bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced gastric injury with a novel, liquid lipid-aspirin formulation: results from a pooled, patient level analysis of two randomized endoscopy studies In healthy volunteers
Authors: Bhatt D.L , Scheiman J , Angiolillo D.J , Steg P.G , Dangas G.D , Fan W , Prats J , Deliargyris E.N
Published: November 2020

Background

Gastrointestinal (GI) toxicity from aspirin is high at the time of initiation of therapy.

Objective

The current analysis aimed to determine rates of endoscopically detected gastroduodenal erosions and ulcers after 7 days of either immediate release aspirin (IR-ASA) or a novel, pharmaceutical lipid-aspirin complex (PL-ASA) liquid formulation that has an antiplatelet effect similar to IR-ASA.

Methods

Two randomized, single blind, multicenter active control studies comparing upper GI damage after 7 days of 325 mg PL-ASA or IR-ASA in healthy volunteers not taking a gastroprotectant and who had a negative baseline endoscopy were pooled at the patient level. The primary outcome was the composite of >5 erosions and/or ≥1 ulcer (≥3 mm deep) assessed by a treatment-blinded reviewer at repeat endoscopy on day 7.

Results

Out of 451 randomized subjects (mean age 57 years, 47% males), 441 completed the 7-day endoscopy and represent the full analysis set. PL-ASA significantly reduced the primary outcome by 34% compared with IR-ASA (25.7% vs. 39%, p=0.0032) (figure). Notably, for ulcers there was a 61% reduction with PL-ASA (6.0% vs. 14.8%, p=0.0018) (Figure 1). The mean number of gastric erosions per patient was also reduced with PL-ASA (2.8±7.3 vs. 4.2±7.5, p<0.0001), while erosions in the duodenum were not different (1.4±7.1 vs. 0.9±2.3, p=0.45).

Conclusion

The novel PL-ASA liquid capsules reduced rates of GI injury compared with IR-ASA tablets. The combination of reliable platelet inhibition with less GI injury makes PL-ASA an attractive new aspirin therapy option.

Figure 1

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): PLx Pharma
Premorbid, cardioselective beta-blocker exposure decreases ICU mortality in septic patients defined by sepsis-3
Authors: Kuo M , Chou R.H , Wu C.H , Huang P.H , Lin S.J
Published: November 2020

Introduction

Beta-blockers may exert a protective effect against the catecholaminergic myocardial injury in septic patients. The difference between cardioselective and non-selective beta blockers was not fully elaborated. The aim of this study was to investigate the association between premorbid prescriptions of different class of beta-blockers and mortality rate in septic patients.

Methods

We retrospectively screened 2678 patients admitted to the ICU during December 2015 to July 2017. Premorbid beta-blocker exposure was defined as prescription of any beta blocker for at least 1 month. Bisoprolol, esmolol, and atenolol were classified as cardioselective beta-blockers, and others were classified as non-selective beta-blockers.

Results

Among 1262 septic patients, 209 (16.6%) cases were long-term beta-blockers users. Patients with premorbid beta-blocker exposure were associated with higher BP, lower HR, lactate concentration, and improved ICU mortality. However, only premorbid cardioselective beta-blocker users (adjusted HR 0.26; 95% CI 0.11–0.64; p=0.003), but not non-selective beta-blocker users (adjusted HR 0.66; 95% CI 0.29–1.51; p=0.326), were associated with reduced ICU mortality.

Conclusion

Only premorbid cardioselective beta-blockers, but not non-selective beta-blockers, were associated with improved mortality in septic patients. These findings supported the cardioprotective effect and clinical benefits of beta-blocker in septic patients.

Kaplan-Meier Curve of ICU Mortality

Funding Acknowledgement

Type of funding source: None
Medically induced bradycardia in the elderly and senile patients
Authors: Nikulina N.N , Iakushin S.S , Chernysheva M.B , Seleznev S.V
Published: November 2020

Background

Elderly and senile people are most likely to develop cardiovascular diseases, while they have a higher risk of adverse drug reactions. Systemic analysis of medically induced bradycardia (MIB) has not been performed.

Aim

To analyze the clinical features of MIB in patients ≥65 and ≥75 years according to the Hospital Register of Cardiac Drug Overdoses (storm) data.

Materials and methods

Analyzed 17,826 cases of hospitalization in the Regional Vascular Center from 01 Jan 2017 to 31 Dec 2019, of them with all types of cardiac drug overdoses – 363, of them with MIB – 52.6% (n=191).

