Explainable machine learning using echocardiography to improve risk prediction in patients with chronic coronary syndrome.

Aims: The European Society of Cardiology guidelines recommend risk stratification with limited clinical parameters such as left ventricular (LV) function in patients with chronic coronary syndrome (CCS). Machine learning (ML) methods enable an analysis of complex datasets including transthoracic echocardiography (TTE) studies. We aimed to evaluate the accuracy of ML using clinical and TTE data to predict all-cause 5-year mortality in patients with CCS and to compare its performance with traditional risk stratification scores. Methods and results: Data of consecutive patients with CCS were retrospectively collected if they attended the outpatient clinic of Amsterdam UMC location AMC between 2015 and 2017 and had a TTE assessment of the LV function. An eXtreme Gradient Boosting (XGBoost) model was trained to predict all-cause 5-year mortality. The performance of this ML model was evaluated using data from the Amsterdam UMC location VUmc and compared with the reference standard of traditional risk scores. A total of 1253 patients (775 training set and 478 testing set) were included, of which 176 patients (105 training set and 71 testing set) died during the 5-year follow-up period. The ML model demonstrated a superior performance [area under the receiver operating characteristic curve (AUC) 0.79] compared with traditional risk stratification tools (AUC 0.62-0.76) and showed good external performance. The most important TTE risk predictors included in the ML model were LV dysfunction and significant tricuspid regurgitation. Conclusion: This study demonstrates that an explainable ML model using TTE and clinical data can accurately identify high-risk CCS patients, with a prognostic value superior to traditional risk scores.

Comparison of the Diagnostic Yield of Intracoronary Acetylcholine Infusion and Acetylcholine Bolus Injection Protocols During Invasive Coronary Function Testing.

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina with no obstructive coronary arteries in patients. Both can be diagnosed by invasive coronary function testing (ICFT) using acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared with a 1-minute ACh bolus injection protocol in testing CED and CAS. We evaluated 220 consecutive patients with angina and no obstructive coronary arteries who underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion, and thereafter 110 patients using 1-minute bolus injections, because of a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low-dose ACh and CAS according to the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%, p = 0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3 vs 1-minute protocol (24% vs 44%, p = 0.004). Including T-wave abnormalities in the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as a diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as a diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

Impact of sex on the assessment of the microvascular resistance reserve.

BACKGROUND: The microvascular resistance reserve (MRR) is an innovative index to assess the vasodilatory capacity of the coronary circulation while accounting for the presence of concomitant epicardial disease. The MRR has shown to be a valuable diagnostic and prognostic tool in the general coronary artery disease (CAD) population. However, considering the fundamental aspects of its assessment and the unique hemodynamic characteristics of women, it is crucial to provide additional considerations for evaluating the MRR specifically in women. AIM: The aim of this study was to assess the diagnostic and prognostic applicability of the MRR in women and assess the potential differences across different sexes. METHODS: From the ILIAS Registry, we enrolled all patients with a stable indication for invasive coronary angiography, ensuring complete physiological and follow-up data. We analyzed the diagnostic value by comparing differences between sexes and evaluated the prognostic value of the MRR specifically in women, comparing it to that in men. RESULTS: A total of 1494 patients were included of which 26% were women. The correlation between MRR and CFR was good and similar between women (r = 0.80, p < 0.005) and men (r = 0.81, p < 0.005). The MRR was an independent and important predictor of MACE in both women (HR 0.67, 0.47-0.96, p = 0.027) and men (HR 0.84, 0.74-0.95, p = 0.007). The optimal cut-off value for MRR in women was 2.8 and 3.2 in men. An abnormal MRR similarly predicted MACE at 5-year follow-up in both women and men. CONCLUSION: The MRR seems to be equally applicable in both women and men with stable coronary artery disease.

Digital Solutions to Optimize Guideline-Directed Medical Therapy Prescriptions in Heart Failure Patients: Current Applications and Future Directions.

