Background Despite recent advances in treatment, heart failure (HF) continues to be associated with high mortality rates. In this setting, 123iodine-meta-iodobenzylguanidine (123I-MIBG) scintigraphy emerges as a promising tool for the prediction of clinical outcomes in HF due to its ability to assess cardiac sympathetic innervation. However, 123I-MIBG scintigraphy's correlation with myocardial remodeling and cardiopulmonary exercise capacity has not yet been fully elucidated. Objectives To evaluate cardiac sympathetic activity through 123I-MIBG scintigraphy, and to analyze its correlation with myocardial remodeling and exercise capacity in HF patients. Methods Symptomatic HF patients (NYHA class II–III) stratified by LVEF as HFpEF (LVEF 45%) and HFrE'F (LVEF <45%) and healthy controls were enrolled. HF patients were euvolemic under optimized treatment at the time of enrollment. All individuals underwent CMR with morphology/function and extracellular volume fraction (ECV) assessment, global longitudinal strain (GLS) by echocardiogram, cardiopulmonary exercise testing (CPET), cardiac sympathetic imaging 123I-MIBG scintigraphy (mIBG), and NT-proBNP. Results Eighty individuals were recruited allocated into the following groups: HFpEF (n=33, 59.42±12.63 years, LVEF: 59.82±9.87, NT-proBNP: 409.40±693.37, H2FPEF-score: 5±2), HFrEF (n=28, 53.93±11.40 years; LVEF: 29.81±8.67, NT-proBNP: 1662,34±2016,73) and healthy controls (42.65±13.96 years, LVEF: 65.27±4.73, NT-proBNP: 44,43±33,28) were enrolled. While ECV was elevated in HF groups (HFpEF: 0.32±0.05%, HFrEF: 0.31±0.41% and controls: 0.26±0.03, p<0.05), adjusted maximum oxygen consumption (VO2max) was markedly reduced vs. controls (HFpEF: 18.58±6.29mL/kg/min, HFrEF: 17.60±3.89mL/kg/min, controls: 29.73±9.98mL/kg/min, p<0.001). The MIBG heart-to-mediastinum ratio at 4 hours (H/M) was significantly lower in HF compared with controls (HFpEF: 1.59±0.25, HFrEF: 1.45±0.15 and controls: 1.92±0.25, p<0.001). Interestingly, the H/M ratio was more impaired with HFrEF compared to HFpEF (Fig. 1A). As a result, the mean myocardial washout rate was increased in HF patients (HFrEF 36.38±14.35, HFpEF 29.92±18.33 vs. controls 8.0±27.01, p<0.001). In addition, considering all HF patients, H/M was inversely associated with ECV (R: −0.45, p<0.001, Fig. 1B), NT-proBNP (R: −0.55, p<0.001) and VO2max (R: −0.27, p: <0.024, Fig. 1C). GLS was inversely associated with H/M in HFrEF but not HFpEF (HFrEF: R: −0.535, p<0.001 and HFpEF: R: −0.036, p=NS, Fig. 1D). Conclusion Cardiac sympathetic activity assessed by 123I-MIBG was abnormal in patients with HF with reduced and preserved EF as compared to controls. H/M, a validated marker for cardiac sympathetic activity, showed a strong correlation with markers of functional capacity and myocardial remodeling. Sympathetic innervation appears to be a limiting factor for global longitudinal strain in HFrEF, while in HFpEF longitudinal strain is independent of sympathetic activity Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The São Paulo Research Foundation
Background An abnormal increase of cardiomyocyte mass of the left ventricle is observed in physiological and pathological phenotypes of hypertrophy. Aims To apply CMR tissue characterization using native T1/T2 and post-contrast T1 mapping and identify tissue phenotypes corresponding to physiological and pathological hypertrophy, in athletes and heart failure (HF), respectively. Methods/Results 187 individuals were prospectively enrolled, in 4 groups: Athletes (n=56, 32±13 years), HF with and without preserved ejection fraction (HFpEF: n=49, 62±12 years; HFrEF: n=49, 54±16 years, H2FpEF-score: 