Results

Average age of those hospitalized with MIB – 74.0 [65.0; 80.0] years: 76.0% were ≥65 years, 49.4% – ≥75 years. Among the cohort ≥65 years, there were more women – 74.3% (vs 52.3%, p=0.003), ≥75 years – 74.4% vs 65.5% (p=0.107). The ratio of absolute and relative overdoses did not depend on age and was 1:9. The frequency of pulse-reducing drug admission before hospitalization did not differ in age groups. In General, in the cohort with MIB: 68.4% – beta-blockers, 25.8% – digoxin, 38.9% – antiarrhythmic drugs with pulse-reducing action (PRA), 9.5% – imidazoline receptor agonists, 10.5% – calcium channel blockers with PRA, 7.4% – other drugs with PRA, while 54.5% of patients received a combination of ≥2 drugs with PRA, 15.7% – ≥3, and even 3.1% – ≥4. In older age groups, a Glomerular Filtration Rate (GFR) decrease in was more often: among ≥65 years GFR <60 ml/min × 1.73 m2 – 83.2% (vs 40.0% in younger patients, p<0.001), <45 ml/min × 1.73 m2 – 61.5% (vs 22.5%, p<0.001), <30 ml/min × 1.73 m2 – 34.5% (vs 15.0%, p<0.001), <15 ml/min × 1.73 m2 – 11.1% (vs 7.5%, p<0.264); among patients ≥75 years: GFR <60 ml/min × 1.73 m2 – 87.4% (vs 60.8%, p<0.001), <45 ml/min × 1.73 m2 – 66.0% (vs 40.2%, p<0.001), <30 ml/min × 1.73 m2 – 37.1% (vs 23.4%, p<0.018), <15 ml/min × 1.73 m2 – 12.0% (vs 8.4%, p<0.357). Patients ≥65 and ≥75 years were more likely to require: emergency hospitalization (97.0% vs 84.1% in younger patients, p<0.001 and 97.0% vs 91.1%, p=0.033), treatment in the intensive care unit (44.7% vs 20.5%, p=0.003 and 48.8% vs 29.2%, p=0.001), temporary pacemaker (58.3% vs 20.0%, p=0.107 and 57.1% vs 40.0%, p=0.284). Hospital mortality in persons ≥75 was 7.7% (vs 1.8% in younger patients, p=0.047), ≥65 – 3.8% (vs 4.6%, p=0.814).

Conclusions

Older age groups predominate among those hospitalized for MIB. They are characterized by a more pronounced lesion of glomerular filtration, a more severe condition, and a higher risk of death. Practical physicians underestimate the danger of prescribing drugs with PRA, especially in the form of combined therapy, in patients of older age groups, with impaired glomerular filtration, which requires drawing attention to this problem.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): Ryazan State Medical University
Impact of ventricular assistance devices on patients submitted to heart transplantation
Authors: Perez-Ortega S , Prats J , Querol E
Published: November 2020

Background

The introduction of veno-arterial extracorporeal life support (v-a ECLS) widens the spectrum of patients that can be included in the heart transplant program, some examples are extended myocardial infarction, fulminant myocarditis or advanced cardiac insufficiency. In addition to this, the implementation of extracorporeal cardiopulmonary resuscitation (ECPR) extends even more the range of patients that can be benefitted of this therapy as a bridge to transplant.

Purpose

Our objective is to describe the incidence of v-a ECLS in those patients submitted to a heart transplant and to establish whether or not this technique increases the risk of mortality in this population.

Methods

Retrospective and descriptive statistical analysis of 82 consecutive patients submitted to heart transplant between 2015 and 2019 in a High Technology University Hospital.

Demographic and clinical data, extracorporeal life support, extracorporeal cardiopulmonary resuscitation and assistance device type, together with survival at 30 days and one year were collected.

Results

82 patients were transplanted during the study period distributed as follows:

47 (51.69%) were elective and 35 (48.1%) emergent being 25 (30.12%) of grade 1A and 10 (12.19%) of grade 1B. 52% had prior intra-aortic balloon contrapulsation.

Patients transplanted under ECLS were 80% men and average age of 53 (SD 15) years old. The most prevalent diagnosis was acute myocardial infarction Killip IV (32%), followed by terminal heart failure (28%).

32% of the patients were under peripheral ECMO, 36% under left ventricular assistance, 20% under biventricular assist device, and 12% required ECPR. 72% of devices were implanted in the operating room and 16% in the ICU.

The one-year survival of the sample was 88%. 2 patients died after transplantation (8%) during the first month, and 1 patient died within the first year. All three patients had terminal heart failure and the VAD implant was inserted electively

Conclusions

ECLS prior to cardiac transplantation allow selected patients to arrive alive to the transplant. The choice among devices is related to the diagnosis and expected duration of the therapy but we have not found in our series effects on subsequent mortality. Survival at one year in the subjects analysed is greater than the national registry of the last 10 years, although the tendency is to improve every year.

This new scenario implies an increment of the complexity in the management of these patients and requires an special effort in terms of staff ratio and training. In our centre, the implementation of ECLS resulted in an increment of our staff and formative sessions.

Funding Acknowledgement

Type of funding source: None
Elderly patients with chronic heart failure have higher risk of geriatric syndromes: results of the nursing study
Authors: Tsareva I , Vorobyeva N , Semochkina G , Kotovskaya Y , Tkacheva O
Published: November 2020

Background

The prevalence of chronic heart failure (CHF) and geriatric syndromes increases with age, however the associations between these conditions have not yet been studied.

Purpose

To evaluate the associations between CHF and geriatric syndromes in elderly patients.

Methods

Four hundred and seventy-two in-patients (18% male) aged 75–100 (mean 81±4) years were included in the nursing study. Patients were examined by nurses with a specially designed nursing assessment algorithm that included Mini-Cog test, Morse Fall scale, Norton scale, Barthel Activities of daily living Index, Short Physical Performance Battery (SPPB) tests, Mini Nutritional Assessment (MNA) scale, Geriatric Depression Scale (GDS-15), and a number of other questionnaires.