PURPOSEOF REVIEW: Guideline-directed medical therapy (GDMT) underuse is common in heart failure (HF) patients. Digital solutions have the potential to support medical professionals to optimize GDMT prescriptions in a growing HF population. We aimed to review current literature on the effectiveness of digital solutions on optimization of GDMT prescriptions in patients with HF. RECENT FINDINGS: We report on the efficacy, characteristics of the study, and population of published digital solutions for GDMT optimization. The following digital solutions are discussed: teleconsultation, telemonitoring, cardiac implantable electronic devices, clinical decision support embedded within electronic health records, and multifaceted interventions. Effect of digital solutions is reported in dedicated studies, retrospective studies, or larger studies with another focus that also commented on GDMT use. Overall, we see more studies on digital solutions that report a significant increase in GDMT use. However, there is a large heterogeneity in study design, outcomes used, and populations studied, which hampers comparison of the different digital solutions. Barriers, facilitators, study designs, and future directions are discussed. There remains a need for well-designed evaluation studies to determine safety and effectiveness of digital solutions for GDMT optimization in patients with HF. Based on this review, measuring and controlling vital signs in telemedicine studies should be encouraged, professionals should be actively alerted about suboptimal GDMT, the researchers should consider employing multifaceted digital solutions to optimize effectiveness, and use study designs that fit the unique sociotechnical aspects of digital solutions. Future directions are expected to include artificial intelligence solutions to handle larger datasets and relieve medical professional's workload.

Severe silent ischaemia detected with an Apple Watch in the home setting: a case report.

Background: The Apple Watch has the capability to record a lead 1 electrocardiogram (ECG) and can identify and report atrial fibrillation. The use for detecting myocardial ischaemia is not endorsed by Apple but is documented in this case. Case summary: A 76-year-old man made a lead 1 ECG with his Apple Watch immediately after exercising on a cross trainer. He was fully asymptomatic. The ECG showed an unusual negative T-wave in this lead 1 that deepened in a few minutes and returned to normal after 22 min. He consulted a cardiologist and a standard exercise ECG confirmed the negative T-wave in lead 1 after maximal exercise and in addition showed widespread ST-depression indicating myocardial ischaemia, again without any clinical symptoms. Further studies revealed severe obstructive three-vessel coronary artery disease that was considered not suitable for percutaneous intervention. A coronary artery bypass operation on all involved vessels was performed successfully. Recovery was uneventful and an exercise ECG repeated 11 weeks later was normal. Discussion: We demonstrated that the lead 1 ECG made with the Apple Watch can reliably record T-wave changes indicating myocardial ischaemia. The use of the Apple Watch to document ischaemic changes should be studied systematically for its potential to identify myocardial ischaemia, mainly triggered by symptoms but maybe for asymptomatic persons as well.

Comparison between interventional versus medical therapy in patients with rheumatic mitral valve stenosis in Tanzania.

BACKGROUND: Rheumatic heart disease remains the most common cardiovascular disease in children and young adults. The outcome of interventional versus medical therapy on the long term is not fully elucidated yet. This study provides contemporary data on the clinical profile, treatment and follow up of patients with rheumatic mitral stenosis (MS) in Tanzania. METHODS: Patients' medical information, investigations and treatment data were recorded in this prospective cohort study. They were followed up for 6-24 months to determine the long-term outcome. Interventional therapy was defined as a combination of surgery and percutaneous balloon mitral valvuloplasty. Kaplan-Meier curves and Cox proportional hazards model were used in analyses. p-Value < 0.05 was considered statistically significant. RESULTS: We enrolled 290 consecutive patients. Interventions were done in half of the patients. Median follow up was 23.5 months. Mortality was higher in the medical than interventional treatment (10.4% vs. 4%, log-rank p = 0.001). Median age was 36 years, females (68.3%) and low income (55.5%). Multivalvular disease was found in 116 (40%) patients, atrial fibrillation (31.4%), stroke/transient ischaemic attack (18.9%) and heart failure class III-IV (44.1%). Median (IQR) duration of disease was 3 (4) years, secondary prophylaxis (27.7%) and oral anticoagulants use (62.3%). In multivariable analysis, the risk of death among patients on medical was 3.07 times higher than those on interventional treatment (crude HR 3.07, 95% CI 1.43-6.56, p = 0.004), 2.44 times higher among patients with arrhythmias versus without arrhythmias (crude HR 2.44, 95% CI 1.19-4.49, p = 0.015) and 2.13 times higher among patients with multivalvular than single valve disease (crude HR 2.13, 95% CI 1.09-4.16, p = 0.026). CONCLUSIONS: Intervention is carrying low mortality compared to medical treatment. Arrhythmias and multivalvular disease are associated with a high mortality. Rheumatic MS is more prevalent in young people, females and individuals with low income. There is a late hospital presentation and a low use of both secondary prophylactic antibiotics and anticoagulants.

