Background: SARS-CoV-2 infection affects the cardiopulmonary system in both the acute and long-term phase. This study aimed to comprehensively assess symptoms and potential long-term impairments 6, 18 and 30 months in patients previously hospitalized for severe Covid-19 infection. Methods: This prospective registry included patients hospitalized for PCR-confirmed Covid-19 infection. Approximately 6 months post-discharge, follow-up examination included patient history, clinical examination, echocardiography, electrocardiogram, cardiac magnetic resonance imaging (cMRI), chest computed tomography (CT) scan, pulmonary function test (PFT), six-minute walk test (6MWT) and a comprehensive laboratory panel. Patients with pathologic findings during the first visit underwent a second (at 18 months) and third (at 30 months) follow-up examination. Those without pathologic findings or who refused further medical examinations were contacted via phone to inquire about symptoms. Results: Between July 2020 and April 2022, 200 patients (91% general ward, 9% intensive care unit) were recruited. Due to dropouts, the second visit was conducted in 170 patients, and the third visit in 139 (74 in person, 65 via telephone). Long Covid criteria were fulfilled by 73% at 6 months, 52% at 18 months and 49% at 30 months post-discharge, with fatigue being the most common symptom (Figure 1). Echocardiography at 6 months showed impaired left ventricular function in 15 patients, with normalization in 80% at 18 months and further 66% at 30 months (Figure 2). cMRI revealed pericardial effusions in 28 patients at 6 months, which resolved in 47% at 18 months and in further 60% at 30 months. Signs of peri- or myocarditis were present in 7 patients at 6 months and were resolved in all 4 patients who attended control studies at 18 months. Chest CT scans at 6 months identified post-infectious residues in 41 patients, with full recovery in 20% at 18 months without further normalization after 30 months. The length of in-hospital stay was identified as a significant predictor for persisting Long Covid 6 months after discharge (95% CI: 1.005 - 1.12, p=0.03). Conclusion: While the prevalence of Long Covid decreased over time, a significant symptom burden persisted at 6, 18 and even 30 months after severe Covid-19 infection. Structural and functional abnormalities were less frequent compared to reported symptoms, posing a challenge in substantiating the causes of these symptoms.

IntroductionSARS-CoV-2 infection affects the cardiopulmonary system in the acute as well as long-term phase. The aim of the present study was to comprehensively assess symptoms and possible long-term impairments 6 and 18 months after hospitalization for severe COVID-19 infection.MethodsThis prospective registry included patients with PCR-confirmed COVID-19 infection requiring hospitalization. Follow-up approximately 6 months post discharge comprised a detailed patient history, clinical examination, transthoracic echocardiography, electrocardiogram, cardiac magnetic resonance imaging (cMRI), chest computed tomography (CT) scan, pulmonary function test (PFT), six-minute walk test (6MWT) and a laboratory panel. At the time of the second follow-up visit at 18 months, patients without pathologic findings during the first study visit were contacted by phone to inquire about the course of their symptoms. In all other patients all initial examinations were repeated.ResultsTwo hundred Patients, who were hospitalized for COVID-19, were contacted by phone and were recruited for the study. Due to dropouts the second study visit was performed in 170 patients. A comparison between the two study visits at 6 and 18 months post discharge showed the following results: Six months after discharge, 73% and 18 months after discharge 52% fulfilled the criteria for Long COVID with fatigue being the most common symptom (49%). Echocardiography at 6 months post discharge showed an impaired left ventricular function in 8% of which 80% returned to normal. Six months post discharge, cMRI revealed pericardial effusion in 17% which resolved in 47% of the 15 patients who underwent a control cMRI. Signs of peri- or myocarditis were present in 5% of the patients and were resolved in all 4 patients who attended control studies. At 6 months, chest CT scans identified post-infectious residues in 24%. In the 25 repeated chest CT scans 20% showed full recovery. Length of in-hospital stay was identified as a significant predictor for persisting Long COVID (95% CI: 1.005–1.12, p = 0.03).ConclusionComparing 6 to 18 months, the prevalence of Long COVID decreased over time, but a high symptom burden remained. Structural and functional abnormalities were less frequent than the portrayed symptoms, and it thus remains a challenge to substantiate the symptoms.