Results

CHF was observed in 180 patients (38%). Functional class (FC) of II (NYHA) was diagnosed in 133 (74%) of them, FC of III – in 47 (26%). Patients with and without CHF did not differ by age and gender. CHF patients had lower points on Norton scale (17,6±2,0 vs 18,2±1,8; p<0,001), Barthel Index (92,0±13,9 vs 95,0±9,1; p=0,009), SPPB (5,3±3,2 vs 6,0±3,3; p=0,018), and higher points on Morse Fall scale (44,3±19,9 vs 39,3±21,1; p=0,007) and GDS-15 (4,7±3,2 vs 4,2±3,3; p=0,041) compared to non-CHF patients. CHF patients had higher frequency of frailty (75% vs 65%; p=0,029), depression (47% vs 38%; p=0,041), and cognitive impairment (54% vs 41%; p=0,008). Univariate regression analysis showed that CHF presence increased the frailty risk by 1,6 times (OR 1,59; 95% CI 1,05–2,40; p=0,029), the depression risk – by 1,5 times (OR 1,48; 95% CI 1,02–2,16; p=0,041), and the cognitive impairment risk – by 1,7 times (OR 1,65; 95% CI 1,14–2,40; p=0,009). Among CHF patients, severity of CHF clinical manifestations correlated with severity of geriatric syndromes. CHF patients with FC of II had higher points of Norton scale (17,8±1,9 vs 16,9±2,1; p=0,005), Barthel Index (93,4±12,9 vs 88,3±15,8; p=0,005), SPPB (4,4±3,3 vs 3,9±3,0; p=0,001), walk speed (0,58±0,26 vs 0,45±0,22 m/s; p=0,002), and lower points of GDS-15 (4,4±3,3 vs 5,5±2,9; p=0,008) compared to CHF patients with FC of III. The frequency of depression was higher in CHF patients with FC of III (64% vs 41%; p=0,008). Univariate regression analysis showed that in CHF patients with FC of III the depression risk was higher by 2,5 times (OR 2,50; 95% CI 1,26–4,98; p=0,009) compared to CHF patients with FC of II.

Conclusion

Elderly CHF patients had higher risk of geriatric syndromes such as frailty, depression, and cognitive impairment. Among CHF patients, severity of CHF clinical manifestations correlated with severity of geriatric syndromes.

Funding Acknowledgement

Type of funding source: None
Deep neural network trained on surface ECG improves diagnostic accuracy of prior myocardial infarction over Q wave analysis
Authors: Rogers A , Tung J.S , Tooley J , Bhatia N.K , Kang G , Alhusseini M.I , Baykaner T , Wang P.J , Perez M , Clifford G , Tereshchenko L , Narayan S.M
Published: November 2020

Background

Detection of prior myocardial infarction (MI) may inform arrhythmia treatment and prognosis, yet cardiac imaging is resource intensive. ECG Q-wave analysis is quick and inexpensive but has poor accuracy for assessing prior MI.

Purpose

To evaluate the ability of a deep neural network (DNN) trained on the surface ECG to identify patients with prior MI.

Methods

We assessed 608 well-characterized patients (61.4±14.5 years, 31.2% female) at 2 academic centers. From one 12-lead ECG, median beats were calculated in 3 orthogonal planes (X, Y, Z; Fig. 1A) and used to train a DNN to identify a history of prior MI. Accuracy was compared to manual assessment of pathologic Q waves, defined as a deflection >25% of the subsequent R wave, >40ms in width, and >0.2mV amplitude in 1 of 3 ECG planes.

Results

Of 608 patients, 175 had history of MI (28.7%). The DNN outperformed the accuracy of pathologic Q waves. In training, DNN converged to >98% accuracy and in testing, its accuracy was 71±5% (Fig. 1B) (k=5-fold cross validation). This outperformed the 62% accuracy of pathologic Q waves in this study (red dotted line, Fig. 1B). In the validation cohort, DNN provided an area under the receiver operating characteristics curve of 0.730 (Fig. 1C).

Conclusion

Deep learning of a 12-lead ECG can identify features of prior myocardial injury more accurately than Q-wave analysis. In attempting to improve these results further, studies should explain what inputs weighted DNN decisions, and identify those that reflect abnormalities detectable clinically or on imaging.

Figure 1

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): NIH NRSA F32
The impact of digital flashcards on cardiovascular physiology academic performance in a medical course – a dose-dependent effect between the amount of training and academic success
Authors: Santos-Ferreira D , Guimaraes B , Tsisar S , Goncalves-Teixeira P , Ladeiras-Lopes R , Fontes-Carvalho R , Leite-Moreira A
Published: November 2020

Background

Digital flashcards are used to review factual knowledge through active-recall and spaced-repetition, while allowing subsequent self-assessment.

Purpose

To assess if using digital flashcards is associated with cardiovascular physiology academic success and better knowledge retention in short- and medium-terms, through a dose-dependent effect.

Methods

We conducted a single-faculty cohort study of 2nd-year medical students enrolling in cardiovascular physiology course, using a platform comprising 676 original flashcards. The grades from 0–20 scale of three exams were analyzed, being the latest optional and performed 1 month after the end of the course. One-sample t-test was used to compare the grades between flashcard users versus non-users, and the amount of training was correlated with the exams results using Pearson's correlation. Also, multiple linear regression models were created, using the respective grades as the dependent variable. A p value of <0.05 was considered statistically significant.

Results

From 312 students enrolled, 279 agreed to participate in this study, and 87% used the platform. Flashcard-users exhibited higher grades versus non-users (11.83±3.57 vs. 9.50±3.55, p<0.001; 12.47±3.03 vs. 11.45±3.24, p=0.225; 10.24±4.66 vs. 7.51±4.46, p=0.041; 1st, 2nd and 3rd exams, respectively). Among flashcard-users, the amount of training was positively correlated with the academic success (r=0.366, r=0.350, r=0.286; 1st, 2nd and 3rd exams, respectively, p≤0.001 for all). Multiple linear regression models showed a statistically significant association between the theoretical exam results and the number of flashcards studied – for every 1000, there was an increase in 0.98 (p=0.001), 1.22 (p=0.017) and 1.00 (p=0.022) in the grades of the 1st, 2nd and 3rd exams, respectively.

