Activation of Immune System May Cause Pathophysiological Changes in the Myocardium of SARS-CoV-2 Infected Monkey Model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an extremely contagious disease whereby the virus damages the host's respiratory tract via entering through the ACE2 receptor. Cardiovascular disorder is being recognized in the majority of COVID-19 patients; yet, the relationship between SARS-CoV-2 and heart failure has not been established. In the present study, SARS-CoV-2 infection was induced in the monkey model. Thereafter, heart tissue samples were collected, and pathological changes were analyzed in the left ventricular tissue by hematoxylin and eosin, trichrome, and immunohistochemical staining specific to T lymphocytes and macrophages. The findings revealed that SARS-CoV-2 infection induces several pathological changes in the heart, which cause cardiomyocyte disarray, mononuclear infiltrates of inflammatory cells, and hypertrophy. Furthermore, collagen-specific staining showed the development of cardiac fibrosis in the interstitial and perivascular regions in the hearts of infected primates. Moreover, the myocardial tissue samples displayed multiple foci of inflammatory cells positive for T lymphocytes and macrophages within the myocardium. These findings suggest the progression of the disease, which can lead to the development of severe complications, including heart failure. Additionally, SARS-CoV-2 antigen staining detected the presence of virus particles in the myocardium. Thus, we found that SARS-CoV-2 infection is characterized by an exaggerated inflammatory immune response in the heart, which possibly contributes to myocardial remodeling and subsequent fibrosis.

Pathophysiology of Takotsubo Cardiomyopathy: Reopened Debate.

Takotsubo cardiomyopathy (TTC), a persistently obscure dysfunctional condition of the left ventricle, is uniquely transient but nevertheless dangerous. It features variable ventricular patterns and is predominant in women. For 30 years, pathophysiologic investigations have progressed only slowly and with inadequate focus. It was initially proposed that sudden-onset spastic obliteration of coronary flow induced myocardial ischemia with residual stunning and thus TTC. Later, it was generally accepted without proof that, in the presence of pain or emotional stress, the dominant mechanism for TTC onset was a catecholamine surge that had a direct, toxic myocardial effect. We think that the manifestations of TTC are more dynamic and complex than can be assumed from catecholamine effects alone. In addition, after reviewing the recent medical literature and considering our own clinical observations, especially on spasm, we theorize that atherosclerotic coronary artery disease modulates and physically opposes obstruction during spasm. This phenomenon may explain the midventricular variant of TTC and the lower incidence of TTC in men. We continue to recommend and perform acetylcholine testing to reproduce TTC and to confirm our theory that coronary spasm is its initial pathophysiologic factor. An improved understanding of TTC is especially important because of the condition's markedly increased incidence during the ongoing COVID-19 pandemic.

Impact of COVID-19 on the incidence of cardiac arrhythmias in implantable cardioverter defibrillator recipients followed by remote monitoring.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has been a fast-growing worldwide pandemic. AIMS: We aimed to investigate the incidence of cardiac arrhythmias among a large French cohort of implantable cardioverter defibrillator recipients over the first 5 months of 2020. METHODS: Five thousand nine hundred and fifty-four implantable cardioverter defibrillator recipients were followed by remote monitoring during the COVID-19 period (from 01 January to 31 May 2020). Data were obtained from automated remote follow-up of implantable cardioverter defibrillators utilizing the Implicity® platform. For all patients, the type of arrhythmia (atrial fibrillation, ventricular tachycardia or ventricular fibrillation), the number of ventricular arrhythmia episodes and the type of implantable cardioverter defibrillator-delivered therapy were recorded. RESULTS: A total of 472 (7.9%) patients presented 4917 ventricular arrhythmia events. An increase in ventricular arrhythmia incidence was observed after the first COVID-19 case in France, and especially during weeks #10 and #11, at the time of major governmental measures, with an increase in the incidence of antitachycardia pacing delivered therapy. During the 11 weeks before the lockdown order, the curve of the percentage of live-stream television coverage of COVID-19 information matched the ventricular arrhythmia incidence. During the lockdown, the incidence of ventricular arrhythmia decreased significantly compared with baseline (0.05±0.7 vs. 0.09±1.2 episodes per patient per week, respectively; P<0.001). Importantly, no correlation was observed between ventricular arrhythmia incidence and the curve of COVID-19 incidence. No changes were observed regarding atrial fibrillation/atrial tachycardia episodes over time. CONCLUSIONS: An increase in ventricular arrhythmia incidence was observed in the 2 weeks before the lockdown order, at the time of major governmental measures. Ventricular arrhythmia incidence decreased dramatically during the lockdown.

Impairment of right ventricular longitudinal strain associated with severity of pneumonia in patients recovered from COVID-19.

Myocardial injury caused by COVID-19 was reported in hospitalized patients previously. But the information about cardiac consequences of COVID-19 after recovery is limited. The aim of the study was comprehensive echocardiography assessment of right ventricular (RV) in patients recovered from COVID-19. This is a prospective, single-center study. After recovery from COVID-19, echocardiography was performed in consecutive 79 patients that attended follow-up visits from July 15 to November 30, 2020. According to the recovery at home vs hospital, patients were divided into two groups: home recovery (n = 43) and hospital recovery (n = 36). Comparisons were made with age, sex and risk factor-matched control group (n = 41). In addition to conventional echocardiography parameters, RV global longitudinal strain (RV-GLS) and RV free wall strain (RV-FWS) were determined using 2D speckle-tracking echocardiography (2D STE). Of the 79 patients recovered from COVID-19, 43 (55%) recovered at home, while 36 (45%) required hospitalization. The median follow-up duration was 133  ±  35 (87-184) days. In patients recovered from hospital, RV-GLS and RV-FWS were impaired compared to control group (RV-GLS: -17.3  ±  6.8 vs. -20.4  ±  4.9, respectively [p = 0.042]; RV-FWS: -19.0  ±  8.2 vs. -23.4  ±  6.2, respectively [p = 0.022]). In subgroup analysis, RV-FWS was impaired in patients severe pneumonia (n = 11) compared to mild-moderate pneumonia (n = 28), without pneumonia (n = 40) and control groups (-15.8  ±  7.6 vs. -21.6  ±  7.6 vs. -20.8  ±  7.7 vs. -23.4  ±  6.2, respectively, [p = 0.001 for each]) and RV-GLS was impaired compared to control group (-15.2  ±  6.9 vs. -20.4  ±  4; respectively, [p = 0.013]). A significant correlation was detected between serum CRP level at hospital admission and both RV-GLS and RV-FWS (r = 0.285, p = 0.006; r = 0.294, p = 0.004, respectively). Age (OR 0.948, p = 0.010), male gender (OR 0.289, p = 0.009), pneumonia on CT (OR 0.019, p = 0.004), and need of steroid in treatment (OR 17.424, p = 0.038) were identifed as independent predictors of impaired RV-FWS (> -18) via multivariate analysis. We demonstrated subclinic dysfunction of RV by 2D-STE in hospitalized patients in relation to the severity of pneumonia after recovery from COVID-19. 2D-STE supplies additional information above standard measures of RV in this cohort and can be used in the follow-up of these patients.

Arrhythmia Risk Profile and Ventricular Repolarization Indices in COVID-19 Patients: A Systematic Review and Meta-Analysis.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has been associated with cardiac arrhythmias. Several electrocardiographic markers have been used to predict the risk of arrhythmia in patients with COVID-19. We aim to investigate the electrocardiographic (ECG) ventricular repolarization indices in patients with COVID-19. METHODOLOGY: We performed a comprehensive systematic literature search from PubMed, EuropePMC, SCOPUS, Cochrane Central Database, and Google Scholar Preprint Servers. The primary endpoints of this search were: Tp-e (T-peak-to-T-end) interval, QTd (QT dispersion), and Tp-e/QTc ratio in patients with newly diagnosed COVID-19 from inception up until August 2020. RESULTS: There were a total of 241 patients from 2 studies. Meta-analysis showed that Tp-e/QTc ratio was higher in COVID-19 group (mean difference 0.02 [0.01, 0.02], p < 0.001; I2: 18%,). Tp-e interval was more prolonged in COVID-19 group (mean difference 7.76 [3.11, 12.41], p < 0.001; I2: 80%) compared to control group. QT dispersion (QTd) also was increased in COVID-19 group (mean difference 1.22 [0.61, 1.83], p < 0.001 ; I2:30%). CONCLUSIONS: Several electrocardiographic markers including Tp-e/QTc, Tp-e interval, and QTd are significantly increased in patients with COVID-19.

The Predictive Role of Combined Cardiac and Lung Ultrasound in Coronavirus Disease 2019.

BACKGROUND: The aim of this study was to evaluate sonographic features that may aid in risk stratification and to propose a focused cardiac and lung ultrasound (LUS) algorithm in patients with coronavirus disease 2019. METHODS: Two hundred consecutive hospitalized patients with coronavirus disease 2019 underwent comprehensive clinical and echocardiographic examination, as well as LUS, irrespective of clinical indication, within 24 hours of admission as part of a prospective predefined protocol. Assessment included calculation of the modified early warning score (MEWS), left ventricular systolic and diastolic function, hemodynamic and right ventricular assessment, and a calculated LUS score. Outcome analysis was performed to identify echocardiographic and LUS predictors of mortality or the composite event of mortality or need for invasive mechanical ventilation and to assess their adjunctive value on top of clinical parameters and MEWS. RESULTS: A simplified echocardiographic risk score composed of left ventricular ejection fraction < 50% combined with tricuspid annular plane systolic excursion < 18 mm was associated with mortality (P = .0002) and with the composite event (P = .0001). Stepwise analyses evaluating echocardiographic and LUS parameters on top of existing clinical risk scores showed that addition of tricuspid annular plane systolic excursion and stroke volume index improved prediction of mortality when added to clinical variables but not when added to MEWS. Once echocardiography was added, and patients were recategorized as high risk only if having both high-risk MEWS and high-risk cardiac features, specificity increased from 63% to 87%, positive predictive value from 28% to 48%, and accuracy from 66% to 85%. Although LUS was not associated with incremental risk prediction for mortality above clinical and echocardiographic criteria, it improved prediction of need for invasive mechanical ventilation. CONCLUSIONS: In hospitalized patients with coronavirus disease 2019, a very limited echocardiographic examination is sufficient for outcome prediction. The addition of echocardiography in patients with high-risk MEWS decreases the rate of falsely identifying patients as high risk to die and may improve resource allocation in case of high patient load.

Left and right ventricular dysfunction in patients with COVID-19-associated myocardial injury.

PURPOSE: SARS-COV-2 infection can develop into a multi-organ disease. Although pathophysiological mechanisms of COVID-19-associated myocardial injury have been studied throughout the pandemic course in 2019, its morphological characterisation is still unclear. With this study, we aimed to characterise echocardiographic patterns of ventricular function in patients with COVID-19-associated myocardial injury. METHODS: We prospectively assessed 32 patients hospitalised with COVID-19 and presence or absence of elevated high sensitive troponin T (hsTNT+ vs. hsTNT-) by comprehensive three-dimensional (3D) and strain echocardiography. RESULTS: A minority (34.3%) of patients had normal ventricular function, whereas 65.7% had left and/or right ventricular dysfunction defined by impaired left and/or right ventricular ejection fraction and strain measurements. Concomitant biventricular dysfunction was common in hsTNT+ patients. We observed impaired left ventricular (LV) global longitudinal strain (GLS) in patients with myocardial injury (-13.9% vs. -17.7% for hsTNT+ vs. hsTNT-, p = 0.005) but preserved LV ejection fraction (52% vs. 59%, p = 0.074). Further, in these patients, right ventricular (RV) systolic function was impaired with lower RV ejection fraction (40% vs. 49%, p = 0.001) and reduced RV free wall strain (-18.5% vs. -28.3%, p = 0.003). Myocardial dysfunction partially recovered in hsTNT + patients after 52 days of follow-up. In particular, LV-GLS and RV-FWS significantly improved from baseline to follow-up (LV-GLS: -13.9% to -16.5%, p = 0.013; RV-FWS: -18.5% to -22.3%, p = 0.037). CONCLUSION: In patients with COVID-19-associated myocardial injury, comprehensive 3D and strain echocardiography revealed LV dysfunction by GLS and RV dysfunction, which partially resolved at 2-month follow-up. TRIAL REGISTRATION: COVID-19 Registry of the LMU University Hospital Munich (CORKUM), WHO trial ID DRKS00021225.

Acute right ventricular dysfunction in severe COVID-19 pneumonia.

To investigate the right heart function in coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS), a retrospective analysis of 49 COVID-19 patients with ARDS was performed. Patients were divided into severe group and critically-severe group according to the severity of illness. Age-matched healthy volunteers were recruited as a control group. The cardiac cavity diameters, tricuspid annular plane systolic excursion (TAPSE), tricuspid valve regurgitation pressure gradient biggest (TRPG), pulmonary arterial systolic pressure (PASP), maximum inferior vena cava diameter (IVCmax) and minimum diameter (IVCmin), and inferior vena cava collapse index (ICV-CI) were measured using echocardiography. We found that the TAPSE was significantly decreased in pneumonia patients compared to healthy subjects (P < 0.0001), and it was significantly lower in critically-severe patients (P = 0.0068). The TAPSE was less than 17 mm in three (8.6%) severe and five (35.7%) critically-severe patients. In addition, the TAPSE was significantly decreased in severe ARDS patients than in mild ARDS patients. The IVCmax and IVCmin were significantly increased in critically-severe patients compared to healthy subjects and severe patients (P < 0.01), whereas the ICV-CI was significantly decreased (P < 0.05). COVID-19 patients had significantly larger right atrium and ventricle than healthy controls (P < 0.01). The left ventricular ejection fraction (LVEF) in critically-severe patients was significantly lower than that in severe patients and healthy controls (P < 0.05). Right ventricular function was impaired in critically-severe COVID-19 patients. The assessment and protection of the right heart function in COVID-19 patients should be strengthened.

A pilot study on right ventricular longitudinal strain as a predictor of outcome in COVID-19 patients with evidence of cardiac involvement.

AIMS: The aim of this investigation was to evaluate echocardiographic parameters of cardiac function and in particular right ventricular (RV) function as a predictor of mortality in patients with coronavirus disease-2019 (COVID-19) pneumonia. METHODS AND RESULTS: This prospective observational study included 35 patients admitted to a UK district general hospital with COVID-19 and evidence of cardiac involvement, that is, raised Troponin I levels or clinical evidence of heart failure during the first wave of the COVID-19 pandemic (March-May 2020). All patients underwent echocardiography including speckle tracking for right ventricular longitudinal strain (RVLS) providing image quality was sufficient (30 out of 35 patients). Upon comparison of patients who survived COVID-19 with non-survivors, survivors had significantly smaller RVs (basal RV diameter 38.2 vs 43.5 mm P = .0295) with significantly better RV function (Tricuspid annular plane systolic excursion (TAPSE): 17.5 vs 15.3 mm P = .049; average RVLS: 24.3% vs 15.6%; P = .0018). Tricuspid regurgitation (TR) maximal velocity was higher in survivors (2.75 m/s vs 2.11 m/s; P = .0045) indicating that pressure overload was not the predominant driver of this effect and there was no significant difference in left ventricular (LV) ejection fraction. Kaplan-Meier and log-rank analysis of patients split into groups according to average RVLS above or below 20% revealed significantly increased 30-day mortality in patients with average RVLS under 20% (HR: 3.189; 95% CI: 1.297-12.91; P = .0195). CONCLUSION: This study confirms that RVLS is a potent and independent predictor of outcome in COVID-19 patients with evidence of cardiac involvement.

COVID-19, thromboembolic risk, and Virchow's triad: Lesson from the past.

COronavirus Infectious Disease which started in 2019 (COVID-19) usually presents with the signs and symptoms of pneumonia. However, a growing number of recent reports highlight the fact that the infection may be by far more than only a respiratory disease. There is evidence of an increased thromboembolic risk in COVID-19 patients, with a variety of manifestations in terms of ischemic stroke, deep vein thrombosis, acute pulmonary embolism, acute myocardial infarction, systemic arterial embolism, and placental thrombosis. The German physician Rudolph Virchow, about two centuries ago, described three pivotal factors contributing together to thromboembolic risk: endothelial injury, hypercoagulability, and blood stasis. COVID-19-associated hypercoagulability is unique and distinctive, and has its own features involving the immune system. Many of the drugs proposed and currently undergoing evaluation for the treatment of COVID-19 have one or more of the Virchow's triad elements as a target. The three factors outlined by Virchow are still able to explain the venous and arterial hypercoagulable state in the dramatic COVID-19 setting. Nowadays, we have decidedly more sophisticated diagnostic tools than Virchow had, but many of the challenges that we are facing are the same as Virchow faced in the 19th century.

Takotsubo Syndrome: Finally Emerging From the Shadows?

It is now 30 years since Japanese investigators first described Takotsubo Syndrome (TTS) as a disorder occurring mainly in ageing women, ascribing it to the impact of multivessel coronary artery spasm. During the intervening period, it has become clear that TTS involves relatively transient vascular injury, followed by prolonged myocardial inflammatory and eventually fibrotic changes. Hence symptomatic recovery is generally slow, currently an under-recognised issue. It appears that TTS is induced by aberrant post-ß2-adrenoceptor signalling in the setting of "surge" release of catecholamines. Resultant activation of nitric oxide synthases and increased inflammatory vascular permeation lead to prolonged myocardial infiltration with macrophages and associated oedema formation. Initially, the diagnosis of TTS was made via exclusion of relevant coronary artery stenoses, plus the presence of regional left ventricular hypokinesis. However, detection of extensive myocardial oedema on cardiac MRI imaging offers a specific basis for diagnosis. No adequate methods are yet available for definitive diagnosis of TTS at hospital presentation. Other major challenges remaining in this area include understanding of the recently demonstrated association between TTS and antecedent cancer, the development of effective treatments to reduce risk of short-term (generally due to shock) and long-term mortality, and also to accelerate symptomatic recovery.

Update of takotsubo syndrome in the era of COVID-19.

Takotsubo cardiomyopathy or takotsubo syndrome (TTS) has become a well-known disease not only in Japan but also in the rest of the world. Early reports suggested that TTS is a self-limiting disease with better prognosis than acute coronary syndrome. However, recent data showed that TTS is not a benign disease as compared with acute coronary syndrome. In addition to the apical ballooning, several other types of wall motion abnormalities have been classified as variants of TTS. In particular, right ventricular involvement, or biventricular TTS, is not uncommon and is associated with poor in-hospital as well as long-term outcomes. With respect to the pathophysiology, modulation (desensitization) of the beta-adrenergic receptor is suspected as a possible mechanism for transiently depressed myocardial contraction. Although specific treatments to improve prognosis of TTS are still uncertain, observational data suggest favorable impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Finally, in the era of COVID-19, we should pay attention to a variety of cardiovascular conditions related to COVID-19. TTS is one of these conditions that can be triggered by both emotional and physical impact of the COVID-19 pandemic.

Who Has Seen Patients With ST-Segment-Elevation Myocardial Infarction? First Results From Italian Real-World Coronavirus Disease 2019.

Background After the coronavirus disease 2019 outbreak, social isolation measures were introduced to contain infection. Although there is currently a slowing down of the infection, a reduction of hospitalizations, especially for myocardial infarction, was observed. The aim of our study is to evaluate the impact of the infectious disease on ST-segment-elevation myocardial infarction (STEMI) care during the coronavirus disease 2019 pandemic, through the analysis of recent cases of patients who underwent percutaneous coronary intervention. Methods and Results Consecutive patients affected by STEMI from March 1 to 31, 2020, during social restrictions of Italian government, were collected and compared with patients with STEMI treated during March 2019. During March 2020, we observed a 63% reduction of patients with STEMI who were admitted to our catheterization laboratory, when compared with the same period of 2019 (13 versus 35 patients). Changes in all time components of STEMI care were notably observed, particularly for longer median time in symptom-to-first medical contact, spoke-to-hub, and the cumulative symptom-to-wire delay. Procedural data and in-hospital outcomes were similar between the 2 groups, whereas the length of hospitalization was longer in patients of 2020. In this group, we also observed higher levels of cardiac biomarkers and a worse left ventricular ejection fraction at baseline and discharge. Conclusions The coronavirus disease 2019 outbreak induced a reduction of hospital access for STEMI with an increase in treatment delay, longer hospitalization, higher levels of cardiac biomarkers, and worse left ventricular function.

Echocardiographic features of patients with COVID-19 infection: a cross-sectional study.

COVID-19 patients with cardiac involvement have a high mortality rate. The aim of this study was to investigate the echocardiographic features in COVID-19 patients between severe and non-severe groups. For this single-center study, data from patients who were treated for COVID-19 between March 25, 2020 and April 15, 2020 were collected. Two-dimensional echocardiography (2DE) images were obtained for all patients. Patients were divided into two groups based on the severity of their COVID-19 infections. 2DE parameters indicating right ventricular (RV) and left ventricular (LV) functions were compared between the two groups. A total of 90 patients hospitalized for COVID-19 were included in this study. The mean age of the severe group (n = 44) was 63.3 ± 15.7 years, and 54% were male. The mean age of non-severe group (n = 46) was 49.7 ± 21.4 years, and 47% were male. In the severe group, RV and LV diameters were larger (RV, 36.6 ± 5.9 mm vs. 33.1 ± 4.8 mm, p = 0.003; LV 47.3 ± 5.8 mm vs. 44.9 ± 3.8 mm, p = 0.023), the LE ejection fraction (LVEF) and the RV fractional area change (RV-FAC) were lower (LVEF, 54.0 ± 9.8% vs. 61.9 ± 4.8%, p < 0.001; RV-FAC, 41.4 ± 4.1% vs. 45.5 ± 4.5%, p < 0.001), and pericardial effusions were more frequent (23% vs. 0%) compared to patients in the non-severe group. A multiple linear regression analysis determined that LVEF, right atrial diameter, high-sensitivity troponin I, d-dimer, and systolic pulmonary artery pressure, were independent predictors of RV dilatation. The results demonstrate that both right and left ventricular functions decreased due to COVID-19 infection in the severe group. 2DE is a valuable bedside tool and may yield valuable information about the clinical status of patients and their prognoses.

Reversible cardiac dysfunction in severe COVID-19 infection, mechanisms and case report.

A previously healthy 49-year-old male patient presented with COVID-19 infection and required mechanical ventilation and extracorporeal membrane oxygenation due to severe hypoxemia. Echocardiography showed cardiac dysfunction with an apical sparing strain pattern, which rapidly normalized within a week. Apical sparing myocardial strain in patients with COVID-19 infection may suggest reverse-type stress cardiomyopathy.