Abstract Background Covid-19 infection affects the cardiopulmonary system in the acute as well as long-term phase. The aim of the present study was to deliver a comprehensive report of symptoms and possible long-term impairments 6 and 18 months after hospitalization for severe Covid-19 infection. Methods This prospective registry included patients after PCR-confirmed Covid-19 infection, who were treated as in-patients at our Covid-19 department. Follow-up approximately 6 months post discharge comprised a detailed patient history, clinical examination, transthoracic echocardiography, electrocardiogram, cardiac magnetic resonance imaging (cMRI), chest computed tomography (CT) scan, pulmonary function test (PFT), six-minute walk test (6MWT) and a comprehensive laboratory panel including brain natriuretic peptide and troponin T. At the time of the second follow-up visit at 18 months, patients who did not show any abnormalities during the first study visit or refused to return for a follow-up visit, were contacted by phone to inquire about the course of symptoms (n=42). In all other patients with abnormalities during the first study visit, blood testing, echocardiography and 6MWT were repeated. CT, cMRI and lung function test were only performed in case of pathological findings during the first study visit. Results Between July 2020 and April 2022 200 patients were recruited (91% general ward, 9% intensive care unit). Due to dropouts the second study visit was only performed in 149 patients. A comparison between the two study visits at 6 and 18 months post discharge showed the following results: Six months after discharge, 73% and 18 months after discharge 52% fulfilled the criteria for Long-Covid with fatigue being the most common symptom (figure 1). Echocardiography at 6 months post discharge showed a reduced left ventricular function in 8% (n=15), of which 80% returned to normal at 18 months (n=5, figure 2). Six months post discharge, cMRI revealed pericardial effusion in 17% (n=25) and resolved in 43% of the 7 patients who underwent a control cMRI. Signs of peri- or myocarditis were present in 5% of the patients (n=7) at 6 months and were resolved in all 4 patients in control studies. PFT detected reduced vital capacity in 11% of patients (n=17). Values improved in 50% and normalized in 10% of the 10 patients, who attended the second study visit. At 6 months, pulmonary CT scans identified post-infectious residues in 22% (n= 39), of which 24% showed full recovery. A predictor for persisting Long-Covid was the length of in-hospital stay (95% CI: 1.005 - 1.12, p=0.03) as an indicator for the severity of the initial disease course. Conclusion Comparing 6 to 18 months after severe Covid-19 infection, the prevalence of Long-Covid decreased over time, but a high symptom burden remains. Structural and functional abnormalities were less frequent compared to the portrayed symptoms, and it remains a challenge to substantiate the symptoms.SymptomsFunctional and Structural changes

We aimed to identify cardiopulmonary long-term effects after severe COVID-19 disease as well as predictors of Long-COVID in a prospective registry. A total of 150 consecutive, hospitalized patients (February 2020 and April 2021) were included six months post hospital discharge for a clinical follow-up. Among them, 49% experienced fatigue, 38% exertional dyspnea and 75% fulfilled criteria for Long-COVID. Echocardiography detected reduced global longitudinal strain (GLS) in 11% and diastolic dysfunction in 4%. Magnetic resonance imaging revealed traces of pericardial effusion in 18% and signs of former pericarditis or myocarditis in 4%. Pulmonary function was impaired in 11%. Chest computed tomography identified post-infectious residues in 22%. Whereas fatigue did not correlate with cardiopulmonary abnormalities, exertional dyspnea was associated with impaired pulmonary function (OR 3.6 [95% CI: 1.2-11], p = 0.026), reduced GLS (OR 5.2 [95% CI: 1.6-16.7], p = 0.003) and/or left ventricular diastolic dysfunction (OR 4.2 [95% CI: 1.03-17], p = 0.04). Predictors of Long-COVID included length of in-hospital stay (OR: 1.15 [95% CI: 1.05-1.26], p = 0.004), admission to intensive care unit (OR cannot be computed, p = 0.001) and higher NT-proBNP (OR: 1.5 [95% CI: 1.05-2.14], p = 0.026). Even 6 months after discharge, a majority fulfilled criteria for Long-COVID. While no associations between fatigue and cardiopulmonary abnormalities were found, exertional dyspnea correlated with impaired pulmonary function, reduced GLS and/or diastolic dysfunction.

Background: In patients with transthyretin amyloid cardiomyopathy, tafamidis was shown to slow the decline in 6-minute walking distance as compared with placebo. We aimed to define the impact of tafamidis and optimal background treatment on functional capacity as determined by cardiopulmonary exercise testing (CPET). Methods: Seventy-eight consecutive patients were enrolled in the study. They underwent CPET at baseline, and outcome defined as death or heart failure hospitalization was obtained for a time period of up to 30 months. Fifty-four patients completed a follow-up CPET at 9±3 months (range, 4–16 months). Improvement in peak VO 2 at follow-up was defined as ∆peak VO 2 ≥1.0 mL/(kg·min), stable peak VO 2 was defined as 0≤∆peak VO 2 <1.0 mL/(kg·min), and decline in peak VO 2 was defined by ∆peak VO 2 <0 mL/(kg·min). Results: Baseline peak VO 2 >14 mL/(kg·min) as well as minute ventilation/carbon dioxide production slope≤34 were associated with a lower risk of death or heart failure hospitalization ( P =0.002, P =0.007, respectively). In 54 patients, who received tafamidis and underwent repeat CPET testing, an improvement in physical performance ( P =0.002) was observed at follow-up. When comparing pre and post-treatment parameters, 29 patients (54%) showed an increase in percent predicted peak VO 2 ( P <0.0001), an improvement of peak VO 2 ( P <0.0001), and better physical performance at follow-up ( P <0.0001). Patients with stable or improved peak VO 2 had less advanced heart disease at baseline ( P =0.046). Conclusions: Our findings demonstrate that baseline peak VO 2 and baseline minute ventilation/carbon dioxide production slope predict outcomes and an improvement in physical performance as measured by CPET was observed in patients receiving tafamidis, who had less advanced disease at baseline, emphasizing the importance of early diagnosis.

Abstract Background Multiple studies have described acute effects of the Covid-19 infection on the heart, but little is known about the long-term cardiac and pulmonary effects and complications after recovery. The aim of this analysis was to deliver a comprehensive report of symptoms and possible long-term impairments after hospitalization because of Covid-19 infection as well as to try to identify predictors for Long-Covid. Methods This was a prospective, multicenter registry study. Patients with verified Covid-19 infection, who were treated as in-patients at our dedicated Covid hospital (Clinic Favoriten), have been included in this study. In all patients, testing was performed approximately 6 months post discharge. During the study visit the following tests and investigations were performed: detailed patient history and clinical examination, transthoracic echocardiography, electrocardiography, cardiac magnetic resonance imaging (MRI), chest computed tomography (CT) scan, lung function test and a comprehensive list of laboratory parameters including cardiac bio markers. Results Between July 2020 and October 2021, 150 patients were recruited. Sixty patients (40%) were female and the average age was 53.5±14.5 years. Of all patients, 92% had been admitted to our general ward and 8% had a severe course of disease, requiring admission to our intensive care unit. Six months after discharge the majority of patients still experienced symptoms and 75% fulfilled the criteria for Long-Covid. Only 24% were completely asymptomatic (figure 1). Echocardiography detected reduced global longitudinal strain (GLS) in 11%. Cardiac MRI revealed pericardial effusion in 18%. Furthermore, cardiac MRI showed signs of former peri- or myocarditis in 4%. Pulmonary CT scans identified post-infectious residues, such as bilateral ground glass opacities and fibrosis in 22%. Exertional dyspnea was associated with either reduced forced vital capacity measured during pulmonary function tests in 11%, with reduced GLS and/or diastolic dysfunction, thus providing evidence for a cardiac and/or pulmonary cause. Independent predictors for Long-Covid were markers of a more severe disease course like length of in-hospital stay, admission to an intensive care unit, type of ventilation as well as higher NT-proBNP and/or troponin levels. Conclusion Even 6 months after recovery from Covid-19 infection, the majority of previously hospitalized patients still suffer from at least one symptom, such as chronic fatigue and/or exertional dyspnea. While there was no association between fatigue and cardiopulmonary abnormalities, impaired lung function, reduced GLS and/or diastolic dysfunction were significantly more prevalent in patients presenting with exertional dyspnea. On chest CT approximately one fifth of all patients showed post infectious changes in chest CT including evidence for myo- and pericarditis as well as accumulation of pericardial effusions. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Major fund

Drugs which interact with the renin angiotensin aldosterone system (RAAS) aim to reduce the negative effects of angiotensin (Ang) II. Treatment with these drugs anticipate a compensatory up-regulation of renin; however, it has been shown that there is a large variability in circulating plasma renin (PRA), even in patients with optimal medical therapy in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Our aim was to measure plasma renin activity (PRA-S), its response to RAAS inhibitor (RAASi) therapies and its effects on outcome in patients with HF with preserved ejection fraction (HFpEF). For this purpose, 150 HFpEF patients were included into a prospective single-center registry. Equilibrium (eq) angiotensin metabolites were measured from serum samples using mass spectroscopy. PRA-S (eqAng I + eqAng II) was calculated and compared in respect to the primary endpoint defined as all-cause death. PRA-S in patients with RAASi therapy was not significantly higher than in patients without RAASi (p = 0.262). Even after adjusting for confounding factors, PRA-S remained predictive for all-cause death in the multivariable model with a hazard ratio of 2.14 (95%CI 1.20–3.82, p = 0.010). We conclude that high PRA-S is associated with poor prognosis in patients with HFpEF, regardless of RAASi treatment, which could ultimately result in hyperactivated RAAS and consecutive negative effects on the cardiovascular and renal system, leading to poor outcome in patients with HFpEF.

Abstract Background Established heart failure (HF) treatments have shown no effects in HF and preserved ejection fraction (HFpEF). Subgroup analyses of the HFpEF populations suggest that certain patients benefit from HF treatments. This underlines the importance of individualized therapy regimens in HFpEF. Sodium-glucose transporter 2 (SGLT-2) inhibitors are emerging as a promising treatment of HF. The mechanisms leading to improved outcomes include 1) treatment of diabetes, 2) osmodiuresis preventing volume overload, 3) enhancement of the cardio protective Angiotensin (Ang) 1–7 pathway, instead of Ang II. We aimed to characterize patients by factors which are modified by SGLT-2 inhibitors to identify individuals who may benefit from these drugs. Methods HFpEF patients were included in a single center registry. Baseline evaluation included assessment of HbA1c, fluid status measured by body composition monitor and plasma angiotensin concentration. A “SGLT-2 score” with a maximum of 3 points was calculated using the following parameters: 1) HbA1c >6.5%, 2) overhydration, defined as a fluid overload of >1,5L and 3) plasma renin activity (PRA) levels above the median as a parameter of over-all RAS activity. Primary outcome was defined as all-cause death or HF hospitalization. All parameters used in the “SGLT-2 score” were independently predictive for the chosen endpoint. Kaplan Meier analyses was used to show the association between the score and outcomes. Results 90 patients were included in this registry. Median HbA1c was 6.0%, median fluid status was 1.2L and the median Ang II levels in the “high PRA-group” were 5.35.1 pmol/L. After a mean follow up time of 44.0±38.7 months, 60 patients (66.6%) reached the endpoint. Kaplan Meier analysis showed an association between SGLT-2 score and outcome (p=0.003). Conclusion Patients with HbA1c >6.5%, overhydration and high RAS activity have poor outcomes. We propose the future use of this score to identify a subgroup of HFpEF patients who may benefit from SGLT-2 inhibitors. Kaplan Meier analysis Funding Acknowledgement Type of funding source: None