Conclusion

Studying cardiovascular physiology through digital flashcards has a moderate correlation with the exams results, exhibiting a positive and consistent dose-dependent effect, both in short- and medium-terms. Therefore, this strategy seems to improve academic success by increasing knowledge retention.

Study algorithm

Funding Acknowledgement

Type of funding source: None
Hospital@Home: a proof of concept
Authors: Umans V , Van Ramshorst J , De Boer S.P.M , Bos-Schaap A.J.C.M , Walburg S
Published: November 2020

Background

Expenditure in healthcare in the Netherlands is so increasing that currently 1 in 7 employees are working in the health care/cure. Future expansion is under constrain given the 10% of GDP use and shortage of working force.Dutch healthcare consists of a cure section (mostly hospitals) and nursing care@home. Both entities have different national budgets (€25 + €20bln)

Methods

In a proof of concept, we explored a new Hospital@Home (H@H) model combining hospital cure and home-care budgets in a 800 mi2 district with 850,000 inhabitants. The objective comprises 4 proofs: (1)provide hospital care@home, (2) combine financial budgets (3) increasing working forces by combining teams, (4) increased satisfaction of pts and nursing staff.

Results

We proofed a joining budgets of the hospital and home-care group for cardiology. The homecare-budget was sufficient to hire 3 nurse practitioners who are trained by the cardiologists and work with 16 home-care cardiovascular nurses for H@H treatment. The hospital budget provided a virtual EHR cardiology ward and supplied the home care-nurses with a nursing app to assess the patients EHR. Budgets were sufficient to obtain the home-heartfailure monitoring application. The cardiology-group developed the H@H program for endocarditis treatment and heartfailure telemonitoring. Clinically, in the first 6 months, 50% of hospitalized endocarditis pts were treated with iv antibiotics@home with an average 16.5 days per pt shorter admission days without complications. 33% of eligible hospitalized heartfailure pts consented for telemonitoring@home while up-titrated on medication. Video-consulting reduced outpatient visits with 75%. Patient satisfaction was 75/100.

Conclusion

In this proof of concept, the H@H program provided hospital cure at home by merging hospital and home-care nursing staff and ICT budgets. Patient satisfaction score were driven by shorter admissions and less hospital visits. We call for further exploration of efforts to facilitate combined home-care and hospital-cure transmural budgets to confirm this proof of concept.

Funding Acknowledgement

Type of funding source: None
ICHealth: large-scale digital health data on evidence-based cardiovascular medications, hospitalizations and epidemiological characteristics of heart failure patients in Brazil
Authors: Santo K , Marton P , Lapa M , Pereira P , Amaro E , Berwanger O
Published: November 2020

Introduction

Heart failure (HF) is one of the main causes of morbimortality in Brazil. However, little is known about the characteristics of the Brazilian HF population assisted at the community level, including the use of HF medications and frequency of hospitalizations. ePHealth is an app-based large-scale digital data collection platform that currently has health data on more than 1.5 million people.

Purpose

To assess the use of evidence-based HF medications, hospitalizations and epidemiological characteristics of HF patients in Brazil.

Methods

This is an observational retrospective study of the digital health data collected using the ePHealth platform on individuals, who self-reported a diagnosis of HF. Data collected included sociodemographics, clinical data, risk factors, comorbidities, medications and hospitalizations.

Results

Data collected at more than 40,000 home visits on 5907 individuals with HF were analysed. Majority of them were female, aged 55 to 75 years and brown (Figure 1). About 36% were married, 20% were illiterate, 65% were retired and 66% earned ≤2 minimum wages. Mean BMI was 26.7 kg/m2 (SD 5.9), risk factors and comorbidities were frequent (Figure 1). The use of HF medications was very low (Table 1). There were 575 hospitalizations (9.7%), due to the main following reasons: probable or definite heart failure decompensation (89, 15.5%), heart attack (60, 10.4%), cardiovascular procedures (54, 9.4%) and stroke (42, 7.3%).

Conclusion

This data suggests that community-level use of evidence-based cardiovascular medications in a population of individuals with HF in Brazil is very low and that hospitalizations are frequent. This study also provides a better understanding of the characteristics of a population of HF individuals, using large-scale real-world data collected on a community-level via an entirely digital platform. ePHealth is a disruptive platform able to provide data on the burden of HF and other cardiovascular diseases, informing decisions on implementation of prevention and management programmes.

Figure 1. HF population characteristics

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): ePHealth
Burnout in residency: are cardiology residents more affected?
Authors: Sigal A.R , Alves De Lima A.E , Cousirat Liendro M
Published: November 2020

Introduction

Burnout syndrome is a state of mental and physical wear caused by stressful working conditions, characterized by depersonalization, tiredness and lack of personal fulfillment. Its consequences are severe, ranging from sleep disorders to higher suicide risk. Residents in training are more prone to suffering this syndrome, especially in Argentina where over 30% of cardiology residents work over 80 hours and sleep less than 35 hours a week. There is a lack of robust data in Argentina regarding the incidence of this syndrome in residents and whether cardiology residents are more prone to suffering it compared to other clinical specialties.

Methods

We conducted a national, multicentric, voluntary, self-administered survey to determine burnout levels in residents across multiple specialties. Burnout syndrome was defined using the Maslach inventory tool as having all three of the following: high scores in tiredness (>26) and depersonalization (>9), and low score in personal fulfillment (>34). Discreet variables were analyzed by median and interquartile range, while proportions were used for nominal variables. We used Chi-squared test to compare categorical variables.