4.8 [3–9]), and healthy controls (n=33, 41±13.7 years). All participants underwent cardiopulmonary exercise testing and a multiparametric CMR study to assess morphology/function, T2, native T1, extracellular volume fraction (ECV), and intracellular lifetime of water (a marker of cardiomyocyte diameter). As expected, LVEF varied significantly among groups (Athletes: 64.7±6.1%, HFpEF: 59.3±10.7%, HFrEF: 29.4±8.5%, and controls: 65.4±4.3%, p<0.001) and was markedly reduced in HFrEF. Both LV mass index (Athletes: 64.1±15.8 g/m2, HFpEF: 62.3±24 g/m2, HFrEF: 79.5±36.7 g/m2, and controls: 42±9.2 g/m2, p<0.001) and cardiomyocyte mass index (calculated as (1 − ECV) x LV mass/BSA) (Athletes: 47.9±13.1 g/m2, HFpEF: 42.2±17.2 g/m2, HFrEF: 55.69±24.70 g/m2, and controls: 30.7±6.9 g/m2, p<0.001, Fig. 1A) were elevated in athletes and HF, compared to controls. Athletes and HFpEF patients showed concentric LV remodeling, while the eccentric LV remodeling was observed in HFrEF (Fig. 1B). In the HF groups NT-proBNP was elevated (Athletes: 34.6±16.8 ng/dL, HFpEF: 473.2±700.1 ng/dL, HFrEF: 1,365.3±1,772 ng/dL, and controls: 34.3±29 ng/dL, p<0.005), and adjusted maximum oxygen consumption was markedly reduced (Athletes: 49.4±9.3 mL/kg/min, HFpEF: 18.3±5.5 mL/kg/min, HFrEF: 17.1±4.2 mL/kg/min, and controls: 30.3±10.2 mL/kg/min, p<0.005). ECV was larger in both HF groups (athletes: 0.27±0.04, HFpEF: 0.31±0.05, HFrEF: 0.32±0.04, and controls: 0.26±0.02, p<0.001). The intracellular lifetime of water was longer among athletes compared to controls and shorter in HFrEF compared to HFpEF (Athletes: 0.17±0.07, HFpEF: 0.15±0.05, HFrEF: 0.13±0.05, and controls: 0.14±0.05, p<0.001). Native T1 was reduced in athletes compared to controls and elevated in the HF groups (Athletes: 1,173.4±63.2 ms, HFpEF: 1,262.8±62.4 ms, HFrEF: 1,275.1±59.9 ms, and controls: 1,212.78±76.01 ms, p<0.001). Lastly, the an increased T2 was indicative of edema in HF patients (Fig. 2). Conclusions In a prospective observational study with CMR T1/T2 mapping, physiological hypertrophy is characterized by increased cardiomyocyte diameter, normal ECV, and a decrease in native T1, due to the larger cardiomyocyte volume. In contrast, with pathological hypertrophy in HF, is associated with an increased and an above-normal native T1. Cardiomyocyte diameter appears reduced in HFrEF compared to HFpEF, reflecting the transition to an eccentric LV shape. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The São Paulo Research Foundation
Background ATTR-related Familial Amyloid Polyneuropathy (FAP) is a hereditary disease that primarily affects peripheral nerve function. Few studies have investigated cardiac involvement and myocardial tissue remodeling in FAP. Aim To investigate subclinical myocardial tissue remodeling in FAP patients without cardiomyopathy using a multiparametric CMR protocol. Results Thirty-one FAP patients (46.9±16.1 years, 57% female, 60% Val30Met mutation) and 33 healthy controls (41.3±13.7 years, 58% female) were enrolled, undergoing a multiparametric CMR protocol for assessment of ventricular morphology and function, native myocardial T1, extracellular volume fraction (ECV) and intracellular lifetime of water). Cardiopulmonary exercise capacity was evaluated with a cycle ergometer. Cardiac high-sensitive troponin T (cTnT) and NT-proBNP were measured to assess for cardiac injury. The majority of ATTR-PN patients were in stage 1 (70%) with mild symptoms of sensory, motor and autonomic neuropathy. Adjusted maximum oxygen consumption was reduced among FAP patients compared to healthy controls (FAP: 22.2±8.2 mL/kg/min vs. controls: 30.3±10.2 mL/kg/min, p<0.001). Although