This study sought to characterize cardiac amyloidosis (CA) patients with respect to hemodynamic parameters and asses their prognostic impact in different CA cohorts. Intracardiac and pulmonary arterial pressures (PAPs) are among the strongest predictors of outcomes in patients with heart failure (HF). Despite that, the hemodynamic profiles of patients with CA and their relation to prognosis have rarely been investigated. Invasive hemodynamic, clinical, and laboratory assessment, as well as cardiac magnetic resonance imaging were performed in our CA cohort. A total of 61 patients, 35 (57.4%) with wild-type transthyretin amyloidosis (ATTRwt) and 26 (42.6%) with light-chain amyloidosis (AL) were enrolled. ATTRwt patients had lower N-terminal prohormone of brain natriuretic peptide values and were less frequently in New York Heart Association class ≥ III. Intracardiac and PAPs were elevated, but hemodynamic parameters did not differ between CA groups. Whereas in ATTRwt, the median mean PAP (hazard ratio (HR): 1.130, p = 0.040) and pulmonary vascular resistance (HR: 1.010, p = 0.046) were independent predictors of outcome, no hemodynamic parameter was associated with outcome in the AL group. Cardiac ATTRwt and AL patients feature elevated intracardiac and PAPs and show similar hemodynamic profiles. However, hemodynamic parameters are of greater prognostic relevance in ATTRwt, potentially providing a new therapeutic target.

Background Pericardial and pleural effusion are common findings in patients with cardiac amyloidosis (CA). It is not known, whether effusions correlate with right ventricular (RV) function in these patients. Furthermore, data on the prognostic significance of pleural and pericardial effusion in CA is scarce. Methods Patients with transthyretin (ATTR) and light chain (AL) CA were included in a clinical registry. All patients underwent transthoracic echocardiography at baseline. The presence of pericardial and pleural effusion was determined in every patient. The clinical endpoint was defined as cardiac death or heart failure hospitalization. Results In total, 143 patients were analysed. Of these, 85 patients were diagnosed with ATTR and 58 patients with AL. Twenty-four patients presented with isolated pericardial effusion and 35 with isolated pleural effusion. In 19 patients, both pericardial and pleural effusion were found and in 65 patients no effusion was present at baseline. The presence of pleural effusion correlated well with poor RV function, measured by global RV free-wall strain ( p = 0.007) in patients with AL, but not in ATTR. No such correlation could be found for pericardial effusion in either amyloidosis subtype. Patients with AL presenting with pleural effusion had worse outcomes compared to patients with pericardial effusion alone or no effusion at baseline. In the ATTR group, there was no difference in outcomes according to presence and type of effusion. Conclusion More than 50% of patients with CA presented with pleural and/or pericardial effusions. While pleural effusion was clearly associated with poor RV function in AL, we were not able to detect this association with pericardial effusion.

Transthyretin amyloid cardiomyopathy (ATTR-CA) is caused by deposition of amyloid fibrils in the myocardium. Tafamidis is a kinetic stabilizer of TTR that prevents tetramer dissociation and amyloidogenesis. Thirty-eight patients with diagnosis of ATTR-CA were treated with tafamidis (20mg or 61mg) for a period of six months. In our explorative analysis we aimed to evaluate the effects of tafamdis by changes from baseline of the serum NT-proBNP concentration, 6MWD, as well as cardiac structure and function, compared to untreated amyloidosis patients. The analysis showed a significant reduction in the serum NT-proBNP concentration in tafamidis-treated patients compared to untreated patients (median difference, −1042.5 pg/mL, p=0.015). Tafamidis also improved the walking distance at month six, while reduction in untreated patients was observed (mean difference, +29.27 m, p=0.175). Echocardiographic findings revealed a decrease in LV size (mean, −1.56 mm) as well as improvements regarding the LA size (mean difference, −2.51 mm) and the GLS (mean difference, 0.80%) in tafamidis-treated patients. T1 mapping in cardiac MRI showed a decrease in ECV (mean, −1.79%) in patients receiving tafamidis, while an increase in ECV in untreated patients was observed (mean, +0.41%). Treatment with tafamidis for a period of six months in patients with ATTR-CA results in a significant improvement in NT-proBNP levels and may have positive effects on exercise capacity, cardiac function and myocardial amyloid deposition compared to untreated amyloidosis patients. Picture 1. Change from baseline. Type of funding source: None

