The pathogenesis, epidemiology and biomarkers of susceptibility of pulmonary fibrosis in COVID-19 survivors.

Pulmonary fibrosis (PF), a pathological outcome of chronic and acute interstitial lung diseases associated to compromised wound healing, is a key component of the "post-acute COVID-19 syndrome" that may severely complicate patients' clinical course. Although inconclusive, available data suggest that more than a third of hospitalized COVID-19 patients develop lung fibrotic abnormalities after their discharge from hospital. The pathogenesis of PF in patients recovering from a severe acute case of COVID-19 is complex, and several hypotheses have been formulated to explain its development. An analysis of the data that is presently available suggests that biomarkers of susceptibility could help to identify subjects with increased probability of developing PF and may represent a means to personalize the management of COVID-19's long-term effects. Our review highlights the importance of both patient-related and disease-related contributing risk factors for PF in COVID-19 survivors and makes it definitely clear the possible use of acute phase and follow-up biomarkers for identifying the patients at greatest risk of developing this disease.

Determinants of Ventricular Arrhythmias in Mitral Valve Prolapse.

BACKGROUND: Mitral valve prolapse (MVP) may be associated with ventricular arrhythmias (VA) even in the absence of significant valvular regurgitation. Curling, mitral annulus disjunction (MAD) and myocardial fibrosis (late gadolinium enhancement [LGE]) may account for arrhythmogenesis. OBJECTIVES: This study investigated the determinants of VA in patients with MVP without significant regurgitation. METHODS: This study included 108 patients with MVP (66 female; median age: 48 years) without valve regurgitation. All patients underwent 12-lead electrocardiography, 12-lead 24-hour electrocardiographic Holter monitoring, exercise stress test, and cardiac magnetic resonance. Patients were divided into 2 groups (arrhythmic and no-arrhythmic MVP), according to the presence of VA with a right bundle branch block pattern. RESULTS: The 62 patients (57%) with arrhythmic MVP showed: 1) higher MAD (median length: 6.0 vs 3.2 mm; P = 0.017); 2) higher prevalence of curling (79% vs 52%; P = 0.012); and 3) higher prevalence of left ventricular LGE (79% vs 52%; P = 0.012). Mediation analysis showed that curling had both a direct (P = 0.03) and indirect effect mediated by LGE (P = 0.04) on VA, whereas the association between MAD and VA was completely mediated by LGE. Patients with severe VA showed more pronounced morphofunctional alterations, in terms of MAD (7.0 vs 4.6 mm; P = 0.004) and presence and severity of curling (respectively, 91% vs 64%; P = 0.010; and 4 vs 3 mm; P = 0.004), compared to those without severe VA. CONCLUSIONS: In patients with MVP the occurrence of VA with right bundle branch block morphology is the expression of more severe morphologic, mechanical, and tissue alterations. Curling has both a direct and an indirect effect on VA.

Dyspnea in Post-Acute COVID-19: A Multi-Parametric Cardiopulmonary Evaluation.

Post-acute COVID-19 is characterized by the persistence of dyspnea, but the pathophysiology is unclear. We evaluated the prevalence of dyspnea during follow-up and factors at admission and follow-up associated with dyspnea persistence. After five months from discharge, 225 consecutive patients hospitalized for moderate to severe COVID-19 pneumonia were assessed clinically and by laboratory tests, echocardiography, six-minute walking test (6MWT), and pulmonary function tests. Fifty-one patients reported persistent dyspnea. C-reactive protein (p = 0.025, OR 1.01 (95% CI 1.00-1.02)) at admission, longer duration of hospitalization (p = 0.005, OR 1.05 (95% CI 1.01-1.10)) and higher body mass index (p = 0.001, OR 1.15 (95% CI 1.06-1.28)) were independent predictors of dyspnea. Absolute drop in SpO2 at 6MWT (p = 0.001, OR 1.37 (95% CI 1.13-1.69)), right ventricular (RV) global longitudinal strain (p = 0.016, OR 1.12 (95% CI 1.02-1.25)) and RV global longitudinal strain/systolic pulmonary artery pressure ratio (p = 0.034, OR 0.14 (95% CI 0.02-0.86)) were independently associated with post-acute COVID-19 dyspnea. In conclusion, dyspnea is present in many patients during follow-up after hospitalization for COVID-19 pneumonia. While higher body mass index, C-reactive protein at admission, and duration of hospitalization are predictors of persistent dyspnea, desaturation at 6MWT, and echocardiographic RV dysfunction are associated with this symptom during the follow-up period.

