bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of achieving the minimum clinically important difference for the Incremental Shuttle Walk Test in a cardiac rehabilitation population
Authors: Alotaibi J , Doherty P , Doherty P
Published: November 2020

The primary aim of this study was to identify the determinants of achieving the minimum clinically important difference (MCID) for the Incremental Shuttle Walk Test (ISWT) in the CR population. The secondary aim was to examine whether achieving MCID in ISWT at the end of the CR programme is associated with the likelihood of patients meeting the physical activity recommendation or whether it is associated with the patients' self-reported physical fitness (Dartmouth COOP tool) at the end of the CR programmme.

Method

Routine clinical data related to patients who undertook ISWT as a pre- and post-CR functional capacity assessment were taken from National Audit of Cardiac Rehabilitation (NACR) during the 2013 to 2016 and retrospectively analysed. A sub-analysis was conducted to address the secondary aim. Logistic regression approaches, taking account of potential confounders were constructed.

Results

For the main study, data from 9,786 patients (mean age of 63.9±10.7), 77.5% of whom were male, were analysed. Sixteen determinants for achieving the MCID for ISWT in CR patients were identified. A sub-analysis was also conducted on 7,950 to address the secondary aim. Patients who achieved the MCID were 30% more likely to meet the physical activity recommendation and 60% more likely to rate themselves positively on the self-reported physical fitness Dartmouth COOP scale.

Funding Acknowledgement

Type of funding source: None
Age, sex and underlying heart rate as determinants of nocturnal heart rate variability among wearable smart ring users
Authors: Kentta T.V , Karsikas M , Rantanen A , Kinnunen H , Koskimaki H
Published: November 2020

Background

Heart rate variability (HRV) is an important marker of overall health and especially cardiovascular health. Decreased HRV has been associated with reduced vagal control of heart rate and with adverse outcome in several studies.

Purpose

The purpose of this study was to investigate the impact of demographic factors (age and sex) and underlying heart rate on nocturnal HRV among wearable smart ring users.

Methods

De-identified data was gathered from 104,431 wearable smart ring users over the course of one week (640,911 nights; 65% men and 35% women; age 42.6±12.1 years). Inclusion criteria included self-reported age of ≥20 years and sleep duration ≥4 hours. The ring estimates heart rate and HRV with photoplethysmographic (PPG) sensors and calculates the root mean square of successive differences (rMSSD) between adjacent inter-beat-intervals (IBI) for 5-minute segments throughout each night. The average HRV in these segments was then taken to represent the cardiac parasympathetic activity among each user. In addition, rate-corrected HRV was calculated by dividing the rMSSD value with mean IBI (crMSSD = 100 * rMSSD/IBI).

Results

Nocturnal HRV was significantly dependent on age and underlying heart rate (Figure). The observed rMSSD values declined with age (P<0.001) in both men and women. Concomitant decrease in rMSSD was observed with increasing heart rate in each age group (P<0.001). Statistically significant sex-related differences were observed in HRV. Men had higher crMSSD during the early decades of life (<40 years) than women. This difference diminished with age and women ≥50 years had higher crMSSD than their male coevals. The average resting heart rate decreased with age and was lower among men throughout the age groups (P<0.001).

Conclusions

Normal aging is associated with reduced cardiac vagal modulation and is reflected as decreased nocturnal HRV values among male and female wearable smart ring users. The underlying heart rate is a significant factor for the degree of HRV throughout life. In this population, the sex-related differences observed during the early decades of life diminish on the verge of midlife and are reversed later in life with women showing higher HRV during and after midlife.

Effects of age and HR on HRV

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): Oura Health Ltd
Heart failure patients' adherence to hybrid comprehensive telerehabilitation and its impact on prognosis based on data from TELEREH-HF randomized clinical trial
Authors: Piotrowicz E , Pencina M , Opolski G , Zareba W , Banach M , Kowalik I , Orzechowski P , Szalewska D , Pluta S , Irzmanski R , Glowczynska R , Kalarus Z , Piotrowicz R
Published: November 2020

Background

Adherence to treatment guidelines in heart failure (HF) patients (pts) is of major prognostic importance, but thorough implementation of guidelines in routine care remains insufficient. Introducing hybrid comprehensive telerehabilitation (HCTR) consisting of telecare, telerehabilitation and remote monitoring of implantable devices might be an option to improve adherence to recommendation and can affect the prognosis. Purpose to investigate the association of adherence to HCTR with mortality and hospitalization. Methods The present analysis formed part of TELEREH-HF multicenter, randomized trial that enrolled 850 HF pts (NYHA I-III,LVEF≤40%). Patients were randomized 1:1 to HCTR plus usual care or usual care only and followed up for 14 to 26 months. During the first 9 weeks, pts underwent either an HCTR (1 week in hospital and 8 weeks at home) or usual care. This analysis focuses on pts randomized to HCTR. Adherent pts were those who adhered both to the number of training sessions prescribed and to the duration of the prescribed cycle by at least80%; non-adherent pts, were those who adhered<20% to the prescribed number of training sessions and their duration. The remaining pts were classified as partially adherent.

