, there were 296 deaths (194 in derivation and 102 in validation). Optimized modeling defined a 32 protein PRS (hazard ratio [HR] 2.33, p<2.00E-16) which was also statistically significant when tested in the validation cohort (PRS HR=1.19, p=4.87E-02) and showed some improvement in risk stratification (Table).

Methods Variables Estimate 95% CI P Validation Testing MAGGIC 1.06 1.027, 1.092 2.84E-04 NTproBNP 1.84 1.430, 2.359 1.88E-06 PRS 1.19 1.001, 1.408 4.87E-02 Risk Stratification Assessment C-statistic improvement 0.012 −0.076, 0.101 8.30E-01 IDI 0.034 0.007, 0.095 <2.00E-16 Continuous-NRI 0.286 −0.062, 0.475 9.00E-02 Median Improvement in Risk Score 0.015 0.001, 0.078 2.00E-02

Conclusion

A plasma multi-protein predictive score can improve risk stratification in HF patients on top of a validated clinical score and NTproBNP. Additional investigation is warranted to define mechanisms underlying individual proteins and explore proteomic clinical applications.
P6340Mortality and prognostic factors in dilated cardiomyopathy versus ischaemic heart disease in patients with heart failure with reduced ejection fraction - a Swedish population-based study
Authors: Silverdal J , Bollano E , Sjoland H , Pivodic A , Dahlstrom U , Fu M
Published: October 2019

Background

In heart failure with left ventricular ejection fraction reduction <40% (HFrEF) the increased mortality in patients with underlying ischaemic heart disease (IHD) compared to multi-aetiological non-ischaemic HFrEF is established. The prognostic difference over time in comparison with dilated cardiomyopathy (DCM) is less clear.

Purpose

To evaluate the difference in mortality between IHD and DCM in HFrEF, overall, in specific subgroups and over time.

Methods

By applying multivariable Cox regression analyses on Swedish Heart Failure Registry data from the years 2000 to 2012 (including 51,060 patients), the incidence of mortality in 8,982 patients with non-valvular clinical IHD-HFrEF was compared to 2,220 patients with DCM-HFrEF overall and for subgrouping variables of age category, sex and EF group (<30% and 30–39%), adjusted for additional 23 baseline variables.

Results

The overall mortality was higher in IHD-HFrEF with the crude mortality of 42.1% and the event rate 15.4 (95% confidence interval [CI]: 14.9 - 15.9) per 100 person years compared with 19.4% and 5.5 (95% CI: 5.0–6.1) in DCM-HFrEF. The probability of survival in IHD-HFrEF was lower than in DCM-HFrEF (Figure). After multivariable adjustment the risk for mortality in IHD-HFrEF remained increased with a hazard ratio (HR) of 1.34 (95% CI: 1.18–1.50). The adjusted HR was higher in all groups of age <80 years and in both sexes, with a significantly higher risk in women than in men (HR 1.85 vs 1.22, p for interaction = 0.002). Overall, HR was increased regardless of EF group but analyses by both age group and EF group revealed significantly increased mortality in EF <30% only for age groups <80 years. No significant temporal trend was seen between IHD-HFrEF and DCM-HFrEF.

Probability of survival

Conclusions

In patients with heart failure and reduced ejection fraction, ischaemic heart disease compared to dilated cardiomyopathy was associated with increased mortality in all age groups below 80 years of age, throughout the 13-year study period.

Acknowledgement/Funding

The Swedish Heart-Lung Foundation. The regional ALF agreement between Västra Götalandsregionen and University of Gothenburg (ALFGBG-72196, prof.Fu)
P6365Contrasting the impact of the European (ESC/ESH 2018) versus American (ACC/AHA 2017) high blood pressure clinical practice guidelines in Poland
Authors: Wyszomirski A , Pencina M J , Whelton P K , Wojtyniak B , Gaciong Z , Bandosz P , Zieleniewicz P , Zdrojewski T
Published: October 2019

Background

The 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines for the management of arterial hypertension and the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the prevention, detection, evaluation, and management of high blood pressure in adults differ in approach to defining stages of hypertension and recommendations for treatment of high blood pressure.