Subclinical Myocardial Injury in Patients Recovered from COVID-19 Pneumonia: Predictors and Longitudinal Assessment.

(1) Background: Emerging data regarding patients recovered from COVID-19 are reported in the literature, but cardiac sequelae have not yet been clarified. To quickly detect any cardiac involvement at follow-up, the aims of the research were to identify: elements at admission predisposing subclinical myocardial injury at follow up; the relationship between subclinical myocardial injury and multiparametric evaluation at follow-up; and subclinical myocardial injury longitudinal evolution. (2) Methods and Results: A total of 229 consecutive patients hospitalised for moderate to severe COVID-19 pneumonia were initially enrolled, of which 225 were available for follow-up. All patients underwent a first follow-up visit, which included a clinical evaluation, a laboratory test, echocardiography, a six-minute walking test (6MWT), and a pulmonary functional test. Of the 225 patients, 43 (19%) underwent a second follow-up visit. The median time to the first follow-up after discharge was 5 months, and the median time to the second follow-up after discharge was 12 months. Left ventricular global longitudinal strain (LVGLS) and right ventricular free wall strain (RVFWS) were reduced in 36% (n = 81) and 7.2% (n = 16) of the patients, respectively, at first the follow-up visit. LVGLS impairment showed correlations with patients of male gender (p 0.008, OR 2.32 (95% CI 1.24-4.42)), the presence of at least one cardiovascular risk factor (p < 0.001, OR 6.44 (95% CI 3.07-14.9)), and final oxygen saturation (p 0.002, OR 0.99 (95% CI 0.98-1)) for the 6MWTs. Subclinical myocardial dysfunction had not significantly improved at the 12-month follow-ups. (3) Conclusions: in patients recovered from COVID-19 pneumonia, left ventricular subclinical myocardial injury was related to cardiovascular risk factors and appeared stable during follow-up.

Role of Cardiac Imaging Modalities in the Evaluation of COVID-19-Related Cardiomyopathy.

Cardiac involvement has been described during the course of SARS-CoV-2 disease (COVID-19), with different manifestations. Several series have reported only increased cardiac troponin without ventricular dysfunction, others the acute development of left or right ventricular dysfunction, and others myocarditis. Ventricular dysfunction can be of varying degrees and may recover completely in some cases. Generally, conventional echocardiography is used as a first approach to evaluate cardiac dysfunction in patients with COVID-19, but, in some cases, this approach may be silent and more advanced cardiac imaging techniques, such as myocardial strain imaging or cardiac magnetic resonance, are necessary to document alterations in cardiac structure or function. In this review we sought to discuss the information provided by different cardiac imaging techniques in patients with COVID-19, both in the acute phase of the disease and after discharge from hospital, and their diagnostic and prognostic role. We also aimed at verifying whether a specific form of cardiac disease due to the SARS-CoV-2 can be identified.

Value of Left Ventricular Indexed Ejection Time to Characterize the Severity of Aortic Stenosis.

Aims: The assessment of aortic stenosis (AS) severity is still challenging, especially in abnormal hemodynamic conditions. Left ventricular ejection time (LVET) has been historically related to AS severity, but it also depends on heart rate (HR) and systolic function. Our aim was to verify if correcting LVET (LVET index, LVETI) by its determinants is helpful for the assessment of AS severity, irrespective of hemodynamic conditions. Methods and results: We retrospectively studied 152 patients with AS and 378 patients with heart failure and no-AS. At multivariate analysis, LVET (assessed with pulsed-wave Doppler) showed a strong correlation with stroke volume index (SVI) (Beta 0.354; p < 0.001), HR (−0.385; p < 0.001), AS grade (Beta 0.301; p < 0.001) and, less significantly, ejection fraction (LVEF) (Beta 0.108; p = 0.001). AS grade was confirmed to be a major determinant of LVET, irrespective of forward flow (assessed by SVI and transvalvular flow rate) and LVEF (above and below 50%). A regression equation was derived to index LVET (LVETI) to HR and SVI. By using this formula, LVETI detected severe AS more accurately (AUC 0.812, p < 0.001) than LVET alone (AUC 0.755, p for difference = 0.005). Similar results were observed in patients with abnormal flow status. As an exploratory finding, we observed that the highest tertile of LVETI was associated with a higher rate of aortic valve interventions during follow-up. Conclusions: LVETI correlates with AS severity better than uncorrected LVET, independently from hemodynamic conditions, and may help to discriminate severe AS. This finding needs confirmation in larger prospective multicenter studies.