Results

There were 350 (88.4%) adherent pts, 39 (9.8%) partially adherent pts and 7 (1.8%) non-adherent pts. There were 54 deaths during follow-up in the HCTR arm. Non-adherence or partial adherence was associated with statistically significantly higher risk of cardiovascular (CV) mortality (hazard ratio (HR) = 2.62, p=0.021); all-cause mortality or HF hospitalization (HR=1.71, p=0.038); CV mortality or HF hospitalization (HR=1.89, p=0.014).

Conclusion

The adherence to HCTR was very high. Adherence to HCTR was associated with improved prognosis for CV mortality.

Kaplan-Meier Probability of CV Mortality

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Centre for Research and Development, Warsaw, Poland
Artificial intelligence-based analysis of payment system data can predict one-year mortality of hospitalized patients with heart failure
Authors: Tohyama T , Funakoshi K , Kaku H , Enzan N , Ikeda M , Matsushima S , Ide T , Todaka K , Tsutsui H
Published: November 2020

Background

Individual risk stratification is fundamental in the care of heart failure (HF) patients. However, the prediction performance of risk scores, such as MAGGIC and SHFM, is not adequate and, more importantly, they need additional predictors including various biomarkers, imaging data, and environmental factors. Data from a case-mix payment system including diagnosis and procedures with outcomes can be used to develop the risk prediction models, allowing the use of big data for a more accurate prediction of mortality.

Purpose

This study aimed to develop artificial intelligence (AI) models for predicting 1-year mortality in patients hospitalized due to HF.

Methods

We analyzed the data from 10175 patients enrolled in the Japanese Registry Of Acute Decompensated Heart Failure (JROADHF). Candidate variables included the data obtained from a payment system introduced by the Japanese government, the Diagnosis Procedure Combination (DPC), which included each patient profile (age, sex, height, weight), principal diagnosis for hospitalization, comorbidities, procedures, length of hospital stay, and discharge status. They did not include clinical data available from patients such as vital status, laboratory data including bio-makers, electrocardiographic and echocardiographic data. The collected data were divided into the training set and the validation set (80%: 20%). With the training set, 5 AI models (logistic regression, random forest, support vector machine, neural network, and ensemble classifier) learned the one-year mortality results. AI models were evaluated by using the validation set with ROC analysis. The training and validation steps were repeated 10 times with different seed values to calculate the C-statistic of each model. We also identified the predictors for one-year prognosis acquired from the AI models.

Results

At 1-year of follow-up, a total of 1727 patients had died (17%). Among the machine learning models, the ensemble classifier showed the highest C-statistic of 0.76 (95% confidence interval: 0.75 to 0.77) for predicting mortality. Top predictors acquired from the random forest classifier was ADL (Barthel Index) at discharge, age, body mass index, and length of hospital stay.

Conclusion

By using AI-based analysis of a national case-mix payment system data, the present risk stratification model could predict the one-year mortality of hospitalized HF patients without any quantitative laboratory and physiological data. Furthermore, the present results could emphasize the advantage of this approach using the claim-based data that are routinely collected in a usual daily practice with no need to collect any additional information.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): Japan Agency for Medical Research and Development
HartWacht telemonitoring effectively reduces blood pressure in a real-life setting
Authors: Abeln B.G.S , Blok S , Van Den Born B.J , Somsen G.A , Tulevski I.I , Winter M.M
Published: November 2020

Introduction

Telemedicine platforms have the potential to reduce costs and improve outcomes in blood pressure reduction. Although results in the literature are promising, evidence remains limited and few home monitoring programs have successfully been integrated into daily clinical practice. The HartWacht home monitoring program is set-up for remote monitoring and treatment of patients with therapy resistant hypertension (systolic blood pressure>140 mmHg and >1 antihypertensive drugs). HartWacht is fully integrated into clinical care and is reimbursed by the majority of Dutch healthcare insurers.

Purpose

The purpose of this study is to evaluate the effectiveness of the HartWacht program in blood pressure treatment in a real-life setting, and evaluate the number of interventions necessary to reach normotension.

Methods

In this single center retrospective cohort study, we included all patients with therapy resistant hypertension that were included in the HartWacht program by their treating physician. At baseline, all patients measure blood pressure twice a day for the duration of one week, after which blood pressure measurements were performed once a week. Two pre-set alarms informed a team of designate nurses if blood pressures exceeded 140/90 mmHg (orange alarm) or 180/110 mmHg (red alarm). After one red or two successive orange alarms, the patient was contacted by telephone for guideline driven lifestyle advice or medication adjustment in consultation with a cardiologist. After every intervention, a blanking period of four weeks was set in which no orange alarms were visible.

Results

The cohort consisted of 161 patients (mean age 63±9.8 years; 54% male). The median follow up time was 318 days. At baseline, the mean blood pressure was 155/91 mmHg. During follow-up mean blood pressure decreased significantly to 134/83 mmHg (p<0.001 for both systolic and diastolic blood pressure). At follow up, 102 (62%) patients were normotensive. During follow up participants received a mean of 0.46 lifestyle advices and 0.74 medication changes in 1.07 consultations.