Results

312 residents from 15 Argentinian provinces completed the survey, of which 148 (47.4%) represented cardiology residents, 112 (35.9%) other clinical specialties, and 52 (16.7%) surgical specialties. 63.1% were female. 16% were first year residents, 25% second year, 23% third year and 25% fourth year, with 8% chief of residents. 41% were from the public setting. 24% of all residents screened had a positive test for burnout syndrome. Cardiology residents had a higher burnout incidence (27.7%) than residents of other specialties (17%) (OR 1.87; 95% IC 1.02–3.45; p=0.04). A numerical (but not statistically significant) trend for higher lack of personal realization was found (OR 1.67; 95% CI 0.97–2.88; p=0.06).

Conclusion

In this trial, a higher incidence of burnout syndrome was found in Argentine cardiology residents than in other clinical specialties. This may be explained by an almost significant increase in lack of personal realization. Trials with an increased sample size need to be carried out to reinforce this hypothesis and determine causation, in order to support and influence policymakers to create a less stresful work environment in order to prevent burnout syndrome.

Funding Acknowledgement

Type of funding source: None
Independent predictors of repeat emergency room presentations in patients with noncardiac chest pain: insights from a cohort of 1066 consecutive patients with 4770 repeat presentations
Authors: Yang Y.H , Grainger R , Gornall M , Obeidat M , Campbell M , Batouskaya K , Khand A
Published: November 2020

Introduction

Repeat attendances with noncardiac chest pain (NCCP) to emergency room (ER) are frequent..Our aim was to analyse predictors of repeat presentations to ER in patients with NCCP.

Methods

We prospectively enrolled 1066 consecutive presentations with NCCP to a major urban hospital ER. Index of multiple deprivation (IMR) was computed. Charlson comorbidity (CCM) index was determined. Repeat presentation to ER to any national hospital was determined by a national linked database (pop. 53.5m).

Results

Median age was 43 (IQR 28, 59), 50.8% were male. 63% were current or previous smokers. 1 year incidence of adjudicated MI, coronary revascularisation and all-cause death was 0.6%, 2% and 5.3% respectively. There was a total of 4770 repeat ER presentations. After taking account of death independent predictors for repeat presentation were current smoking (OR 1.844, p=0.001) and CCM score ≥1 (OR 1.58, p=0.014) (table).

Conclusions

Smoking and patients with multiple comorbidities represent health policy targets for lessening hospital burden of NCCP.

Funding Acknowledgement

Type of funding source: Public hospital(s). Main funding source(s): Liverpool University Hospital NHS Trust; North-West Educational Cardiac Group
Cardiovascular disease recurrence and long-term mortality in a tri-ethnic British cohort: a retrospective study
Authors: Vyas M , Chaturvedi N , Hughes A , Marmot M , Tillin T
Published: November 2020

Background

People of South Asian and of African Caribbean descent have elevated risks of some cardiovascular diseases compared to Europeans. How ethnicity relates to recurrent risk, and explanations for between ethnic group differences in recurrence are unclear. We characterized long-term risk of major adverse cardiovascular event (MACE) and mortality following a non-fatal cardiovascular event in a tri-ethnic British cohort.

Methods

We linked hospital and mortality records of a population-based cohort of South Asian, African Caribbean and European men and women aged 40–69 years with no prior history of cardiovascular disease. We identified index and recurrent cardiovascular events (stroke, transient ischaemic attack, myocardial infarction, or ischaemic heart disease), and mortality from 1988 to 2017. Using multivariable proportional hazards models, we separately calculated the adjusted hazard ratios (HR) of MACE and death following index event. We adjusted for demographics, vascular and lifestyle risk factors. We used interaction terms to evaluate if diabetes or decade of index event modified the association between ethnicity and outcomes.

Results

We included 801 participants with first non-fatal cardiovascular events, 647 coronary and 127 cerebrovascular, of whom 335 (41.8%) were European, 396 (49.5%) South Asian, and 70 (8.7%) African Caribbean. During a mean follow-up of 5.3 years, 537 patients developed MACE and 338 died. Crude incidence rate of MACE was higher in South Asians (135.9 per 1000-person-years) compared to Europeans (117.1) and African Caribbeans (123.6). Higher risk of MACE in South Asian compared to Europeans was eliminated in the adjusted models (HR 0.97, 95% confidence interval 0.77–1.21), whereas their mortality advantage was eliminated when the younger age at index event was accounted for (HR 0.95, 0.72–1.26). African Caribbeans had similar outcomes to Europeans (HR MACE 1.04, 0.74–1.47; and HR death 1.07, 0.70–1.64). There was no modification by diabetes for outcomes, whereas survival following index event improved more in South Asian, than African Caribbean, compared to European over three decades (Pinteraction = 0.04).

Conclusions

Baseline vascular risk factors explained the observed ethnic variation in cardiovascular disease recurrence and long-term mortality, with a relative improvement in survival of minority ethnic groups over time.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): UK Medical Research Council, Wellcome Trust
Study design, result reporting and publication of late-stage cardiovascular trials
Authors: Kapelios C , Naci H , Vardas P , Mossialos E
Published: November 2020

Introduction

Preregistration of study protocols in publicly accessible databases is required for publication of study results in high-impact medical journals. Nonetheless, data on the characteristics of clinical trials registered in these databases and their outcome, in terms of result reporting and publication are limited.

Methods

The purpose of this study was to perform a comprehensive analysis of the characteristics of late-stage, cardiovascular disease (CVD) trials registered in Clinicaltrials.gov. We searched for interventional, late-phase (annotated as phase III) CVD studies in adults first posted after 1/1/2013 and completed up to 31/12/2018. Data on study design, result reporting, result spinning and publication were collected, and potential associations with a pre-defined set of explanatory factors were examined.