Purpose

To contrast the implications of the ESC/ESH versus ACC/AHA hypertension guidelines among the general population in Poland – a country representing a high CVD risk region in Europe.

Methods

We used data from a representative random sample of 1439 Polish adults aged 40 to 79 from the research program NATPOL 2011. The analysis was weighted in order to reflect the structure of the population in Poland and was stratified by age and gender. We applied the ESC/ESH 10-year SCORE (Systematic COronary Risk Evaluation) and the ACC/AHA ASCVD (atherosclerotic CV disease) risk assessment tools and followed guideline-specific algorithms to detect hypertension and follow recommendations for treatment.

Results

The overall prevalence of hypertension among Polish adults according to the ACC/AHA guideline was 76.9% (95% CI, 74.7–79.0%) versus 51.8% (95% CI, 49.2–54.4%) according to the ESC/ESH guidelines. Application of the ACC/AHA guideline recommendations would result in antihypertensive drug treatment for 63.0% (95% CI, 60.5–65.5%) of Polish adults compared with 46.2% (95% CI, 43.6–48.7%) based on application of the ESC/ESH guidelines (difference 16.8% (95% CI, 14.9–18.8%), table 1).

Table 1 2017 ACC/AHA guideline 2018 ESC/ESH guideline Δ (difference) Hypertension Recommended treatment Hypertension Recommended treatment Hypertension Recommended treatment % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) Age   40–49 (n=391) 63.2 (58.4–68.0) 37.3 (32.6–42.1) 32.0 (27.4–36.6) 21.2 (17.2–25.3) 31.2 (26.6–35.8) 16.1 (12.5–19.8)   50–59 (n=452) 77.7 (73.8–81.5) 61.7 (57.2–66.2) 49.1 (44.5–53.7) 40.0 (35.5–44.6) 28.5 (24.4–32.7) 21.7 (17.9–25.5)   60–69 (n=356) 82.3 (78.3–86.3) 75.3 (70.8–79.8) 62.4 (57.3–67.4) 61.5 (56.5–66.6) 19.9 (15.8–24.1) 13.8 (10.2–17.3)   70–79 (n=231) 90.0 (86.2–93.9) 90.0 (86.2–93.9) 74.5 (68.8–80.1) 76.6 (71.2–82.1) 15.6 (10.9–20.3) 13.4 (9.0–17.8) Gender   Male (n=689) 80.4 (77.4–83.4) 67.5 (64.0–71.0) 52.5 (48.8–56.3) 47.2 (43.4–50.9) 27.9 (24.5–31.2) 20.3 (17.3–23.3)   Female (n=741) 73.6 (70.4–76.7) 58.8 (55.3–62.4) 51.2 (47.6–54.8) 45.2 (41.6–48.8) 22.4 (19.4–25.4) 13.6 (11.2–16.1)

Conclusions

Application of the ACC/AHA guideline would result in a considerable increase in the prevalence and antihypertensive drug treatment of hypertension in Polish adults compared with application of the ESC/ESH guidelines.
P6389Infection and type 2 myocardial infarction: a large observational study from emergency department
Authors: Putot A , Buet-Derrida S , Avondo A , Ray P , Maza M , Zeller M , Cottin Y
Published: October 2019

Background

Troponin elevation is frequent in patients with acute infection (AI) admitted to emergency unit (EU). Acute infection (AI) has been suggested as a common trigger in type 2 myocardial infarction (T2MI), corresponding to a myocardial oxygen supply-demand mismatch without atherothrombosis. We aim to characterize risk factors of T2MI occurrence and in-hospital mortality among patients admitted to an EU with AI and elevated troponin.