Conclusion

Home monitoring and treatment of patients therapy resistant hypertension with HartWacht resulted in a significant overall reduction of blood pressure, with >60% of patients being normotensive at last follow-up.

Normotension in HartWacht patients

Funding Acknowledgement

Type of funding source: None
Accurate detection of atrial fibrillation using a smartphone remains uncertain: a systematic review and meta-analysis
Authors: Gill S , Sartini C , Uh H.W , Ghoreishi N , Cardoso V , Bunting K.V , Gkoutos G , Suzart-Woischnik K , Asselbergs F.W , Eijkemans M.J.C , Kotecha D
Published: November 2020

Introduction

Early diagnosis of atrial fibrillation (AF) is essential to reduce complications such as stroke, and improve patient quality of life. Novel screening techniques using smartphone camera photoplethysmography (PPG) can be used for AF detection, but their clinical applicability remains unclear.

Purpose

To assess the diagnostic accuracy of smartphone PPG compared to conventional ECG for AF detection.

Methods

We performed a systematic review of MEDLINE, EMBASE, Cochrane library, and other databases (1980-October 2019), including any study or abstract where smartphone finger-tip PPG was compared with a reference ECG (1, 3 or 12-lead). Outcomes were sensitivity (SE), specificity (SP), positive and negative predictive value (PPV; NPV) and overall accuracy. Bivariate hierarchical random effects meta-analysis was performed for studies with confidence intervals for SE and SP, and funnel plots were used to identify publication bias. Study quality was assessed using the established QUADAS-2 tool by two independent graders.

Results

1350 publications were screened, of which 17 studies were included in the systematic review (7 full text publications and 10 abstracts), providing 21 comparisons of accuracy for AF detection. Most studies were based in secondary care and small (range n=33 to 1095), with a total of 5469 participants including 1384 with AF. Only 4 studies were multicentre. Smartphone applications used were Cardiio Rhythm, Fibricheck, Preventicus and Heartbeats, with 7 studies not specifying the tool used. Overall SE and SP for AF detection were high, ranging from 76 to 100%, and 85 to 100% respectively. PPV ranged from 54 to 100% and NPV from 77 to 100%, with overall accuracy between 61 and 99%. The meta-analysis included 12 comparisons from 10 studies (n=2714; 936 with AF). The pooled SE was 93% (95% CI 90–96%) and SP 97% (95% CI 95–99%); Figure 1A. QUADAS-2 assessment demonstrated poor quality of studies overall, with a high or unclear risk of bias in at least one domain for all studies. There was clear evidence of publication bias; Figure 1B.

Conclusions

PPG offers the potential for large scale, non-invasive, patient-led screening of AF. However, current evidence is limited to biased, low quality studies often with unrealistic results for AF detection. These are insufficient to advise clinicians on the true value of current smartphone PPG technology.

Figure 1. Meta-analysis & publication bias

Funding Acknowledgement

Type of funding source: Public grant(s) – EU funding. Main funding source(s): BigData@Heart EU/EFPIA IMI 116074.
The features and trends of out-of-hospital cardiac arrests in Japanese working generation: long-term aspects of a prospective, nationwide, population-based registry
Authors: Yamagishi Y , Oginosawa Y , Miyamoto T , Tukahara K , Ohe H , Kohno R , Otsuji Y , Abe H
Published: November 2020

Background

Despite sudden cardiac death (SCD) in working generation is a crucial issue in terms of public health, social and economic significance, the long-term SCD condition in working generation is unclear.

Purpose

This study aimed to clarify the features and long-term trends of SCD in working generation from 2005 through 2016 in Japan, using a prospective, nationwide, population based out-of-hospital cardiac arrest (OHCA) registry.

Methods

We performed data analysis of the nation-wide registry in Japan who experienced OHCA during the 12 years. Working generation was defined as 20 to 69 years and we analyzed only definitive cardiogenic OHCA as an approximation of SCD.

Results

The number of definitive cardiogenic OHCA of working generation during the period was 66,214 and 31% of the events in whole population was working generation. Definitive cardiogenic OHCA in working generation in terms of both number and percentage of the population had been decreased from 6522 (0.07‰) in 2005 to 4910 (0.06‰) in 2016, bystander cardiopulmonary resuscitation (CPR) and usage of automated external defibrillator (AED) ratio increased from 32.7% in 2005 to 49.6% in 2016, and 0.3% in 2005 to 14.7% in 2016 respectively, and the survival rate after one-month improved year by year, from 12.8% in 2005 to 34.0% in 2016 (picture below). Among non-medical bystanders, CPR was most often performed by colleagues in this generation, while AED use rate by colleague was smaller, and the time from witness to initial defibrillation was significantly longer than by passerby. Good prognosis was observed in terms of one-month survival ratio and neurological outcome for those undergoing CPR by colleague and passerby compared with other bystanders. For 12 years, although the degree varies, all non-medical bystander had same tendency; bystander CPR and usage of AED ratio increased, and the survival rate after one-month and neurological outcome improved year by year.

Conclusions

Not only the number but the incidence of cardiogenic OHCA in working generation has been decreased in Japan. The positive prognosis of this generation may be related to CPR by colleagues.