Digital consults to optimize guideline-directed therapy: design of a pragmatic multicenter randomized controlled trial.

AIMS: Many heart failure (HF) patients do not receive optimal guideline-directed medical therapy (GDMT) despite clear benefit on morbidity and mortality outcomes. Digital consults (DCs) have the potential to improve efficiency on GDMT optimization to serve the growing HF population. The investigator-initiated ADMINISTER trial was designed as a pragmatic multicenter randomized controlled open-label trial to evaluate efficacy and safety of DC in patients on HF treatment. METHODS AND RESULTS: Patients (n = 150) diagnosed with HF with a reduced ejection fraction will be randomized to DC or standard care (1:1). The intervention group receives multifaceted DCs including (i) digital data sharing (e.g. exchange of pharmacotherapy use and home-measured vital signs), (ii) patient education via an e-learning, and (iii) digital guideline recommendations to treating clinicians. The consults are performed remotely unless there is an indication to perform the consult physically. The primary outcome is the GDMT prescription rate score, and secondary outcomes include time till full GDMT optimization, patient and clinician satisfaction, time spent on healthcare, and Kansas City Cardiomyopathy Questionnaire. Results will be reported in accordance to the CONSORT statement. CONCLUSIONS: The ADMINISTER trial will offer the first randomized controlled data on GDMT prescription rates, time till full GDMT optimization, time spent on healthcare, quality of life, and patient and clinician satisfaction of the multifaceted patient- and clinician-targeted DC for GDMT optimization.

Prognostic Implications of Individual and Combinations of Resting and Hyperemic Coronary Pressure and Flow Parameters.

Background: Coronary pressure- and flow-derived parameters have prognostic value. Objectives: This study aims to investigate the individual and combined prognostic relevance of pressure and flow parameters reflecting resting and hyperemic conditions. Methods: A total of 1,971 vessels deferred from revascularization after invasive pressure and flow assessment were included from the international multicenter registry. Abnormal resting pressure and flow were defined as distal coronary pressure/aortic pressure ≤0.92 and high resting flow (1/resting mean transit time >2.4 or resting average peak flow >22.7 cm/s), and abnormal hyperemic pressure and flow as fractional flow reserve ≤0.80 and low hyperemic flow (1/hyperemic mean transit time <2.2 or hyperemic average peak flow <25.0 cm/s), respectively. The clinical endpoint was target vessel failure (TVF), myocardial infarction (MI), or cardiac death at 5 years. Results: The mean % diameter stenosis was 46.8% ± 16.5%. Abnormal pressure and flow were independent predictors of TVF and cardiac death/MI (all P < 0.05). The risk of 5-year TVF or MI/cardiac death increased proportionally with neither, either, and both abnormal resting pressure and flow, and abnormal hyperemic pressure and flow (all P for trend < 0.001). Abnormal resting pressure and flow were associated with a higher rate of TVF or MI/cardiac death in vessels with normal fractional flow reserve; this association was similar for abnormal hyperemic pressure and flow in vessels with normal resting distal coronary pressure/aortic pressure (all P < 0.05). Conclusions: Abnormal resting and hyperemic pressure and flow were independent prognostic predictors. The abnormal flow had an additive prognostic value for pressure in both resting and hyperemic conditions with complementary prognostic between resting and hyperemic parameters.