Feasibility and Role of Right Ventricular Stress Echocardiography in Adult Patients.

BACKGROUND: The great technological advancements in the field of echocardiography have led to applications of stress echocardiography (SE) in almost all diagnostic fields of cardiology, from ischemic heart disease to valvular heart disease and diastolic function. However, the assessment of the right ventricle (RV) in general, and in particular in regard to the contractile reserve of the RV, is an area that has not been previously explored. We, therefore, propose a study to investigate the potential use of SE for the assessment of RV function in adult patients. AIMS AND OBJECTIVES: The primary aim is to evaluate the feasibility of right ventricular SE. The secondary aim is to assess right ventricular contractile reserve. MATHERIALS AND METHODS: Eighty-one patients undergoing a physical or dobutamine stress echocardiogram for cardiovascular risk stratification or chest pain were the subject of the study. An exercise leg cycle using a standard WHO protocol was used to simultaneously assess the right and left ventricular global and regional function as well as acquiring Doppler data. Whereas the patient had limitations in mobility, a dobutamine SE was be performed. We evaluated the average values of tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), S-wave, systolic pulmonary artery pressure (sPAP), and right ventricle global longitudinal (free wall) strain (RVGLS) during baseline and at the peak of the effort. RV contractile reserve was defined as the change in RVGLS from rest to peak exercise. We also assessed the reproducibility of these measurements between two different expert operators (blind analysis). RESULTS: At least 3 over 5 RV function parameters were measurable both during baseline and at the peak of the effort in 95% of patients, while all 5 parameters in 65% of our population, demonstrating an excellent feasibility. All RV-studied variables showed a statistically significant increase (P < 0.001) at peak compared to the baseline. The average percentage increases at peak were 31.1% for TAPSE, 24.8% for FAC, 50.6% for S-wave, 55.2% for PAPS, and 39.8% for RV strain. The reproducibility between operators at baseline and peak was excellent. Our study demonstrates that TAPSE, FAC, and S-wave are highly feasible at rest and at peak, while TAPSE, S-wave, and sPAP are the most reliable measurements during RV stress echo. CONCLUSION: RVGLS is useful in the assessment of RV contractile reserve in patients with good acoustic window. Further studies are needed to evaluate the impact of contrast echocardiography in improving RV contractile reserve assessment during SE.

[Current clinical applications of three-dimensional echocardiography]. / Principali applicazioni dell'ecocardiografia tridimensionale nell'attuale pratica clinica.

Three-dimensional echocardiography (3DE) represents one of the most innovative advances in cardiovascular imaging over the last 20 years. Recent technological developments have fueled the full implementation of 3DE in clinical practice and expanded its impact on patient diagnosis, management, and prognosis. One of the most important clinical applications of transthoracic 3DE has been the quantitation of cardiac chamber volumes and function. The main limitations affecting two-dimensional echocardiography calculations of chamber volumes (i.e. geometric assumptions about cardiac chamber shape and view foreshortening) are overcome by 3DE that allows an actual measurement of their volumes. Transesophageal 3DE has been applied mainly to assess the anatomy and function of heart valves, congenital defects and masses in the beating heart. As reparative cardiac surgery and transcatheter procedures have become more and more popular to treat structural heart disease, transesophageal 3DE has become not only one of the main imaging modalities for procedure planning but also for intra-procedural guidance and assessment of procedural results. New image rendering modalities such as 3D printing, holographic display, and fusion of 3DE images with other radiological or nuclear modalities will further expand the clinical applications and indications of 3DE.

The VALID-CRT risk score reliably predicts response and outcome of cardiac resynchronization therapy in a real-world population.