none of FAP patients reported heart failure symptoms, NT-proBNP (FAP: 251.240±624.446 ng/dL, vs. controls: 34.3±29 ng/dL, p<0.005) and cTnT (FAP: 13.2 [3.0, 19.0] ng/dL, vs. controls: 3.6 [3.0, 6.0] ng/dL, p<0.005) were elevated, and both correlated with ECV (cTnT: R=0.81, P<0.001; NT-proBNP: R=0.61, P=0.001, Fig. 1). While LVEF was preserved among FAP patients (FAP: 67.9±8.2% vs. controls: 65.4±4.3%, p=NS), LVmass index was increased compared to control subjects (FAP: 58.5±18.8 vs. and controls: 42±9.2 g/m2, p<0.005). Both native T1 (FAP: 1,303.924±120.152, vs. controls: 1,212.78±76.01 ms, p<0.05) and ECV (FAP: 0.36±0.1, vs. controls: 0.26±0.02, p<0.001) were markedly elevated among FAP patients. In contrast the intracellular lifetime of water, a validated marker of cardiomyocyte size was reduced in the FAP group (FAP: 0.082±0.04 vs. controls: 0.14±0.05, p<0.001). There was a trend for ECV to increase linearly with FAP stage, and native T1 trended higher in stage 1 and 2 patients compared to stage 0. Both ECV (R=0.89, p<0.001) and native T1 (R=0.62, p<0.001) were correlated with LVmass index (Fig 2). Conclusion In FAP without clinical signs of cardiac involvement, significant extracellular matrix expansion was present. The increase of LV mass in these patients is associated with expansion of the extracellular matrix, possibly as a result of diffuse replacement fibrosis, and below-normal cardiomyocyte diameter. These findings from serum biomarkers and CMR tissue phenotyping provide evidence of sub-clinical cardiac involvement through adverse myocardial tissue remodeling in FAP patients presenting with mostly mild symptoms of peripheral neuropathy. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pfizer
Introduction: Physiological and pathological cardiac hypertrophy differ in terms of mechanisms, phenotypes, and outcomes. We aimed to characterize the cardiac tissue phenotype of athletes and HF patients. Methods: Prospectively enrolled participants underwent CMR and CPET. HF patients (NYHA class II-III) were classified as HFpEF (LVEF>=45%) or HFrEF (LVEF<45%). Results: One-hundred and eighty participants were categorized in four groups: athletes (n=44, 32±12 years), HFpEF (n=47, 61±11 years, H2FPEF score 5±2), HFrEF (n=47, 54±10 years), and healthy controls (n=42, 41±13 years). LVEF was markedly reduced in HFrEF (athletes 65±6%, HFpEF 59±11, HFrEF 29±9, controls 66±4, p<.001). LV mass index (athletes 65±6%, HFpEF 59±11, HFrEF 29±9, controls 66±4, p<.001) and cardiomyocyte mass index (athletes 64±15g/m 2 , HFpEF 66±24, HFrEF 82±36, controls 42±8, p<.001) were greater in athletes and in HF patients (Fig 1A). Athletes and HFpEF patients had concentric LV remodeling, while HFrEF patients showed eccentric remodeling (Fig 1B). Intracellular lifetime of water was longer in athletes and shorter in HFrEF (athletes .17±.07s, HFpEF .15±.05, HFrEF .13±.05, controls .14±.05, p<.001) (Fig 2A). ECV was similarly increased in both HF groups (athletes .28±.04%, HFpEF .31±.05, HFrEF .31±.05, controls .28±.04, p<.001) (Fig 2B). Native T1 (athletes 1175±55ms, HFpEF 1261±61, HFrEF 1274±61, controls 1229±75, p=.01) correlated with CPET maximal oxygen consumption (VO 2 max) in HF patients (r=-.023, p=.048) (athletes 52±10, HFpEF 18±6, HFrEF 17±4, controls 29±9, p<.001). Conclusion: Physiological hypertrophy was characterized by increased cardiomyocyte diameter, normal ECV, and shorter native T1 due to its greater cardiomyocyte volume. Contrastingly, pathological hypertrophy’s longer native T1 was a result of its higher ECV and correlated with VO 2 max in HF. Cardiomyocyte diameter was smaller in HFrEF than in HFpEF.