Changes in microvascular resistance following percutaneous coronary intervention - From the ILIAS global registry.

BACKGROUND: Microvascular resistance (MR) has prognostic value in acute and chronic coronary syndromes following percutaneous coronary intervention (PCI), however anatomic and physiologic determinants of the relative changes of MR and its association to target vessel failure (TVF) has not been investigated previously. This study aims to evaluate the association between changes in MR and TVF. METHODS: This is a sub-study of the Inclusive Invasive Physiological Assessment in Angina Syndromes (ILIAS) registry which is a global multi-centre initiative pooling lesion-level coronary pressure and flow data. RESULTS: Paired pre-post PCI haemodynamic data were available in n = 295 vessels out of n = 828 PCI treated patients and of these paired data on MR was present in n = 155 vessels. Vessels were divided according to increase vs. decrease % in microvascular resistance following PCI (ΔMR % ≤ 0 vs. ΔMR > 0%). Decreased microvascular resistance ΔMR % ≤ 0 occurred in vessels with lower pre-PCI fractional flow reserve (0.67 ± 0.15 vs. 0.72 ± 0.09 p = 0.051), coronary flow reserve (1.9 ± 0.8 vs. 2.6 ± 1.8 p < 0.0001) and higher hyperemic microvascular resistance (2.76 ± 1.3 vs. 1.62 ± 0.74 p = 0.001) and index of microvascular resistance (24.4 IQ (13.8) vs. 15. 8 IQ (13.2) p = 0.004). There was no difference in angiographic parameters between ΔMR % ≤ 0 vs. ΔMR > 0%. In a cox regression model ΔMR % > 0 was associated with increased rate of TVF (hazard ratio 95% CI 3.6 [1.2; 10.3] p = 0.018). CONCLUSION: Increased MR post-PCI was associated with lesions of less severe hemodynamic influence at baseline and higher rates of TVF at follow-up.

Sex differences in prevalence and outcomes of the different endotypes of chronic coronary syndrome in symptomatic patients undergoing invasive coronary angiography: Insights from the global ILIAS invasive coronary physiology registry.

BACKGROUND AND AIMS: The management of chronic coronary syndrome (CCS) is informed by studies predominantly including men. This study investigated the relationship between patients sex and different endotypes of CCS, including sex-specific clinical outcomes. METHODS: In patients with CCS undergoing coronary angiography, invasive Fractional Flow Reserve (FFR) and Coronary Flow Reserve (CFR) were measured. Patients were stratified into groups: 1) obstructive coronary artery disease (oCAD) (FFR≤0.80, no revascularization), 2) undergoing revascularization, 3) non-obstructive coronary artery disease with coronary microvascular dysfunction (CMD) (FFR>0.80, CFR≤2.5), and 4) non-obstructive coronary artery disease without CMD (FFR>0.80 and CFR>2.5). RESULTS: 1836 patients (2335 vessels) were included, comprising 1359 (74.0%) men and 477 (26.0%) women. oCAD was present in 14.1% and was significantly less prevalent in women than in men (10.3% vs 15.5%, respectively p < 0.01). Revascularization was present in 30.9% and was similarly prevalent in women and men (28.2% vs. 31.9%, respectively p = 0.13). CMD was present in 24.2% and was significantly more prevalent in women than men (28.6% vs 22.6%, respectively p < 0.01). Normal invasive measurements were found in 564 patients (33.0% women vs 30.0% men, p = 0.23). Male sex was associated with an increased risk of target vessel failure compared to women (HR.1.89, 95% CI 1.12-3.18, p = 0.018), regardless of CCS-endotype. CONCLUSIONS: Sex differences exist in the prevalence and outcomes of different endotypes of CCS in symptomatic patients undergoing invasive coronary angiography. In particular, oCAD (and subsequent revascularization) were more prevalent in men. Conversely, CMD was more prevalent in women. Overall, men experienced a worse cardiovascular outcome compared to women, independent of any specific CCS endotype.