Results

The search yielded 352 studies. One hundred were excluded from further analysis because they were misclassified as CVD studies, while 2 were excluded as duplicate entries. In total, 250 CVD trials were included in the analysis. The most commonly studied fields were hypertension, coronary artery disease and heart failure. Of these, 193 (77.2%) were randomized studies, 99 (39.6%) open label designs, and 126 (50.4%) had industry as main sponsor. 179 trials (71.6%) evaluated the effect of drugs and 27 (10.8%) evaluated devices. Industry-funded trials focused on patent-protected drugs and devices more often than non-industry-funded trials (72.0% vs. 30.6%, P<0.001 and 55.0% vs. 26.3%, P=0.033, respectively). Sixty three studies (25.2%) had results posted on clinicaltrials.gov, and 116 (46.4%) had results published in the scientific literature. No clear indication of result spinning was found in 96 (85%) of published studies. In multivariate analysis, industry sponsorship was statistically significantly associated with results posting (OR: 3.56; 95% CI:1.67–7.60, P=0.001) and publication (OR: 0.41; 95% CI:0.23–0.75, P=0.004). Results spinning was associated with confirmation of the primary hypothesis (OR: 0.23; 95% CI: 0.07–0.75, P=0.015) and results posting (OR: 0.08; 95% CI: 0.01–0.65, P=0.018).

Conclusions

Among late-stage cardiovascular trials only 1/4 had their results posted on clinicaltrials.gov and less than half had results published. Industry sponsors were more likely to invest in research on patent-protected drugs and devices than were non-industry sponsors. Having industry as a sponsor was independently associated with increased likelihood of results posting, but decreased likelihood of results publication. Results reporting was significantly associated with lower risk of results spinning.

Funding Acknowledgement

Type of funding source: None
Antibodies against the c-terminus of apoA-1 as predictors of death in the general population but not as therapeutic targets actionable through cognate peptides immunomodulation
Authors: Vuilleumier N , Antiochos P , Marques Vidal P , Virzi J , Pagano S , Satta N , Hartley O , Brandt K , Burger F , Montecucco F , Kutalik Z , Waeber G , Mach F , Vollenweider P
Published: November 2020

Aims

Autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgGs) have emerged as an independent biomarker for cardiovascular disease and mortality in humans, promote death in ApoE−/− mice, and seem to be preferentially oriented against the c-terminal part of apoA-1 (cterA1). Corresponding specific mimetic peptides were shown to reverse anti-apoA-1 IgG pro-inflammatory effects in vitro. We evaluated the association of IgG against c-terminus apoA-1 (anti-cterA1 IgGs) with all-cause mortality in the community and tested the ability of two cterA1 mimetic peptides to reverse the anti-apoA-1 IgG-induced inflammation in vitro and mortality in ApoE−/− mice.

Methods

Anti-cterA1 IgGs were measured on serum samples of 5220 consecutive participants included in the CoLaus study with median follow-up duration of 5.6 years. The primary study outcome was all-cause mortality. Two chemically engineered optimized cterA1 mimetic peptides were tested i) on HEK cells to modulate interleukin-8 (IL-8) and tumor necrosis-alpha (TNF-α) production, and ii) in apoE−/− mice exposed to 16 weeks of anti-apoA-1 IgG passive immunisation.

Results

Anti-cterA1 IgG independently predicted all-cause mortality, each standard deviation of anti-cterA1 IgG being associated with a 18% increase in mortality risk (Hazard Ratio:1.18, 95%confidence intervals:1.04–1.33; p=0.009). Both cterA1 mimetic peptides reduced the anti-apoA-1 IgG-induced inflammation in a dose-dependent manner in vitro, but did not rescue the anti-apoA-1 IgG-associated mortality in mice.

Conclusions

Anti-cterA1 IgG independently predict all-cause mortality in the general population. By failing to reverse the anti-apoA-1 IgG-induced mortality in mice, our data do not support the hypothesis that these autoantibodies could be actionable through cognate peptides immunomodulation.

Funding Acknowledgement

Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by a grant from the Leenaards Foundation (grant number 3698 to N.V.) by the Swiss National Science Foundation (grant number 310030-163335 to N.V.) and by the De Reuter Foundation (grant number 315112 to N.V.).
Role of phosphodiesterases in the development of takotsubo syndrome
Authors: Huebscher D , Borchert T , Hasenfuss G , Nikolaev V.O , Streckfuss-Boemeke K
Published: November 2020

Background/Purpose

Takotsubo syndrome (TTS) is characterized by acute transient left ventricular dysfunction in the absence of obstructive coronary lesions. We identified a higher sensitivity to catecholamine-induced stress toxicity as mechanism associated with the TTS phenotype in our former study, but the pathogenesis of TTS is still not completely understood. In this study our aim was to prove the hypothesis of an altered phosphodiesterase (PDE)-dependent 3',5'-cyclic adenosine monophosphate (cAMP)-signaling in TTS in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).