Figure 1. OHCA number & 1-month survival rate

Funding Acknowledgement

Type of funding source: None
Management of conflicts of interests of ESC guideline authors
Authors: Seggewiss H , Schurig N , Lempert T
Published: November 2020

Introduction

According to WHO definition medical guidelines are systematically developed statements to support the decisions of clinicians and patients about appropriate health care for specific clinical situations. Guidelines should be based on on results of randomized trials and independence from economic interests. Therefore, not only detailed declaration but also active management of conflicts of interests (COI) of guideline committee members should be declared. The public database LeitlinienWatch (GuidelineWatch) analyzes German and European guidelines with respect to COI declaration and management.

Methods

Between 2015 and 2019 nine German National Standard of Care guidelines (NVL), 10 German Cancer Society (DKG) guidelines, and 10 ESC guidelines were compared according to five criteria. Each criterion was scored 0–3 points (Table). Furthermore, up to 3 extra points could be awarded for methodological quality.

Results

Overall, guidelines of NVL (11.3±3.5) and DKG (9.8±3.3) achieved more points than ESC guidelines (2.8±0.4; p<0.00001). ESC-guidelines scored points only by documentation of COI and sometimes an extra bonuspoint for an internal review process. In all ESC guidelines >50% of the authors had COI. These conflicts did not lead to an exclusion of lead authors or abstentions from voting. A public accessible review was standard practice in NVL-guidelines and more often performed in DKG-guidelines but was lacking in ESC guideline process. Overall, NVL- and DKG-guidelines showed better handling of COI (Table).

Conclusion

Declaration and management of COI are quality criteria for medical guidelines. Current ESC guidelines do not meet international standards for COI management. Therefore, the rules for the ESC guideline process need to be revised.

Funding Acknowledgement

Type of funding source: None
Free dental care for patients at high risk of developing infective endocarditis – a cost-effectiveness study
Authors: Barradas Pires A , Boyalla V , Meras-Colunga P , Dimopoulos K
Published: November 2020

Background

Good dental hygiene is strongly recommended for reducing the risk of developing infective endocarditis (IE). This is particularly important for patients with predisposing cardiac conditions (PCC), such as prosthetic valves, in whom the life-long risk of developing IE is much higher than in the general population. Despite this, the United Kingdom (UK) National Health System (NHS) only provides free dental care until the age of 18 years. Thereafter, adult patients enter a co-payment model, resulting in a large proportion not being able to access adequate dental care.

Purpose

To study the cost-effectiveness of providing free dental care to IE-high-risk patients in the UK.

Methods

A decision analytical cost-effectiveness model was designed as a combination of a Decision Tree (for a short-term model) and a Markov Model (for cost-benefit estimation in a long-term horizon). The costs and benefits (measured as quality-adjusted life-years or QALYs) of free dental care from the age of 18 years, or 50 years, in a high-risk population were assessed using NHS data. The cost of dental care reimbursement varies across the UK, from £18 to £162 per Unit of Dental Activity (UDA), depending on the Dental Practices contracts with the NHS. The cost of dental care used in the model was £26 per UDA, an average of the UK prices. In a co-payment scenario this translates into the NHS paying £4 and the rest of the cost being passed out to the patient. In a free dental care scenario, the NHS would pay the full £26.

Results

In a short-term horizon of 1 year, the model estimated that if 1 million high-risk patients were given access to free dental care, 638 cases IE (53 cases a month) and 95 deaths could be avoided each year. The cost of 1 death averted would be £142,926 (€162,208). The long-term model shows free dental care would translate into an extra cost of £66,687/QALY (€74,844) for the NHS if started at 18 years of age, or £96,287/QALY (€120,864) if started at 50 years of age.

Conclusions

Free dental care in patients at high-risk of IE is not cost-effective within the current willingness-to-pay (WTP) NICE guidelines (£20–30,000/QALY). This is significantly influenced by the elevated cost of dental care in the UK. If the UDAs were reimbursed as £18 homogeneously across the UK, the model results would be closer to the WTP threshold. Further studies are needed to explore alternative scenarios where this policy would be cost-effective.

Transition state probabilities

Funding Acknowledgement

Type of funding source: None
Hospital volumes and the likelihood of stent implantation among patients undergoing catheterization of the left heart: more is more?
Authors: Oettinger V , Zehender M , Von Zur Muehlen C , Bode C , Kaier K , Stachon P
Published: November 2020

Background

Percutaneous coronary intervention (PCI) is an established procedure, but recent studies analyzing the indication for stenting are going to change clinical practice. Previous studies suggested that hospital volume is inversely related to in-hospital mortality but its impact on likelihood of stent implantation and the number of stents remains unclear.

Purpose

There is a conflict of objectives between nationwide care including short transfer and intervention times and a few large centers with maximum technology and experience. We examine the effect of hospital volume on in-hospital mortality, likelihood of stent implantation, number of stents, length of hospital stay, and reimbursement in a recent nationwide cohort from Germany.

Methods

Using German national electronic health records, all patients who underwent coronary angiography with a documented coronary artery disease were identified by ICD and OPS codes. Risk-adjustment was applied using a predefined set of patient characteristics to account for differences in the risk factor composition of the patient populations between centers.