Abstract Background Apical sparing describes a reduced longitudinal strain in the basal segments and preserved or supranormal longitudinal strain in the apical segments of the left ventricular (LV) myocardium. This pattern has been described as a typical finding in patients with cardiac amyloidosis (CA) and restrictive cardiomyopathy. However, apical sparing is not a quantitative parameter and is fairly subjective to the echocardiographer's judgement. It is not known, if a certain degree of apical sparing is also present in patients with only mild LV hypertrophy and diastolic dysfunction such as it is present in heart failure with preserved ejection fraction (HFpEF). Methods Patients with cardiac transthyretin and light chain amyloidosis and patients with HFpEF were included in a clinical registry at our outpatient clinic. CA was diagnosed according to current guidelines. All patients underwent a comprehensive transthoracic echocardiography (TTE) exam at the time of study inclusion. The TTE protocol included standard and speckle-tracking imaging to assess the presence of apical sparing as well as the basal to apical strain gradient. Patients with known coronary artery disease were excluded. Results In total 115 patients were included in this study. Of these, 87 (75.7%) were diagnosed with CA and 28 (24.3%) with HFpEF. Not surprisingly, apical sparing was found in a majority (86.2%) of patients with CA, however mild forms of this phenomenon were also present in 67.9% of patients with HFpEF (p=0.029, Figure 1). Median basal longitudinal strain was significantly more impaired in patients with CA (p<0.001) but there was no difference between longitudinal strain in the apical segments when comparing CA to HFpEF (p=0.443). This resulted in a higher median apical to basal strain gradient in patients with CA (2.3 (IQR 1.7–3.83) versus 1.13 (IQR 1.5–1.8), p<0.001). Figure 1 Conclusion Mild forms of apical sparing can be found in patients without CA. Gradual reduction in strain from base to apex could be an unspecific pathophysiologic mechanism which is remarkably pronounced in patients with CA.

Abstract Background Pericardial and pleural effusion are common findings in patients with cardiac amyloidosis (CA). While this might be suggestive of a sign of right heart failure, it is not known, whether effusions correlate with right ventricular (RV) function in patients with CA. Furthermore, data on the prognostic significance of pleural and pericardial effusion in CA is scarce. Methods Patients with cardiac transthyretin (ATTR) and light chain (AL) amyloidosis were included in a clinical registry at our dedicated CA outpatient clinic. CA was diagnosed according to current guidelines. All patients underwent a comprehensive transthoracic echocardiography (TTE) exam at the time of study inclusion. The TTE protocol included standard and advanced parameters describing left ventricular and RV function, including speckle-tracking imaging to assess global longitudinal left ventricular and RV free wall (RV-FW) strain. The presence of pericardial and pleural effusion was determined in every patient and was verified by cardiac magnetic resonance imaging when present. The size of pericardial effusion was measured at the point of its maximum extension. The clinical endpoint was defined as all-cause death. Results Between March 2012 and February 2019, 177 patients were included in our CA registry, however, TTE image quality was only sufficient for analysis in 143 patients. Of these, 83 patients (59.4%) were diagnosed with ATTR and 60 patients (42.0%) with AL. In total, 23 patients (16.1%) presented with isolated pericardial effusion and 36 (25.2%) with isolated pleural effusion. In 17 patients (11.9%) both pericardial and pleural effusion were found and in 66 patients (46.2%) no effusion was present at baseline. Overall, there was no significant difference in the type of effusion between patients with AL and ATTR. In general, pericardial effusions were small (median diameter 7.1 mm (IQR 5.2–9.7) and none were hemodynamically compromising. Interestingly, the presence of pleural effusion correlated well with poor RV function, measured by RV-FW strain (p=0.034). However, no such correlation could be found for pericardial effusion and RV-FW strain (p=0.319). Kaplan Meier analysis showed that patients presenting with pleural effusion had a worse prognosis compared to patients with pericardial effusion alone or no effusion at baseline (p=0.001, Figure 1). Figure 1 Conclusion More than 50% of patients with CA presented with pleural and/or pericardial effusions. While pleural effusion was clearly associated with poor RV function, we were not able to detect this association with pericardial effusion. In addition, patients with pleural effusions had an exceptionally poor prognosis compared to patients with pericardial effusions or no effusion at baseline.