Methods and results

We generated functional TTS-iPSC-CMs and treated them with catecholamines to mimic a TTS-phenotype. To directly address the hypothesis that local cAMP dynamics might be altered in TTS, we used Förster resonance energy transfer (FRET) based cAMP sensors, which are specifically located in the cytosol or at the sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA) micro domain. We demonstrated that β-adrenergic receptor (β-AR) stimulations resulted in stronger cytosolic FRET responses in TTS-CMs compared to controls. In contrast, no differences of cAMP level were observed in the SERCA-PLN micro domain between TTS- and control-iPSC-CMs. To analyze the interplay of β-AR signaling and specific PDE contribution to the cAMP signaling in TTS, specific PDE-inhibitors were used. We were able to show in the cytosol that after β-AR stimulation, the strong effects of the PDE4 family of control cells were significantly decreased in diseased TTS CMs, which is in line with previously described reduced PDE4 activity in failing mouse hearts. In contrast, the contribution of PDE3 to cytoplasmic cAMP degradation was increased in TTS (Figure 1 A). This is in line with increased PDE3A and down-regulated PDE4D protein expression in TTS-iPSC-CMs compared to control cells. Analysis of PDE-dependent cAMP level in the SERCA micro domain show also a significantly reduced PDE4 activity. But the dynamic cytosolic PDE contribution of PDE2 and PDE3 after catecholamine treatment in TTS is lost in SERCA micro domain (Figure1B).

Conclusion

Our data showed for the first time alterations of local cAMP signaling in healthy and diseased TTS-iPSC-CMs. We demonstrated an isozym shift from PDE4 in control to PDE3 and PDE2 in TTS and identified PDE4 as an important player in the β-adrenergic cAMP signaling in TTS. Therefore, PDE4 activators may be a possible new therapeutic target option in the treatment of TTS.

Figure 1

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): DZHK
Preclinical proof-of-concept study: antisense-mediated knockdown of CALM as a therapeutic strategy for calmodulinopathy
Authors: Yamamoto Y , Makiyama T , Wuriyanghai Y , Kohjitani H , Gao J , Kashiwa A , Hai H , Aizawa T , Imamura T , Ishikawa T , Yoshida Y , Ohno S , Horie M , Makita N , Kimura T
Published: November 2020

Background

Calmodulin (CaM) is a ubiquitous Ca2+ sensor molecule encoded by three distinct calmodulin genes, CALM1–3, and has an important role for cardiac ion channel function. Recently, heterozygous missense mutations in CALM genes were reported to cause a new category of life-threatening genetic arrhythmias such as long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), which is called as “calmodulinopathy”. The patients with calmodulinopathy show poor prognosis and there is no effective treatment for them.

Purpose

Considering the dominant-negative effect of mutant calmodulin proteins produced by heterozygous missense mutations in CALMs, we aimed to prove the concept of antisense-based therapy to treat calmodulinopathy using human iPS cell-derived cardiomyocyte (hiPSC-CM) model.

Methods

We designed multiple locked nucleic acid (LNA) gapmer-antisense oligonucleotides (ASOs) targeting CALM2 and analyzed the silencing efficiency and toxicity in cultured cells to select the most potent ASO. Using CMs differentiated from hiPSCs which were generated form a 12-year-old boy with LQTS carrying a heterozygous CALM2-N98S mutation, CALM2 expression and action potentials (APs) were analyzed to evaluate the efficacy of ASOs.

Results

We identified several ASOs which reduced CALM2 expression without affecting cell viability in human cultured cells (HepG2) (ASO 50 nM, n=2; Figure 1A). Considering further experiments in vivo mouse model, we investigated the CALM2 silencing activity in mouse cultured cells (3T3-L1) without transfection (free-uptake) (ASO 1 μM, n=2; †ASOs have homologous sequence between human and mouse; Figure B). After free-uptake CALM2 silencing analysis in 3T3-L1 cells, we identified that ASO #2 has the most potent CALM2 silencing activity and low cytotoxicity (Figure 1B). ASO #2 effectively reduced CALM2 expression even in hiPSC-CMs (ASO(−): n=3, lipofection: n=4, free-uptake: n=3; P<0.05; Figure 1C). In action potential recordings, we demonstrated that ASO #2 ameliorated prolonged AP durations (APD90) in N98S-hiPSC-CMs at 0.5 Hz pacing (ASO(−): 666±123 ms (n=7), lipofection: 329±21 ms (n=8), free-uptake: 388±34 ms (n=12); P<0.05; Figure 1D).

Conclusion

Our results using patient-derived hiPSC-CM model suggest that ASO-based therapy might be a promising strategy for the treatment of calmodulinopathy.

Figure 1

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): Nissan Chemical Corporation
CaMKII inhibition reduces electrical activation heterogeneities caused by mechanical stretch in the myocardium
Authors: Martinez-Navarro H , Del-Canto I , Cardells M.J , Genoves P , Such-Miquel L , Parra G , Arias-Mutis O , Munoz M , Zarzoso M , Alberola A , Chorro-Gasco F.J , Such L
Published: November 2020

Introduction

Ca2+/calmodulin-dependant protein kinase II (CaMKII) activity in cardiomyocytes plays a crucial role in their contractility. Increased CaMKII signalling has been associated with mechanical stretch, often caused in the border zone of myocardial infarction. CaMKII upregulation causes a mishandling of intracellular calcium, a precursor of multiple pro-arrhythmic mechanisms, such as early afterdepolarisations.

Purpose

In this study, we aim to quantify the effects of KN-93 -a CaMKII inhibitor- on wave dynamics, in order to investigate its effectiveness as an anti-arrhythmic agent.

Methods

An isolated Langendorff model was constructed based on rabbit hearts (n=18) and posteriorly induced to fibrillation. An epicardial multielectrode array (121 electrodes) was used for recording the electrical activity. Mechanical stretch was induced by pushing the anterior myocardial wall from the left-ventricular cavity. Then, a frequency analysis was conducted for the following conditions: before drug infusion, during infusion, during infusion plus stretch, and during infusion post-stretch. Nine hearts represented the untreated group, and the other nine were infused with KN-93 at a concentration of 10 nM (less than 3% of the IC50 value).