OBJECTIVES: The aim of the study was to confirm the value of the VALID-cardiac resynchronization therapy (CRT) risk score in predicting outcome and to assess its association with clinical response (CR) in an unselected real-world CRT population. METHODS AND RESULTS: The present analysis comprised all consecutive CRT patients (pts) enrolled in the CRT-MORE registry from 2011 to 2013. Pts were stratified into five groups (quintiles 1-5) according to the VALID-CRT risk predictor index applied to the CRT-MORE population. In the analysis of clinical outcome, adverse events comprised death from any cause and non-fatal heart failure (HF) events requiring hospitalization. CR at 12-month follow-up was also assessed. We enrolled 905 pts. During a median follow-up of 1005 [627-1361] days, 134 patients died, and 79 had at least one HF hospitalization. At 12 months, 69% of pts displayed an improvement in their CR. The mean VALID-CRT risk score derived from the CRT-MOdular Registry (MORE) population was 0.317, ranging from -0.419 in Q1 to 2.59 in Q5. The risk-stratification algorithm was able to predict total mortality after CRT (survival ranging from 93%-Q1 to 77%-Q5; hazards ratio [HR] = 1.42, 95% confidence interval [CI]: 1.25-1.61, P < .0001), and HF hospitalization (ranging from 95% to 90%; HR = 1.24, 95% CI: 1.06-1.45, P = .009). CR was significantly lower in pts with a high-to-very high risk profile (Q4-5) than in pts with a low-to-intermediate risk profile (Q1-2-3) (55% vs 79%, P < .0001). CONCLUSION: The VALID-CRT risk-stratification algorithm reliably predicts outcome and CRT response after CRT in an unselected, real-world population.

Intervendor Consistency and Accuracy of Left Ventricular Volume Measurements Using Three-Dimensional Echocardiography.

BACKGROUND: Intervendor consistency of left ventricular (LV) volume measurements using three-dimensional transthoracic echocardiography (3DTTE) has never been reported. Accordingly, we designed a prospective study to (1) compare head-to-head the accuracy of three three-dimensional echocardiography (3DE) systems in measuring LV volumes and ejection fraction (EF) against cardiac magnetic resonance (CMR); (2) assess the intervendor variability of LV volumes and EF; and (3) compare the accuracy of fully automated versus semiautomated (i.e., manually corrected) methods of LV endocardial delineation against CMR. METHODS: We studied 92 patients (64% males, 52 years [95% CI, 20-83]) with a wide range of end-diastolic volumes (from 87 to 446 mL) and EFs (from 16% to 77%) using three different 3DE platforms (iE33; Vivid E9; Acuson SC2000) during the same echo study. CMR was performed within 3 ± 5 hours from the 3DE study in 35 patients. RESULTS: LV volumes provided by the three 3DE systems correlated with CMR volumes: end-diastolic volume (iE33: R2 = 0.93; E9: R2 = 0.94; SC2000: R2 = 0.94), end-systolic volume (iE33: R2 = 0.93; E9: R2 = 0.95; SC2000: R2 = 0.94), and EF (iE33: R2 = 0.79; E9: R2 = 0.80; SC2000: R2 = 0.77). In the 92 patients studied, LV volumes and EFs measured with the three systems were similar. Use of fully automated endocardial border detection algorithms significantly underestimated LV volumes, and the degree of underestimation was higher with larger LV volumes. CONCLUSIONS: LV volumes and EFs measured with the three 3DE systems are consistent. Fully automated algorithms underestimated LV volumes. Our findings may help in the clinical interpretation of LV parameters obtained using different 3DE systems and encourage the clinical use of 3DTTE.

Early impairment in left ventricular longitudinal systolic function is associated with an increased risk of incident atrial fibrillation in patients with type 2 diabetes.