The impact of valvular heart disease in patients with chronic coronary syndrome.

Background: The European Society of Cardiology 2019 Guidelines on chronic coronary syndrome (CCS) recommend echocardiographic measurement of the left ventricular function for risk stratification in all patients with CCS. Whereas CCS and valvular heart disease (VHD) share common pathophysiological pathways and risk factors, data on the impact of VHD in CCS patients are scarce. Methods: Clinical data including treatment and mortality of patients diagnosed with CCS who underwent comprehensive transthoracic echocardiography (TTE) in two tertiary centers were collected. The outcome was all-cause mortality. Data were analyzed with Kaplan-Meier curves and Cox proportional hazard analysis adjusting for significant covariables and time-dependent treatment. Results: Between 2014 and 2021 a total of 1,984 patients with CCS (59% men) with a median age of 65 years (interquartile range [IQR] 57-73) underwent comprehensive TTE. Severe VHD was present in 44 patients and moderate VHD in 325 patients. A total of 654 patients (33%) were treated with revascularization, 39 patients (2%) received valve repair or replacement and 299 patients (15%) died during the median follow-up time of 3.5 years (IQR 1.7-5.6). Moderate or severe VHD (hazard ratio = 1.33; 95% CI 1.02-1.72) was significantly associated with mortality risk, independent of LV function and other covariables, as compared to no/mild VHD. Conclusions: VHD has a significant impact on mortality in patients with CCS additional to LV dysfunction, which emphasizes the need for a comprehensive echocardiographic assessment in these patients.

The role and implications of left atrial fibrosis in surgical mitral valve repair as assessed by CMR: the ALIVE study design and rationale.

Background: Patients with mitral regurgitation (MR) commonly suffer from left atrial (LA) remodeling. LA fibrosis is considered to be a key player in the LA remodeling process, as observed in atrial fibrillation (AF) patients. Literature on the presence and extent of LA fibrosis in MR patients however, is scarce and its clinical implications remain unknown. Therefore, the ALIVE trial was designed to investigate the presence of LA remodeling including LA fibrosis in MR patients prior to and after mitral valve repair (MVR) surgery. Methods: The ALIVE trial is a single center, prospective pilot study investigating LA fibrosis in patients suffering from MR in the absence of AF (identifier NCT05345730). In total, 20 participants will undergo a CMR scan including 3D late gadolinium enhancement (LGE) imaging 2 week prior to MVR surgery and at 3 months follow-up. The primary objective of the ALIVE trial is to assess the extent and geometric distribution of LA fibrosis in MR patients and to determine effects of MVR surgery on reversed atrial remodelling. Implications: This study will provide novel insights into the pathophysiological mechanism of fibrotic and volumetric atrial (reversed) remodeling in MR patients undergoing MVR surgery. Our results may contribute to improved clinical decision making and patient-specific treatment strategies in patients suffering from MR.

Health related quality of life of patients following mechanical valve replacement surgery for rheumatic mitral stenosis in Tanzania.