Results

Prior to stretch induction, KN-93 caused no effects in the spectral concentration (SC) and average dominant frequency (ADF) calculated on the infused rabbit hearts. Nevertheless, intrasubject measurements revealed statistically significant differences (p<0.05) between hearts infused with KN-93 and the untreated ones when stretch was induced. Changes in SC were milder in the treated than the untreated group (−6% vs −33%). Also, the stretch-induced increase in ADF was more limited in the treated group (+17% vs +40%). Hearts infused with KN-93 shown a higher resistance to stretch-induced electrical abnormalities, potentially due to better regulated intracellular calcium dynamics.

Conclusion

CaMKII inhibitors show cardioprotective potential, even at very low concentrations. Further research is required to investigate the therapeutic use of these compounds in conditions of intracellular calcium mishandling and its concomitant life-threatening consequences, such as heart failure or Torsade de Pointes.

KN-93 reduces stretch-induced changes

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): Universitat de València; Generalitat Valenciana - Prometeo; Carlos III, CIBERCV
Long-read sequence confirmed a large deletion of MYH6 and MYH7 in a family with atrial septal defect
Authors: Sonoda K , Ohno S , Horie M
Published: November 2020

Background

Genome structural variants (SVs) have larger effect on human genome functions than single nucleotide variants (SNVs). Although short-read sequencing (SRS) is current major next generation sequencing method and has given us a great benefit to elucidate the genetic background of inherited diseases, it does not detect SVs accurately. Long-read sequencing (LRS) produces tens to thousands of kilobases reads and detects the breakpoints of complex SVs. This study aimed to confirm a large deletion, which was suspected by SRS, using LRS by Oxford Nanopore technology (ONT).

Methods

Genomic libraries for SRS was prepared with HaloPlex. Targeted SRS was performed for 58 genes with MiSeq. Genomic libraries for LRS were prepared using the Ligation sequencing 1D kit SQK-LSK109 (ONT). Whole genome LRS was performed with GridION X5 and R9.4 flow cells (ONT).

Results

The patient was a five-month-old boy with atrial septal defect (ASD) and atrial tachycardia. Though SRS failed to identify any causative SNVs, the results with SureCall software (Agilent) suspected a deletion between exon 3 to exon 26 in MYH6 encoding α heavy chains of cardiac myosin. The variants in MYH6 are known to be associated with ASD. Because a deletion between MYH6 exon 26 and MYH7 exon 27 was reported as esv2748480 on the Database of Genomic Variants, we performed long-range PCR from MYH6 intron26 to MYH7 exon26 and found an abnormal 1.5K bases PCR product only in the case. Due to high homology of MYH6 and MYH7, Sanger sequencing failed to detect the break point.

In LRS, 3 flow cells generated 3.8M base-called reads containing 42G bases with N50 of 13K bases. We used NGMLR, which is a long-read mapper, to align the reads to the human reference genome (hg38). SVs were called by Sniffles detecting all types of SVs. The deletion was found to range from chr14: 23390037 to 23419824 (see figure) and did not contain other SVs. There was no pathogenic SV on ACTC1, GATA4, TBX20 and TLL1 which are genes related to ASD on Genetic Testing Registry.

His mother had also ASD and harbored the same deletion.

Conclusions

This is the first report to identify a large deletion between MYH6 and MYH7 in the family with ASD. The combination of SRS and LRS is useful to detect SVs in patients with suspected inherited diseases but carried no causative SNVs.

Funding Acknowledgement

Type of funding source: None
Blocking of interleukin-1 suppresses both angiotensin II-induced renal inflammation and hypertension
Authors: Niida T , Isoda K , Kitamura K , Okabayashi Y , Kadoguchi T , Ohtomo F , Shimada K
Published: November 2020

Background

Clinical hypertension is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. IL-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (AngII)-induced hypertension response. This study aimed to elucidate the effects of IL-1Ra and anti-IL-1beta antibody (01BSUR) on AngII-induced hypertension and renal inflammation.

Methods and results

To determine the contribution of IL-1Ra to AngII-induced renal inflammation, male wild-type (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with AngII (1000ng/kg/min) using subcutaneous osmotic pumps for 14 days. We checked blood pressure, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197±5 vs 169±9 mmHg, p<0.05) in IL-1Ra−/− mice significantly increased compared with WT mice. Furthermore, on day 14 of AngII infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra−/− versus WT mice (p<0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra−/− mice (p<0.05). To examine renal function, we analyzed 24-hour urinary protein excretion and serum levels of blood urea nitrogen, creatinine, and uric acid in IL-1Ra−/− and WT mice. On day 14 of Ang II infusion, all levels increased significantly in IL-1Ra−/− mice compared with WT mice, suggesting that IL-1Ra deficiency reduced renal function following Ang II infusion. In addition, renal histology revealed that glomerular injury (Figure upper panels: PAS staining) and tubulointerstitial fibrosis (Figure lower panels: Elastica Masson staining) increased significantly in Ang II-infused IL-1Ra−/− versus Ang II-infused WT mice. Finally, we administrated 01BSUR to both IL-1Ra−/− and WT mice, and 01BSUR treatment decreased AngII-induced hypertension (162±17 vs 204±6 mmHg, p<0.05) and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra−/− and WT mice compared with IgG2a treatment. These findings suggest that 01BSUR suppresses Ang II-induced inflammation and renal injury.

Conclusions

Inhibition of interleukin-1 by both endogenous IL-1Ra and exogenous 01BSUR decreased AngII-induced hypertension and renal damage in mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI