Prognostic Value of Transthoracic Doppler Echocardiography Coronary Flow Velocity Reserve in Patients With Asymmetric Hypertrophic Cardiomyopathy

Background Microvascular dysfunction might be a major determinant of clinical deterioration and outcome in patients with hypertrophic cardiomyopathy (HCM). However, long‐term prognostic value of transthoracic Doppler echocardiography (TDE) coronary flow velocity reserve (CFVR) on clinical outcome is uncertain in HCM patients. Therefore, the aim of our study was to assess long‐term prognostic value of CFVR on clinical outcome in HCM population. Methods and Results We prospectively included 150 HCM patients (82 women; mean age 48±15 years). Patients’ clinical characteristics, echocardiographic and CFVR findings (both for left anterior descending [LAD] and posterior descending artery [PD]), were assessed in all patients. The primary outcome was a composite of: HCM related death, heart failure requiring hospitalization, sustained ventricular tachycardia and ischemic stroke. Patients were stratified into 2 subgroups depending on CFVR LAD value: Group 1 (CFVR LAD>2, [n=87]) and Group 2 (CFVR LAD≤2, [n=63]). During a median follow‐up of 88 months, 41/150 (27.3%) patients had adverse cardiac events. In Group 1, there were 8/87 (9.2%), whereas in Group 2 there were 33/63 (52.4%, P <0.001 vs. Group 1) adverse cardiac events. By Kaplan‐Meier analysis, patients with preserved CFVR LAD had significantly higher cumulative event‐free survival rate compared to patients with impaired CFVR LAD (96.4% and 90.9% versus 66.9% and 40.0%, at 5 and 8 years, respectively: log‐rank 37.2, P <0.001). Multivariable analysis identified only CFVR LAD≤2 as an independent predictor for adverse cardiac outcome (HR 6.54; 95% CI 2.83–16.30, P <0.001), while CFVR PD was not significantly associated with outcome. Conclusions In patients with HCM, impaired CFVR LAD (≤2) is a strong, independent predictor of adverse cardiac outcome. When the aim of testing is HCM risk stratification and CFVR LAD data are available, the evaluation of CFVR PD is redundant.

Lymphatic Clearance of Immune Cells in Cardiovascular Disease

Recent advances in our understanding of the lymphatic system, its function, development, and role in pathophysiology have changed our views on its importance. Historically thought to be solely involved in the transport of tissue fluid, lipids, and immune cells, the lymphatic system displays great heterogeneity and plasticity and is actively involved in immune cell regulation. Interference in any of these processes can be deleterious, both at the developmental and adult level. Preclinical studies into the cardiac lymphatic system have shown that invoking lymphangiogenesis and enhancing immune cell trafficking in ischaemic hearts can reduce myocardial oedema, reduce inflammation, and improve cardiac outcome. Understanding how immune cells and the lymphatic endothelium interact is also vital to understanding how the lymphatic vascular network can be manipulated to improve immune cell clearance. In this Review, we examine the different types of immune cells involved in fibrotic repair following myocardial infarction. We also discuss the development and function of the cardiac lymphatic vasculature and how some immune cells interact with the lymphatic endothelium in the heart. Finally, we establish how promoting lymphangiogenesis is now a prime therapeutic target for reducing immune cell persistence, inflammation, and oedema to restore heart function in ischaemic heart disease.

Combinational Therapy of Cardiac Atrial Appendage Stem Cells and Pyridoxamine: The Road to Cardiac Repair?

Myocardial infarction (MI) occurs when the coronary blood supply is interrupted. As a consequence, cardiomyocytes are irreversibly damaged and lost. Unfortunately, current therapies for MI are unable to prevent progression towards heart failure. As the renewal rate of cardiomyocytes is minimal, the optimal treatment should achieve effective cardiac regeneration, possibly with stem cells transplantation. In that context, our research group identified the cardiac atrial appendage stem cells (CASCs) as a new cellular therapy. However, CASCs are transplanted into a hostile environment, with elevated levels of advanced glycation end products (AGEs), which may affect their regenerative potential. In this study, we hypothesize that pyridoxamine (PM), a vitamin B6 derivative, could further enhance the regenerative capacities of CASCs transplanted after MI by reducing AGEs’ formation. Methods and Results: MI was induced in rats by ligation of the left anterior descending artery. Animals were assigned to either no therapy (MI), CASCs transplantation (MI + CASCs), or CASCs transplantation supplemented with PM treatment (MI + CASCs + PM). Four weeks post-surgery, global cardiac function and infarct size were improved upon CASCs transplantation. Interstitial collagen deposition, evaluated on cryosections, was decreased in the MI animals transplanted with CASCs. Contractile properties of resident left ventricular cardiomyocytes were assessed by unloaded cell shortening. CASCs transplantation prevented cardiomyocyte shortening deterioration. Even if PM significantly reduced cardiac levels of AGEs, cardiac outcome was not further improved. Conclusion: Limiting AGEs’ formation with PM during an ischemic injury in vivo did not further enhance the improved cardiac phenotype obtained with CASCs transplantation. Whether AGEs play an important deleterious role in the setting of stem cell therapy after MI warrants further examination.

Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia

Objective: Chronic hypoxia induces pulmonary and cardiovascular pathologies, including pulmonary hypertension (PH). L-arginine:glycine amidinotransferase (AGAT) is essential for homoarginine (hArg) and guanidinoacetate synthesis, the latter being converted to creatine by guanidinoacetate methyltransferase. Low hArg concentrations are associated with cardiovascular morbidity and predict mortality in patients with PH. We therefore aimed to investigate the survival and cardiac outcome of AGAT knockout (Agat−/−) mice under hypoxia and a possible rescue of the phenotype.Methods:Agat−/− mice and wild-type (WT) littermates were subjected to normoxia or normobaric hypoxia (10% oxygen) for 4 weeks. A subgroup of Agat−/− mice was supplemented with 1% creatine from weaning. Survival, hematocrit, blood lactate and glucose, heart weight-to-tibia length (HW/TL) ratio, hArg plasma concentration, and Agat and Gamt expression in lung, liver, and kidneys were evaluated.Results: After 6 h of hypoxia, blood lactate was lower in Agat−/−-mice as compared to normoxia (p &lt; 0.001). Agat−/− mice died within 2 days of hypoxia, whereas Agat−/− mice supplemented with creatine and WT mice survived until the end of the study. In WT mice, hematocrit (74 ± 4 vs. 55 ± 2%, mean ± SD, p &lt; 0.001) and HW/TL (9.9 ± 1.3 vs. 7.3 ± 0.7 mg/mm, p &lt; 0.01) were higher in hypoxia, while hArg plasma concentration (0.25 ± 0.06 vs. 0.38 ± 0.12 μmol/L, p &lt; 0.01) was lower. Agat and Gamt expressions were differentially downregulated by hypoxia in lung, liver, and kidneys.Conclusion:Agat and Gamt are downregulated in hypoxia. Agat−/− mice are nonviable in hypoxia. Creatine rescues the lethal phenotype, but it does not reduce right ventricular hypertrophy of Agat−/− mice in hypoxia.

Short-term cardiac outcome in survivors of COVID-19: a systematic study after hospital discharge

Background COVID-19 has caused considerable morbidity and mortality worldwide and cardiac involvement has been reported during infection. The short-term cardiac outcome in survivors of COVID-19 is not known. Objective To examine the heart of patients who survived COVID-19 and to compare the cardiac outcome between patients who recovered from mild-to-moderate or severe illness. Methods With use of ECG and echocardiography, we examined the heart of 105 patients who had been hospitalized with COVID-19 and were consecutively recruited after hospital discharge while attending follow-up visits. Survivors of COVID-19 were compared with 105 matched controls. We also compared the cardiac outcome and lung ultrasound scan between COVID-19 patients who had mild-to-moderate or severe illness. Results Cardiac data were collected a median of 41 days from the first detection of COVID-19. Symptoms were present in a low percentage of patients. In comparison with matched controls, no considerable structural or functional differences were observed in the heart of survivors of COVID-19. Lung ultrasound scan detected significantly greater residual pulmonary involvement in COVID-19 patients who had recovered from severe than mild-to-moderate illness. No significant differences were detected in ECG tracings nor were found in the left and right ventricular function of patients who had recovered from mild-to-moderate or severe illness. Conclusions In a short-term follow-up, no abnormalities were identified in the heart of survivors of COVID-19, nor cardiac differences were detected between patients who had different severity of illness. With the limitations of a cross-sectional study, these findings suggest that patients who recover from COVID-19 do not have considerable cardiac sequelae. Graphic abstract