Results

In 2017, a total of 528,188 patients with a documented coronary artery disease underwent coronary angiography in Germany. Mean age was 69.8 years and 29.3% of patients were female. 55% of all patients received PCI, with a mean number of 1.01 stents implanted per patient. In-hospital mortality was 2.9%, length of hospital stay was 6.5 days and mean reimbursement was €5,531. Multivariable regression analyses showed a positive linear association between hospital volumes and the likelihood of stent implantation (p=0.003) as well as the number of implanted stents (p=0.020). No association was found between hospital volumes and in-hospital mortality (p=0.105), length of hospital stay (p=0.201) or reimbursement (p=0.108). Inspection of the non-linear impact of procedure volumes on stent implantation practices indicates a ceiling effect in the volume-outcome relationship: implantation likelihood and number of stents per patient are lowest in centers with less than 100 procedures per year (34.4% and 0.62, respectively). Then, implantation likelihood and number of stents constantly increase until the volume category of 500 procedures per year and center. For centers with >500 procedures per year, the likelihood of stent implantation and the number of implanted stents remained relatively constant (about 60% and 1.07, respectively).

Conclusion

Patients undergoing coronary angiography in low-volume centers are less frequently subject to PCI but at comparable risk for in-hospital mortality. Furthermore, the data suggest that more complex cases are treated in high volume centers with consistent mortality rates and thus constant safety is ensured in high volume hospitals. Thresholds are discussed.

Impact of hospital volumes on PCI

Funding Acknowledgement

Type of funding source: None
What drives success in models predicting heart failure outcome?
Authors: Gutman R , Shalit U , Caspi O , Aronson D
Published: November 2020

Introduction

The development of acute heart failure (AHF) is a critical decision-point in the natural history of heart failure and carries a dismal prognosis. The lack of appropriate risk-stratification tools for AHF patients limits physician ability to precisely tailor patient-specific therapy regimen at this important juncture. Machine learning (ML) based strategies may enhance risk stratification by incorporating analysis of high-dimensional patient data with multiple covariates and novel prediction methodologies.

In this study, we aimed at evaluating the drivers for success in prediction models and establishing an institute-tailored ML-based prediction model for real-time decision support.

Methods

We used a cohort of all AHF patients admitted during a 12 years period including 10,868 patients. A total of 372 covariates were collected from admission to the end of the hospitalization (demographics, lab-tests, medical therapies, echocardiographic and administrative data). Data preprocessing included features cleaning, train-test split, imputation and normalization. We assessed model performance across two axes (1) type of prediction method and (2) type and number of covariates. The primary outcome was one-year survival from hospital discharge. For the model-type axis we experimented with seven different methods: Logistic Regression (LR), Random Forest (RF), Cox model (Cox), XGBoost, a deep neural-network (NeuralNet) and an ensembled model.

Results

Data pre-processing methodology combined with multiple-covariates achieved an out-ofsample AUROC prediction accuracy of more than 80% with almost all prediction models: L1/L2-LR (80.4%/80.3%); Cox (80.1%); XGBoost (80.7%); NeuralNet (80.5%). The number of covariates was a significant modifier of prediction success (p<0.001), the use of multiple-covariates (372) performed better (AUROC 80.4% for L1-LR) compared with using only a set of known clinical covariates (AUROC 77.8%).

Conclusions

The choice of the predictive modeling method is secondary to the multiplicity and type of covariates for predicting AHF prognosis. The application of a structured data pre-processing combined with the use of multiple-covariates results in an accurate, institute-tailored, risk prediction in AHF.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Yad Hanadiv
Sudden cardiac death in cancer patients: results from the Paris-Sudden Death Expertise Centre
Authors: Mirabel M , Hulot J.S , Lillo-Lelouet A , Jouven X , Marijon E
Published: November 2020

Background

Sudden cardiac death (SCD) in cancer patients regardless of their therapies has not been addressed.

Methods

Population-based registry (2011) via multiple sources to collect every case of SCD in Paris and its suburbs, covering a population of 6.6 million. Data of SCD patients (2011–2017) were analysed by identifying patients with known cancer or past medical history of cancer. Categorical variables were compared using chi-square test or Fisher's exact test; continuous variables using Student t-test or Wilcoxon rank sum test, as appropriate.

Results

Of 22,570 out of hospital cardiac arrests, 3,311 SCD patients (124 cancer patients and 3,187 non cancer patients) were admitted alive to the hospital and were included in the analysis. Characteristics of patients and cardiac arrest circumstances differed on univariate analysis (Table). The final aetiology of SCD varied: more respiratory causes to SCD (pulmonary embolism and hypoxia) among cancer patients and less acute coronary artery syndromes.

Conclusions

SCD in cancer patients differs significantly when compared to non-cancer patients. Coronary events are less prominent whereas respiratory causes are common aetiologies in cancer.