BACKGROUND: The assessment of outcomes of interventions based on the patient's perspective using patient-reported outcome measures (PROMs) has been increasingly highlighted in clinical practice. However, health related quality of life (HRQoL), one of the common constructs measured by PROMs remain unknown among patients after heart valve replacement (HVR) in Tanzania. OBJECTIVES: To assess the HRQoL amongst patients operated on for rheumatic mitral stenosis at Jakaya Kikwete Cardiac Institute (JKCI). METHODS: A prospective study of patients operated on due to rheumatic mitral stenosis at JKCI from January 2020 to April 2021 was undertaken. The HRQoL was assessed by using the MacNew questionnaire, addressing three domains (physical, emotional, and social function); the score ranges from 0 to 7. We categorized HRQoL as low (mean score ≤ 4.9), moderate (5-6) and high (> 6). We analysed several sociodemographic and clinical variables for HRQoL. RESULTS: Out of 54 patients, there were 34 females and 20 males. Their mean (± SD) age was 37.98 (± 12.58) years. The reliability of translated Kiswahili version of MacNew was good. The mean (± SD) global scores were 3.47 ± 0.59, 4.88 ± 0.71 and 6.14 ± 0.50 preoperatively, at 3 months and 6 months respectively (p-values < 0.001 preoperatively vs. 3 months, preoperatively vs. 6 months and at 3 months vs. 6 months). The median of individual mean difference HRQoL score pre-operatively and at 6 months was 2.67. The preoperative and 6 months mean difference HRQoL scores were higher among patients with vs. without atrial fibrillation (2.95 ± 0.59 vs. 2.45 ± 0.53, p = 0.003) and those on anticoagulants (preoperatively) vs. not on anticoagulants (3.14 ± 0.58 vs. 2.57 ± 0.57, 0.009). The mean difference HRQoL scores were similar for sociodemographic and other clinical parameters, including those with stroke vs. without stroke. CONCLUSION: Six months after HVR the overall MacNew HRQoL scores improved markedly. This improvement in HRQoL was regardless of the presence of comorbidities (e.g. stroke and atrial fibrillation) which underscores the importance of considering valvular surgery if they fit the criteria. Clinicians and researchers in low-resource settings should collaborate to promote the utilization of PROMs in the routine care of patients.

Characteristics and immediate outcomes of patients who underwent percutaneous balloon mitral valvuloplasty at the Jakaya Kikwete Cardiac Institute, Tanzania.

BACKGROUND: For rheumatic mitral stenosis (MS), a multidisciplinary evaluation is mandatory to determine the optimal treatment: medical, percutaneous balloon mitral valvuloplasty (PBMV) or valve surgery. Clinical and imaging evaluations are essential for procedural risk assessment and outcomes. PBMV interventions are increasingly available in Africa and are feasible options for selected candidates. Enhancing PBMV training/skills transfer across most of African countries is possible. OBJECTIVES: The aim of this study was to provide insight into the clinical practice of patients with rheumatic MS evaluated for PBMV in a Tanzanian teaching hospital and to define the role of imaging, and evaluate the heart team and training/skills transfer in PBMV interventions. METHODS: From August 2019 to May 2022, 290 patients with rheumatic MS were recruited consecutively in the Tanzania Mitral Stenosis study. In total, 43 (14.8%) patients were initially evaluated for eligibility for PBMV by a heart team. We carried out the clinical assessment, laboratory investigations, transthoracic/oesophageal echocardiography (TTE/TEE) and electrocardiography. RESULTS: The median age was 31 years (range 11-68), and two-thirds of the patients were female (four diagnosed during pregnancy). Two patients had symptomatic MS at six and eight years. Nine patients had atrial fibrillation with left atrial thrombus in three, and two were detected by TEE. Nine patients in normal sinus rhythm had spontaneous echo contrast. The mean Wilkins score was 8.6 (range 8-12). With re-evaluation by the local and visiting team, 17 patients were found to have unfavourable characteristics: Bi-commissural calcification (four), ≥ grade 2/4 mitral regurgitation (six), high scores and left atrial thrombus (three), left atrial thrombus (two), and severe pulmonary hypertension (two). Three patients died before the planned PBMV. Eleven patients were on a waiting list. We performed PBMV in 12 patients, with success in 10 of these, and good short-term outcomes [mean pre-PBMV (16.03 ± 5.52 mmHg) and post-PBMV gradients (3.08 ± 0.44 mmHg, p < 0.001)]. There were no complications. CONCLUSIONS: PBMV had good outcomes for selected candidates. TEE is mandatory in pre-PBMV screening and for procedural guidance. In our cohort, patients with Wilkins score of up to 11 underwent successful PBMV. We encourage PBMV skills expansion in low- and middle-income countries, concentrating on expertise centres.

Effect of allogeneic adipose tissue-derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction - the SCIENCE trial.

AIMS: The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue-derived mesenchymal stromal cells (CSCC_ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: The study was a European multicentre, double-blind, placebo-controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II-III, left ventricular ejection fraction (LVEF) <45%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels >300 pg/ml. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end-systolic volume (LVESV) at 6-month follow-up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug-related severe adverse events or difference in cardiac-related adverse events during a 3-year follow-up period. There were no significant differences between groups during follow-up in LVESV (0.3 ± 5.0 ml, p = 0.945), nor in secondary endpoints of left ventricular end-diastolic volume (-2.0 ± 6.0 ml, p = 0.736) and LVEF (-1.6 ± 1.0%, p = 0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6-min walk test, NT-proBNP, C-reactive protein or quality of life the first year in any groups. CONCLUSION: The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre-defined endpoints and induce restoration of cardiac function or clinical symptoms.

Combined use of hyperemic and non-hyperemic pressure ratios for revascularization decision-making: From the ILIAS registry.

OBJECTIVE: The aim of this study is to evaluate the diagnostic and prognostic value of non-hyperaemic Pd/Pa and to determine its additional value when combined with the gold standard hyperaemic pressure ratio (FFR) to guide revascularization. METHODS: In a large, multi-center, retrospective registry, we included a total of 2141 patients with a clinical indication for coronary angiography providing physiological data in 2726 vessels. A classification was made based on the FFR (cut-off value: 0.80) and non-hyperaemic Pd/Pa (cut-off value: 0.92) values and the primary outcome was target-vessel failure (TVF) at 5-year follow-up. RESULTS: Mean age was 63 ± 10.0 and 75% of the study population were men. Regression analysis showed an overall good correlation between FFR and non-hyperaemic Pd/Pa (r = 0.73, p < 0.005) and discordance was present in 17% of the vessels. Resting Pd/Pa was independently associated with TVF at 5-year follow-up (HR 0.08, 95%CI: 0.02-0.27; p < 0.005). The risk for TVF was the lowest in vessles with concordant normal pressure ratio's, with the highest risk in vessels with any abnormal pressure ratio in which revascularization was deferred. In these vessels, there was no difference in risk for TVF between the discordant and concordant abnormal values. CONCLUSION: Abnormal pressure ratios in both non-hyperemic and hyperemic conditions portend important prognostic value. Combined application of FFR and non-hyperemic Pd/Pa efficiently identifies those vessels with concordant normal resting and hyperemic pressure ratios of which long-term clinical outcomes are excellent. These data lead to hypothesize that the decision to defer revascularization should potentially be based on combined non-hyperemic and hyperemic pressure ratios. CLINICAL TRIAL REGISTRATION: Inclusive Invasive Physiological Assessment in Angina Syndromes Registry (ILIAS Registry), NCT04485234.

Infective endocarditis in developing countries: An update.

Introduction: Despite advances in diagnostic and treatment, morbidity and mortality due to infective endocarditis (IE) has not decreased. There is a discrepancy in epidemiology of IE between developed and developing countries. Over the last years, increased early detection and consequently prevalence of rheumatic heart disease (RHD) and congenital heart disease (CHD) which are considered predisposing conditions for IE, is noted. Here, we present a review of literature on IE in developing countries. Methods: We conducted a systematic literature search of IE studies in developing countries through PubMed and Embase. We have divided the studies into two groups: studies published before 2015 (group 1) and studies ≥ 2015 (group 2). The outcome was defined as a difference in epidemiology, microbiology, treatment, and mortality over time. The Scale for Assessment of Narrative Review Articles guidelines was applied. Findings: In total, 16 studies were included. The total number of IE cases was 1,098 and 1,505 in groups 1 and 2, respectively. We compared 4/7 cohorts from group 1 (n = 789) with 5/9 cohorts from group 2 (n = 636). Six studies were not included in the comparison because they were interacting between the two cohorts. Males predominated in all studies. Rheumatic heart disease was higher in group 1 than in group 2 (42.3% vs. 30.3%, p < 0.001) while for CHD there was no change (17.6% vs. 16.7%, p = 0.672). Streptococci infections was lower in group 1 than group 2 (26.2% vs. 37.7%, p < 0.001). The proportion of Staphylococcus aureus was 15.3% in group 1 and 23.6% in group 2, p < 0.001. Negative blood culture (NBC) was higher in group 1 than in group 2 (42.2% vs. 34.1%, p = 0.002). Patients in group 1 received more surgery than in group 2 (38.8% vs. 28.8%, p < 0.001). Mortality was similar in the two groups (20.9% vs. 22.3%, p = 0.518). Conclusion: This review shows a scarcity of studies on IE in developing countries. Rheumatic heart disease and congenital heart disease are common predisposing conditions. Other risk factors are prosthetic valves, degenerative valve disease (DVD), intravenous drug use, and human immunodeficiency virus infection. While the proportion of IE cases caused by Streptococcus and Staphylococcus has increased, the number of NBC and patients getting surgery has decreased. Mortality has not changed over time. Timely diagnosis and management of patients with RHD and CHD and comprehensive management of IE are warranted.