MTX Treatment Does Not Improve Outcome in Mice with AMI

<b><i>Background:</i></b> Targeting inflammation in patients with coronary artery disease and/or acute myocardial infarction (AMI) is a matter of debate. Methotrexate (MTX) is one of the most widely used immunosuppressants. Cardiovascular Inflammation Reduction Trial (CIRT) recently failed to demonstrate reduced cardiovascular events in MTX-treated patients. However, it is not known if long-term MTX treatment improves cardiac outcome in AMI. Therefore, in this study, we investigated the postischemic phase in MTX-treated mice undergoing AMI. <b><i>Methods:</i></b> Wild-type mice received MTX medication intraperitoneally for 2 weeks. Afterward, AMI was induced by transient left anterior ascending artery ligation. Postischemic cardiac damage after 24 h was assessed. <b><i>Results:</i></b> MTX treatment did not affect infarct size as compared to control (IS/AAR: Con 76.20% ± 12.37%/AAR vs. MTX 73.51 ± 11.72%/AAR, <i>p</i> = 0.64). Moreover, systolic function and structural parameters did not differ between groups (_24hejection fraction: Con 36.49 ± 3.23% vs. MTX 32.77 ± 2.29%, <i>p</i> = 0.41; _24hLVID; d: Con 3.57 ± 0.17 mm vs. MTX 3.19 ± 0.13 mm, <i>p</i> = 0.14). Platelets were increased by MTX (Con 1,442 ± 69.20 × 10³/mm³ vs. MTX 1,920 ± 68.68 × 10³/mm³, <i>p</i> &#x3c; 0.0001). White blood cell and RBC as well as rate of monocytes, granulocytes, lymphocytes, and serum amyloid P levels were equal. <b><i>Conclusion:</i></b> MTX medication did not improve postischemic cardiac damage in a murine model of AMI. Future trials are needed to identify and investigate other anti-inflammatory targets to improve cardiovascular outcome.

Does left ventricular function predict cardiac outcome in Anderson–Fabry disease?

In Anderson–Fabry disease (AFD) the impact of left ventricular (LV) function on cardiac outcome is unknown. Noninvasive LV pressure–strain loop analysis is a new echocardiographic method to estimate myocardial work (MW). We aimed to evaluate whether LV function was associated with outcome and whether MW had a prognostic value in AFD. Ninety-six AFD patients (41.8 ± 14.7 years, 43.7% males) with normal LV ejection fraction were retrospectively evaluated. Inclusion criteria were sinus rhythm and ≥ 2-year follow-up. Standard echocardiography measurements, myocardial mechano-energetic efficiency (MEE) index, global longitudinal strain (GLS) and MW were evaluated. Adverse cardiac events were defined as composite of cardiac death, malignant ventricular tachycardia, atrial fibrillation and severe heart failure development. During a median follow-up of 63 months (interquartile range 37–85), 14 events occurred. Patient age, cardiac biomarkers, LV mass index, left atrium volume, E/Ea ratio, LV ejection fraction, MEE index, GLS and all MW indices were significantly related to adverse outcome at univariate analysis. After adjustment for clinical and echocardiographic parameters, which were significant at univariate analysis, GLS and MW resulted independent predictors of adverse events (p < 0.01). By ROC curve analysis, constructive MW ≤ 1513 mmHg% showed the highest sensitivity and specificity in predicting adverse outcome (92.9% and 86.6%, respectively). MW did not improve the predictive value of a model including clinical data, LV diastolic function and GLS. LV function impairment (both systolic and diastolic) is associated with adverse events in AFD. MW does not provide additive information over clinical features and systolic and diastolic function.

Real-world use and accuracy of stress echocardiography: preliminary insights from the EVAREST study

Background Stress echocardiography is a widely used, non-invasive imaging modality used to identify prognostically significant coronary artery disease. High levels of accuracy have been reported, however this is highly dependent on operator training and image quality. There are currently limited data available on the accuracy of stress echo in every day clinical practice. Purpose The EVAREST study links stress echo clinics in 30 NHS Hospital Trusts in England and therefore provides data to evaluate the performance and diagnostic accuracy of stress echo in “real-world” clinical practice. Methods Analysis was performed on the first 7415 patients recruited prospectively between 2015 and January 2020. Participants are included if they have undergone stress echo to investigate for ischaemic heart disease. Data is collected on medical history and stress echo performance. Participants are followed up for 12 months through health records and patient phone call, with all outcomes undergoing expert adjudication. A positive cardiac outcome is defined as initiation of anti-anginal medications, ≥70% stenosis on coronary angiography, revascularisation, confirmed acute coronary syndrome or cardiac-related death. Results Mean age of patients undergoing stress echo is 65±12.3 years and 56% are male. Average BMI is 28.9±5.6 kg/m2. 71.4% undergo dobutamine stress (DSE) and 28.4% exercise with &lt;1% having a pacemaker-mediated stress. Contrast was used in 71.4% of studies. Stress echos were interpreted at time of clinic visit as positive for inducible ischaemia in 18.2% of patients. One-year outcome data is currently available for 1892 participants. Sensitivity and specificity for clinician prediction of a positive cardiac outcome was 88.7% and 94.4%, respectively. Positive and negative predictive value of stress echo was 76.4% and 97.6%, respectively. Conclusion EVAREST provides unprecedented, large-scale information on the “real world” use and accuracy of stress echo across different healthcare settings in the UK, demonstrating performance consistent with best practice. Ongoing data collection will be used to evaluate sources of heterogeneity in the predictive accuracy of stress echo and identify optimal approaches to further improve performance. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Ultromics Ltd., Lantheus Ltd.