Funding Acknowledgement

Type of funding source: None
The neuro-cardiac junction defines an extracellular microdomain required for neurotrophic signaling
Authors: Mongillo M , Franzoso M , Prando V , Dokshokova L , Di Bona A , Basso C , Gorelik J , Vitiello L , Zaglia T
Published: November 2020

Background

Sympathetic neurons (SNs) innervate the myocardium with a defined topology that allows physiological modulation of cardiac activity. Neurotrophins released by cardiac cells control SN viability and myocardial distribution, which are impaired in heart diseases with reduced (e.g. heart failure) or heterogenous sympathetic stimulation (e.g. arrhythmias). We previously demonstrated that SNs interact directly with cardiomyocytes (CMs) at neuro-cardiac junctions (NCJ), and such structured contact sites allow neurons to efficiently activate β-adrenoceptors on the myocyte membrane.

Aims

We here asked whether NCJs are functional for retrograde (myocyte to neuron) neurotrophic signaling.

Methods and results

Electron microscopy and immunofluorescence on mouse heart slices and SN/CM co-cultures showed that the NGF receptor, TrkA, is preferentially found in correspondence of the NCJ. Consistently, neurons taking structured contact with CMs showed fast TrkA activation and its retrograde transport to the soma, which was monitored using live confocal imaging in cells expressing TrkA-RFP. In accord with NGF dependent effects, CM-contacted SN showed larger synaptic varicosities and did not require NGF supplementation in the culture medium. In support that NGF locally released at NCJs sustains SN viability, the neurotrophin concentration in the culture medium was 1.61 pg/mL, and did not suffice to maintain neuronal viability, which was also perturbed (66% decrease of neuronal density) by silencing NGF expression in CMs. These results support that the NCJ is essential for intercellular neurotrophin signaling. Consistently, by applying competitive inhibition of TrkA with increasing doses of K252a, we estimated NGF concentration at the contact site to be about 1000-fold higher than that released by CM in the culture medium.

To seek for the structural determinants of the NCJ, we focused on dystrophin, based on the finding that the protein accumulates on the CM membrane portion contacted by SNs, as observed in mouse heart slices, and co-cultured CMs. In support of a role of CM-expressed dystrophin in neurotrophic signaling, hearts from dystrophin-KO (mdx) mice showed 74.36% decrease of innervation, with no significant changes of NGF expression. In line with the purported role of NCJs, in co-cultures between wild type SNs and mdx CMs, TrkA activation (TrkA movements toward SN soma (%): WTCM-WTSN=18±4; MDXCM-WTSN= 12±3; p<0,05) and neuronal survival were reduced.

Conclusions

Taken together, our results suggest that NGF-dependent signaling to SNs requires a direct and specialized interaction with myocytes, and that loss of dystrophin at the CM membrane impairs retrograde signaling to the neurons leading to cardiac sympathetic dys-innervation.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): University of Padova
Sirtuin 4 contributes to heart failure development by increasing mitochondrial oxidative stress
Authors: Koentges C , Khan E , Birkle S , Hoelscher M , Pfeil K , Gollmer J , Hoffmann M.M , Bode C , Zirlik A , Bugger H
Published: November 2020

Sirtuin 4 (SIRT4) is a mitochondrial NAD+-dependent deacylase which inhibits the oxidation of glucose and fatty acids, and has been implicated in the regulation of oxidative stress. Given the importance of cardiac energy depletion and ROS during heart failure development, we aimed to define the role of SIRT4 in the development of heart failure. Mice with deletion (SIRT4−/−) or overexpression (SIRT4 TG) of SIRT4 were subjected to transverse aortic constriction (TAC) for 12 weeks or underwent sham procedures. Using echocardiography, ejection fraction (EF) was not different between SIRT4 TG and WT mice subjected to sham operations. In contrast, TAC induced a more pronounced decrease in EF (35% vs. 51%; p<0.05), and a more pronounced increase in LV endsystolic diameter (4.5mm vs. 3.6mm; p<0.05) and myocardial fibrosis (2.2-fold; p<0.05) in SIRT4 TG mice compared to WT mice. Myocardial levels of the lipid peroxidation product 4-hydroxynonenal were increased in WT mice following TAC and were synergistically increased in SIRT4 TG mice following TAC (+66% vs. WT TAC; p<0.05). Administration of the mitochondria-targeted antioxidant MitoQ normalized 4-hydroxynonenal levels, markedly attenuated the decline in EF and almost normalized endsystolic LV diameter in SIRT4 TG mice following TAC. Cardiac function and morphology were unaffected in SIRT4−/− mice during normal or increased workload conditions. Thus, while SIRT4 is not required to maintain cardiac function even in response to increased energy demands, increased expression of SIRT4 accelerates the development of heart failure following TAC, at least in part due to increased mitochondrial oxidative stress.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Research Foundation
Novel mechanism in cardiac injury: immune checkpoints
Authors: Screever E.M , Axelrod M.L , Blair M.A , Trykall D.Z , Barnett J.V , Roden D.M , Johnson D.B , Balko J.M , Meijers W.C , Moslehi J.J
Published: November 2020

Background

Immune checkpoint inhibitors (ICI), specifically directed against CTLA-4 and PD-1, have revolutionized cancer therapy but are associated with immune-related adverse events, including fulminant myocarditis. The mechanisms are unknown, but one possibility is that CTLA-4 and PD-1 play a critical role in cardiovascular homeostasis.