AIMS: It is known that type 2 diabetic patients are at high risk of atrial fibrillation (AF). However, the early echocardiographic determinants of AF vulnerability in this patient population remain poorly known. METHODS: We followed-up for 2years a sample of 180 consecutive outpatients with type 2 diabetes, who were free from AF and ischemic heart disease at baseline. All patients underwent a baseline echocardiographic-Doppler evaluation with tissue Doppler and 2-D strain analysis. Standard electrocardiograms were performed twice per year, and a diagnosis of incident AF was confirmed in affected patients by a single cardiologist. RESULTS: Over the 2-year follow-up period, 14 (7.8%) patients developed incident AF. In univariate analyses, echocardiographic predictors of new-onset AF were greater indexed cardiac mass, larger indexed left atrial volume (LAVI), lower global longitudinal strain (LSSYS), lower global diastolic strain rate during early phase of diastole (SRE), lower global diastolic strain rate during late phase of diastole (SRL), and higher E/SRE ratio. Multivariate logistic regression analysis showed that lower LSSYS remained the only significant predictor of new-onset AF (adjusted-odds ratio 1.63, 95%CI 1.17-2.27; p<0.005) after adjustment for age, sex, diabetes duration, indexed cardiac mass and LAVI. Results were unchanged even after adjustment for body mass index, hypertension and glycemic control. CONCLUSIONS: This is the first prospective study to show that early LSSYS impairment independently predicts the risk of new-onset AF in type 2 diabetic patients with preserved ejection fraction and without ischemic heart disease. Future larger prospective studies are needed to confirm these findings.

New speckle-tracking algorithm for right ventricular volume analysis from three-dimensional echocardiographic data sets: validation with cardiac magnetic resonance and comparison with the previous analysis tool.

AIMS: (i) To validate a new software for right ventricular (RV) analysis by 3D echocardiography (3DE) against cardiac magnetic resonance (CMR); (ii) to assess the accuracy of different measurement approaches; and (iii) to explore any benefits vs. the previous software. METHODS AND RESULTS: We prospectively studied with 3DE and CMR 47 patients (14-82 years, 28 men) having a wide range of RV end-diastolic volumes (EDV 82-354 mL at CMR) and ejection fractions (EF 34-81%). Multi-beat RV 3DE data sets were independently analysed with the new software using both automated and manual editing options, as well as with the previous software. RV volume reproducibility was tested in 15 random patients. RV volumes and EF measurements by the new software had an excellent accuracy (bias ± SD: -15 ± 24 mL for EDV; 1.4 ± 4.9% for EF) and reproducibility compared with CMR, provided that the RV borders automatically tracked by software were systematically edited by operator. The automated analysis option underestimated the EDV, overestimated the ESV, and largely underestimated the EF (bias ± SD: -17 ± 10%). RV volumes measured with the new software using manual editing showed similar accuracy, but lower inter-observer variability and shorter analysis time (3-5') in comparison with the previous software. CONCLUSION: Novel vendor-independent 3DE software enables an accurate, reproducible and faster quantitation of RV volumes and ejection fraction. Rather than optional, systematic verification of border tracking quality and manual editing are mandatory to ensure accurate 3DE measurements. These findings are relevant for echocardiography laboratories aiming to implement 3DE for RV analysis for both research and clinical purposes.

Prognostic Role of Right Ventricular Function in Patients With Heart Failure Undergoing Cardiac Resynchronization Therapy.

BACKGROUND: Because 20% to 40% of patients undergoing cardiac resynchronization therapy (CRT) do not respond to it, identification of potential factors predicting response is a relevant research topic. HYPOTHESIS: There is a possible association between right ventricular function and response to CRT. METHODS: We analyzed 227 patients from the Cardiac Resynchronization Therapy Modular Registry (CRT-MORE) who received CRT according to current guidelines from March to December 2013. Response to therapy was defined as a decrease of ≥15% in left ventricular end-systolic volume (LVESV) at 6 months. RESULTS: The tricuspid annular plane systolic excursion (TAPSE) value that best predicted improvement in LVESV (sensitivity 68%, specificity 54%) was 17 mm. Stratifying patients according to TAPSE, LVESV decreased ≥15% in 78% of patients with TAPSE >17 mm (vs 59% in patients with TAPSE ≤17 mm; P = 0.006). At multivariate analysis, TAPSE >17 mm was independently associated with LVESV improvement (odds ratio: 1.97, 95% confidence interval: 1.03-3.80, P < 0.05), together with ischemic etiology (odds ratio: 0.39, 95% confidence interval: 0.20-0.75, P < 0.01). These results were confirmed for New York Heart Association class III to IV patients (79% echocardiographic response rate in patients with TAPSE >17 mm vs 55% in patients with TAPSE <17 mm; P = 0.012). CONCLUSIONS: Baseline signs of right ventricular dysfunction suggest possible remodeling after CRT. A TAPSE value of 17 mm was identified as a good cutoff for predicting a better response to CRT in patients with both mildly symptomatic and severe heart failure.