Metabolic Maturation Increases Susceptibility to Hypoxia-induced Damage in Human iPSC-derived Cardiomyocytes.

The development of new cardioprotective approaches using in vivo models of ischemic heart disease remains challenging as differences in cardiac physiology, phenotype, and disease progression between humans and animals influence model validity and prognostic value. Furthermore, economical and ethical considerations have to be taken into account, especially when using large animal models with relevance for conducting preclinical studies. The development of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has opened new opportunities for in vitro studies on cardioprotective compounds. However, the immature cellular phenotype of iPSC-CMs remains a roadblock for disease modeling. Here, we show that metabolic maturation renders the susceptibility of iPSC-CMs to hypoxia further toward a clinically representative phenotype. iPSC-CMs cultured in a conventional medium did not show significant cell death after exposure to hypoxia. In contrast, metabolically matured (MM) iPSC-CMs showed inhibited mitochondrial respiration after exposure to hypoxia and increased cell death upon increased durations of hypoxia. Furthermore, we confirmed the applicability of MM iPSC-CMs for in vitro studies of hypoxic damage by validating the known cardioprotective effect of necroptosis inhibitor necrostatin-1. Our results provide important steps to improving and developing valid and predictive human in vitro models of ischemic heart disease.

Prognostic Impact of Coronary Flow Reserve in Patients With Reduced Left Ventricular Ejection Fraction.

Background Intracoronary physiologic indexes such as coronary flow reserve (CFR) and left ventricular ejection fraction (LVEF) have been regarded as prognostic indicators in patients with coronary artery disease. The current study evaluated the association between intracoronary physiologic indexes and LVEF and their differential prognostic implications in patients with coronary artery disease. Methods and Results A total of 1889 patients with 2492 vessels with available CFR and LVEF were selected from an international multicenter prospective registry. Baseline physiologic indexes were measured by thermodilution or Doppler methods and LVEF was recorded at the index procedure. The primary outcome was target vessel failure, which was a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization over 5 years of follow-up. Patients with reduced LVEF <50% (162 patients [8.6%], 202 vessels [8.1%]) showed a similar degree of epicardial coronary artery disease but lower CFR values than those with preserved LVEF (2.4±1.2 versus 2.7±1.2, P<0.001), mainly driven by the increased resting coronary flow. Conversely, hyperemic coronary flow, fractional flow reserve, and the degree of microvascular dysfunction were similar between the 2 groups. Reduced CFR (≤2.0) was seen in 613 patients (32.5%) with 771 vessels (30.9%). Reduced CFR was an independent predictor for target vessel failure (hazard ratio, 2.081 [95% CI, 1.385-3.126], P<0.001), regardless of LVEF. Conclusions CFR was lower in patients with reduced LVEF because of increased resting coronary flow. Patients with reduced CFR showed a significantly higher risk of target vessel failure than did those with preserved CFR, regardless of LVEF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.