Purpose

The purpose of this study is to investigate the role of these immune checkpoints in cardiac injury. We hypothesize that cardiomyocytes can express immune checkpoint ligands in response to stress and that CTLA-4 and/or PD-1 play a key role in cardiac response to injury.

Methods

We measured expression levels of CTLA-4 ligands (Cd80, Cd86) and PD-1 ligands (Pdcdl1, Pdcdl2) in in vitro and in vivo models of cardiac injury, including iPSC-derived cardiomyocytes (iPSC-CM) and diseased human cardiac samples. Immunofluorescent staining and multiplex immunohistochemistry were used to derive more granular data on cell type expressing specific immune checkpoint associated proteins. To determine the functional role of CTLA-4 and PD-1 in cardiac injury, myocardial infarction (MI) was induced in C57Bl/6 mice treated with anti-CTLA-4 or in mice with a genetic knock-out of CTLA-4 and PD-1 (Pdcd1−/−Ctla4+/+ and Pdcd1−/−Ctla4+/−). Flow cytometry was performed 2-days post-MI to determine immune cell infiltration, echocardiography was performed 7-days and 28-days post-MI and plasma samples were analyzed for ANP and Troponin I.

Results

Doxorubicin or hypoxia increased expression of Cd80, Cd86, Pdcdl1 and Pdcdl2 in iPSC-CM. After MI, isolated cardiomyocytes from the ischemic/border zone area yielded significant increased expression of both Cd80 and Cd86, which was confirmed at the protein level. However, pharmacologic inhibition of CTLA-4 during MI resulted in better survival compared to no treatment (p<0.007). No differences were seen in immune cell infiltration, troponin I and ANP levels and echocardiography. Pdcd1−/-Ctla4+/+ and Pdcd1−/−Ctla4+/− mice showed a decrease in immune cell infiltration.

Conclusions

Whole hearts, isolated cardiomyocytes and iPSC-CM from both mice and humans express immune checkpoint ligands in response to cardiac injury. Pharmacologic or genetic inhibition of CTLA-4 and PD-1 in MI did not result in adverse effects regarding survival, cardiac function, immune cell infiltration and heart enzyme levels in mice. These data support the hypothesis that immune checkpoint pathways play a role in cardiac injury and in these preliminary studies immune checkpoint inhibition during cardiac ischemic injury did not result in adverse effects.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466
Loss of smooth muscle SDF-1/CXCL12 leads to cardiac hypertrophy and aortic valve stenosis
Authors: Ghadge S.K , Messner M , Seiringer H , Zeller T , Boernigen D , Weninger W.J , Geyer S.H , Sopper S , Poelzl G , Tepekoeylue C , Zaruba M.M
Published: November 2020

Background

Stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptors CXCR4/CXCR7 have prominent role in cardiovascular development and myocardial repair following ischemic injury. Nevertheless, detailed mechanisms of the cell specific role of SDF-1 are poorly understood. Since SDF-1-EGFP lineage tracking revealed high expression of SDF-1 in smooth muscle cells, we aimed to investigate the cell specific role by generating a smooth muscle cell specific SDF-1 (SM-SDF-1−/−) knockout mouse model.

Methods

SDF-1 expression was analyzed utilizing SDF-1-EGFP reporter mice. Conditional SM-SDF-1 KO mice were generated using Tagln-Cre; SDF-1fl/fl mice. Hearts were analysed with histology and high-resolution episcopic microscopy. Cardiac function was assessed utilizing echocardiography. RNAseq, qRT-PCR, flow cytometry and western blotting were performed. Cardiac fibrosis, apoptotic index, cell proliferation, aortic valve calcification were analyzed. SM-SDF-1−/− mice were treated with the CXCR7 agonist TC14012 (10mg/kg/I.P).

Results

SDF-1-EGFP lineage tracking and immunofluorescence revealed high expression of SDF-1 particularly in smooth muscle cells and less frequently in perivascular and endothelial cells. Conditional SM-SDF-1−/− mice showed a high pre- and perinatal mortality (50%). Immunohistochemistry of SM-SDF-1−/− mice revealed severe cardiac hypertrophy, associated with increased cardiac fibrosis, apoptotic cell death, thinned and dilated arteries and significantly decreased M2 like CD11b+/CD206+ cells. Echocardiography confirmed concentric hypertrophy, with decreased stroke volume. As a possible reason for cardiac hypertrophy, SDF-1 mutants exhibited aortic stenosis due to aortic valve thickening associated with downregulation of the SDF-1 co-receptor CXCR7. We further noticed increased plasma levels of SDF-1 in aortic stenosis patients suggesting a cardioprotective role. Transcriptome analyses from KO hearts showed an abnormal extracellular matrix (ECM) remodelling with a specific upregulation of the important valve related proteoglycans Versican, Glycan. Western blot analysis revealed activation of AKT and ERK, whereas CXCR7 expression was significantly downregulated in KO mice. To rescue the phenotype we treated KO mice with the CXCR7 agonist (TC14012) which partially attenuated aortic valve remodelling through activation of the ERK signalling pathway.