Methods

Among the medical records of all the patients admitted from January 2014 to December 2016 in a university hospital EU (n=82 543), patients with a diagnosis of AI and elevated troponin Ic (≥0.10μg/L) (n=714) were systematically adjudicated as T2MI in the presence of symptoms or signs of myocardial ischemia (typical chest pain and/or ECG changes).

Results

Among the 714 patients included (aged 85, 50% male), 185 (26%) were classified as T2MI, of whom infection site was pulmonary tract (n=111), urinary tract (n=27), skin (n=15), digestive tract (n=9) or other or indefinite site (n=23). By multivariate analysis, a history of chronic obstructive pulmonary disease (COPD) (OR (95% CI): 0.53 (0.30–0.96)), high temperature (OR: 0.86 (0.74–0.99) per °C) and elevated creatinine (0R 0.998 (0.996–1.000) per μmol/L) were associated with a lower risk of T2MI, whereas age, site of infection, C-reactive protein and troponin rates were not predictors of T2MI. Death rate was similar among patients with or without T2MI (21 vs 23%, p=0.6). In contrast, age, troponine, creatinine or C-reactive protein elevations were independent co-variates associated with mortality.

Conclusions

Our large real-life study shows that in patients admitted to an EU with AI and troponin elevation, T2MI is a common feature, in the absence of temperature elevation, renal insufficiency or history of COPD. In such patients, inflammatory and cardiac biomarkers levels were independently associated with early mortality.
P6415Combined assessment of contrast-enhanced ultrasound of carotid plaque and carotid intima-media thickness improves the prediction of future coronary events in patients with coronary artery disease
Authors: Deyama J , Nakamura T , Ono S , Kobayashi A , Horikoshi T , Yoshizaki T , Watanabe Y , Uematsu M , Kobayashi T , Fujioka D , Saito Y , Nakamura K , Kawabata K , Obata J , Kugiyama K
Published: October 2019

Background

This study examined whether combined ultrasound assessment of plaque size and intraplaque neovascularization in the carotid artery had an additive effect for predicting coronary events in patients with coronary artery disease (CAD).

Methods

CEUS of the carotid plaques using perfluorobutane microbubbles as an ultrasound contrast agent and Ultrasound assessment of carotid plaque maximum intima-media thickness (max IMT) was performed in 221 patients with CAD and carotid plaque IMT over 2mm. Intraplaque neovascularization was identified on the basis of microbubbles within the carotid plaque and graded as: G0, not visible; G1, moderate; or G2, extensive microbubbles. All study patients were followed up prospectively for 5 years or until the occurrence of a cardio-vascular event.

Result

During the follow-up period, 53 coronary events (9 cardiac deaths, 44 ACSs) were occurred. Multivariate Cox hazards analysis showed that max IMT and CEUS grade were independent predictors of coronary events (HR 1.59, 95% CI 1.15–2.21 p=0.005 and HR 2.26, 95% CI 1.52–3.36 p<0.01) that were independent of age, gender, diabetes and LDL-C levels. C-statistics for logistic models predicting future coronary events using conventional risk factors with or without the addition of max IMT alone, CEUS grade alone, and both max IMT and CEUS grade in combination (area under the ROC curve; 0.55,0.61,0.69 and 0.71, respectively). The addition of the plaque enhanced intensity to traditional risk factors resulted in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.42, p=0.002; and IDI 0.04, p=0.002).

CEUS grade and ROC curve for 3models

Conclusions

Combined ultrasound assessment of carotid plaque IMT and intraplaque neovascularization has an additive value on the prediction of coronary events.
P6434Evaluation of the nociceptive flexor reflex, as a new method for the diagnosis of microvascular angina
Authors: Petrova V B , Boldueva S A , Leonova I A , Petrova A B
Published: October 2019

The purpose of this study was to study the diagnostic value of the nociceptive flexor reflex (NFR) method in patients with microvascular angina.

Materials and methods

The study included 49 patients with MVA (main group), 40 patients with classical angina II-III f.c. (comparison group 1), 42 patients with silent myocardial ischemia (comparison group 2) and 32 healthy volunteers (control group). Criteria for inclusion in the group with MVA: chest pain, positive stress test, unchanged coronary arteries according to coronary angiography, the presence of myocardial perfusion disturbance and reduction of the coronary reserve according to positiron-emission tomography of the myocardium at rest, with adenosine and cold one test. Chest pain syndrome was observed in all 49 patients. All subjects studied the functional activity of nociceptive and antinociceptive systems using the nociceptive flexor reflex method on the equipment of expert class electromyography system, the pain threshold (Pb) values, the reflex threshold (Pr) were calculated and the ratio of pain and reflex threshold was calculated to calculate the pain threshold / threshold reflex (Pb/Pr), which in healthy people is about 0.9–1.0.

Results and discussion

In te study of NFR in patients with MVA in the group as a whole, a decrease in the pain threshold, reflex threshold and Pb/Pr ratio compared with normal values were found. The pain threshold in patients in the group was lower (statistically significantly) when compared with the group 1, the group 2 and the control group (p<0.0001; p<0.0001; p<0.0001, respectively). The reflex threshold in patients of the MCC group was also significantly lower when compared with the group 1, the group 2 and the control group (p<0.001; p<0.0001; p<0.001, respectively). Due to the fact that the low pain threshold was found in 84.4% of the examined patients with MVA who had microvascular dysfunction according to positron-emission tomography, we evaluated the prognostic value of the NFR method for diagnosing the disease. To do this, an assessment was made of the odds ratio (OR) of identifying MVA in groups of patients with different levels of index K (the ratio of the pain threshold value to the reflex threshold value). We have chosen the value of index K with the highest specificity and high sensitivity equal to 0.8892.

Based on the data obtained, the diagnostic value of the NFR method was calculated during the verification of the MVA. When conducting a mathematical analysis, it was found that this technique has high sensitivity (84.4%), specificity (95.12%), positive (90.48%) and negative predictive value (91.76%). We have not found information in the literature on the use of the NFR assessment method and its diagnostic value in MVA.

Findings

Due to the high diagnostic value of determining the NFR, we propose to include this method in the MVA diagnostic algorithm as an additional one.
P6435A diagnostic prediction model of coronary artery disease in patient with chest pain using machine learning
Authors: Rha S W , Choi B G , Choi S Y , Byun J K , Cha J A , Park T S
Published: October 2019

Background

Chest pain is a major symptom of coronary artery disease (CAD), which can lead to acute coronary syndrome and sudden cardiac death. Accurate diagnosis of CAD in patients who experience chest pain is crucial to provide appropriate treatment and optimize clinical outcomes.

Objective

This study was to develop a machine learning model which can predict and diagnose CAD in patients complaining of chest pain based on a large real-world prospective registry database and computing power.

Method

A total of 10,177 subjects with typical or atypical chest pain who underwent a coronary angiography at the cardiovascular center of our University Hospital, South Korea between November 2004 and May 2014 were evaluated in this study. The generation of the diagnostic prediction model for CAD used the classification application by technical support of MATLAB R2017a. The performance evaluation of the learning model generated by machine learning was evaluated by the area under the curve (AUC) of the receiver-operating characteristic (ROC) analysis.

Results

The diagnostic prediction model of CAD had been generated according to the user's accessibility such as the general public or clinician (Model 1–4). The performance of the models has ranged from 0.78 to 0.96 by the AUC of ROC analysis. The prediction accuracy of the models ranged from 70.4% to 88.9%. The performance of the diagnostic prediction model of CAD by machine learning improved as the input information increased.

Figure 1. Study Flow Chart

Conclusion

A diagnostic prediction model of CAD using the machine learning method and the registry database was developed. Further studies are needed to verify our results.
P6444Cardiovascular secondary prevention setting and lipid controlu, update data from PINNACLE BRAZIL REGISTRY
Authors: Saraiva J F K , Cordeiro Mattos A , Saraiva G B F , Pinto I M , Rombaldi A R , Kato N H , Gomes Da Silva L F , Minelli C , Carvalho I T N , Dantas J M M , De Souza Filho J M , Figuinha F C R , Segre C A W , Fonseca H A R , Avezum A
Published: October 2019

Introduction

Lipid control is highly effective and improves clinical outcomes in coronary artery disease (CAD) patients, thus is one of the pillars of the cardiovascular secondary prevention.

Purpose

The aim of this preliminary analysis was to describe the lipid management in CAD patients in Brazil after one year of the clinical practice registry.

Methods

Patients with documented CAD were included by using electronic case report form based on the ACC PINNACLE Registry. The registry has been enrolling patients from general practitioners and specialists. Patients data were evaluated after 01 year of follow-up on regular clinical appointments and the differences on clinical practice were evaluated

Results

Currently, PINNACLE-Brazil enrolled individuals, with 2234 (29.4%) patients with CAD. Prescription of statin therapy was identified in 85.6% baseline and 78.3% follow-up. CAD patients with LDL-c <100 mg/dL were 47.3% baseline and 38.5% follow-up and at least one lipid profile assessment occurred in 60.9% baseline and 51.2% follow-up. CAD patients who have an LDL-c result <100 mg/dL, or >100 mg/dL with a documented plan to achieve LDL-c <100 mg/dL, were 48.1% (baseline) and 38.5% (follow-up).

Conclusion

The preliminary results of PINNACLE-Brazil show that, despite the relatively high prescription rate of statin therapy, LDL-c targeted level for CVD secondary prevention has not been achieved in the majority of patients after 01 year of follow-up. Nationwide knowledge translation initiatives are needed to improve the CVD burden in Brazil

Acknowledgement/Funding

ACC Foundation
P6450Plasminogen activator inhibitor type-1 (PAI-1) expression relates to the presence of myocardial inflammation in patients with nonischemic cardiomyopathy
Authors: Escher F , Agirbasli M , Lassner D , Aleshcheva G , Schultheiss H P
Published: October 2019

Background

Plasminogen activator inhibitor type-1 (PAI-1) is an important inhibitor of the fibrinolytic pathway and an acute phase reactant in response to inflammatory cytokines, resulting in thrombosis, arteriosclerosis, and tissue fibrosis. It has been identified as a potential biomarker for coronary artery disease and metabolic syndrom. However, so far, nothing is known about its importance in nonischemic cardiomyopathy.

Aims

To analyzed PAI-1 expression in patients with different forms of cardiomyopathies and evaluate possible influence of PAI-1-dependent pathomechanisms in patients with intramyocardial inflammation.

Methods and results

In this study, endomyocardial biopsies (EMBs) from 309 patients (mean age 48.0±13.9 years) with different forms of cardiomyopathies were enrolled, including 123 patients with dilated cardiomyopathy (DCM) (mean LVEF 28.01±9.06%) and 186 patients with EMB-proven virus-negative inflammatory cardiomyopathy (DCMi) (mean LVEF 31.76±14.14%). 10 patients (mean LVEF 60.50±4.76%) without viral or inflammation in EMB served as controls. Hemodynamic parameters were measured by catheterization and echocardiography. EMBs were performed at first admission after exclusion of ischemic of valvular heart disease. In EMBs PAI-1 was assessed by immunohistology including digital imaging analysis. PAI-1 expression was significantly higher in patients with DCMi in contrast to DCM patients and controls (0.517±2.20 vs. 0.187±0.598 vs. 0.023±0.032% Area Fraction; p=0.0002). PAI-expression correlates significantly with lymphocytic infiltrates (for CD3 r=0.56, p<0.0001, and LFA-1 r=0.59, p<0.0001). This was found to be independent of hemodynamic parameters, and age.

Conclusion

Myocardial inflammation is associated with a significant increase in PAI-1 expression in DCMi independently of the hemodynamic conditions. This new pathophysiological axis could be a potiential therapeutic target in future treatment stategies in DCMi.