Conclusion

Our data suggest that SDF-1 is critically involved in maintaining the homeostasis of the aortic valve by regulating CXCR7 signalling. Pharmacological activation of CXCR7 might be a promising therapeutic target to limit the progression of aortic valve stenosis.

Ghadge_SM-SDF-1−/−

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund, Austrian research promotion agency
Human genetic determinants of the gut microbiome and their associations with health and disease: a phenome-wide association study
Authors: Groot H , Van De Vegte Y.J , Verweij N , Lipsic E , Karper J.C , Van Der Harst P
Published: November 2020

Background

Recent small-scale studies have suggested a link between the human gut microbiome and highly prevalent diseases. However, the extent to which the human gut microbiome can be considered a determinant of disease and healthy aging has not been well established. In this study, we aimed to determine the spectrum of diseases that are linked to the human gut microbiome through the utilization of its genetic determinants as a proxy for its composition.

Methods

Data from 422,417 unrelated individuals of Caucasian British ancestry with available genotype and matching genetic data from the UK biobank was analysed in this study. 35 single nucleotide polymorphisms (SNPs) known to influence the human gut microbiome were used to perform the phenome-wide association study. Our main outcome was the probability (risk) of health and disease outcomes associated with human genetic determinants of the microbiome.

Results

From the total sample analysed (mean age was 57±8 years), 194,567 (46%) subjects were male. Median exposure was 66-person years (interquartile range 59 to 72). Seven SNPs known to influence the human gut microbiome were significantly associated with 29 health and disease outcomes (false discovery rate <5%, P value <9.14×10–4) including food intake, health status parameters (inflammation, blood pressure and lipid levels), hypertension, type 2 diabetes mellitus, hypercholesterolemia, heart failure, renal failure, and osteoarthritis.

Conclusions

Human genetic determinants of the gut microbiome are associated with 29 specific health and disease outcomes including hypertension, type 2 diabetes mellitus, hypercholesterolemia, heart failure, renal failure, and osteoarthritis. Microbiota and their metabolites play an important role in the interplay between overlapping pathophysiological processes and could be considered as potential targets for the maintenance of health and reduction of disease risk.

Heat map

Funding Acknowledgement

Type of funding source: None
Circular RNAs as prognostic biomarkers after cardiac arrest
Authors: Stefanizzi F , Zhang L , Nielsen N , Devaux Y , Salgado-Somoza A
Published: November 2020

Background/Introduction

More than 400,000 cases of cardiac arrest (CA) occur every year in Europe and only 10% of these patients survive without major neurological sequelae. Predicting outcome after CA would allow adapting healthcare. However, current prognostication modalities and biomarkers lack accuracy, requiring the discovery of new ones. Previous studies suggest that circulating noncoding RNAs (ncRNAs) constitute a reservoir of novel biomarkers. In particular, circular RNAs (circRNAs), a class of long ncRNAs, appear to have a promising biomarker potential.

Purpose

We aimed to identify circulating circRNAs able to predict neurological outcome and survival after CA.

Methods

Whole blood samples were collected from patients of the Target Temperature Management trial (TTM-trial; NCT01020916) 48h after CA in PAXgene RNA tubes. A discovery phase was conducted by RNA sequencing in a subgroup of 46 patients, among which 23 survived with no major neurological sequelae (cerebral performance category score 1 – CPC1) and 23 died within 6 months (CPC5). A validation phase was conducted by quantitative RT-PCR in 542 patients. Logistic regression was used to assess the association between circRNAs and 6-month neurological outcome. Kaplan Meier curves and Cox regression were used to test the ability of circRNAs to predict patients' survival at 6 months.

Results

The discovery phase identified 282 circRNAs in blood samples. Among these, twenty-one circRNAs were differentially expressed between patients with CPC1 and patients with CPC5 (p<0.05). Experiments using RNAse R digestion confirmed the circularity of selected circRNAs. In the validation phase with 542 patients, one circRNA (circ016) was differentially expressed between patients with good neurological outcome at 6 months (CPC1–2) compared to patients with poor neurological outcome (CPC3–5) (p<0.001). Univariate analysis confirmed the association between circ016 and neurological outcome (odds ratio (OR) [95% confidence interval (CI)] 6.1 [2.2–16.7]). After adjustment with clinical and demographic parameters, circ016 remained a significant predictor of neurological outcome (OR [95% CI] 6.0 [1.4–26.1]) (Figure 1). In Kaplan-Meier analysis, circ016 was associated with 6-month survival (log rank test p<0.001). In Cox regression, circ016 predicted 6-month survival with a hazards ratio of 4.4 [2.1–9]. Patients with high levels of circ016 were at high risk of poor neurological outcome and death.

Conclusions

Circulating levels of circRNAs measured 48h after CA are associated with neurological outcome and survival at 6 months. We have identified several circRNAs with potential to aid in outcome prediction after CA. These circRNAs remain to be independently validated in large patient cohorts.

Figure 1

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Research Fund of Luxembourg, Ministry of Higher Education and Research of Luxembourg