Thrombosis occurrence in coronavirus disease 2019 (COVID-19) has been mostly compared to historical cohorts of patients with other respiratory infections. We retrospectively evaluated the thrombotic events that occurred in a contemporary cohort of patients hospitalized between March and July 2020 for acute respiratory distress syndrome (ARDS) according to the Berlin Definition and compared those with positive and negative real-time polymerase chain reaction results for wild-type severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) using descriptive analysis. The association between COVID-19 and thrombotic risk was evaluated using logistic regression. 264 COVID-19-positive (56.8% male, 59.0 years [IQR 48.6-69.7], Padua score on admission 3.0 [2.0-3.0]) and 88 COVID-19-negative patients (58.0% male, 63.7 years [51.2-73.5], Padua score 3.0 [2.0-5.0]) were included. 10.2% of non-COVID-19 and 8.7% of COVID-19 patients presented ≥ 1 clinically relevant thrombotic event confirmed by imaging exam. After adjustment for sex, Padua score, intensive care unit stay, thromboprophylaxis, and hospitalization length, the odds ratio for thrombosis in COVID-19 was 0.69 (95% CI, 0.30-1.64). We, therefore, conclude that infection-induced ARDS carries an inherent thrombotic risk, which was comparable between patients with COVID-19 and other respiratory infections in our contemporary cohort.
Previous evidence suggests that the thromboembolic risk is greater among patients with COVID-19 than among those affected by other types of acute respiratory distress syndrome (ARDS). However, such comparison has been primarily based on historical cohorts. In order to reduce the possible influence of such selection bias, the main goal of this study was to evaluate thromboembolic events in patients with COVID-19 and other ARDS hospitalized in the same time period. For this reason, we have selected patients admitted from March to June, 2020 at the UNICAMP Clinical Hospital who met the ARDS clinical criteria established by the Brazilian Ministry of Health and the Berlin Definition by presenting two or more flu-like symptoms and at least one ARDS-specific manifestation (dyspnea, persistent chest pressure, oxygen saturation lower than 95% at hospital admission, or lip/face cyanosis). Symptom onset or worsening occurred 30 days before hospital admission at the latest, and COVID-19 diagnosis was confirmed or excluded by at least 2 real time polymerase chain reactions or enzyme-linked immunosorbent assays. Descriptive analysis, chi-square and t-tests, as well as binary logistic regression, were used to compare COVID-19 and non-COVID-19 patients. Of the 253 patients hospitalized due to ARDS during this period, 101 COVID-19 and 102 non-COVID-19 patients were included in this study. The remaining patients were excluded due to incomplete medical records (n=16) or absence of COVID-19 testing results (n=34). Table 1 demonstrates the included patients' demographic and clinical baseline features. Both COVID-19 and non-COVID-19 groups showed similar baseline risk of hospital-associated thrombosis (assessed by reduced mobility within the past 3 days or more, previous thromboembolism event, recognized "thrombophilia", and infarction, stroke, trauma or surgery within the past 4 weeks) and oxygen saturation at admission (COVID-19: 92% IQR 90% to 96%; non-COVID-19: 94% IQR 91% to 97%, P=0.44). However, the need for invasive oxygenation support (37.6% vs. 14.7%, P=0.0002) and vasoactive drugs (44.6% vs. 21.6%, P=0.0006) was greater in COVID-19 than in non-COVID-19 patients. Accordingly, those infected by SARS-CoV-2 were more frequently admitted in ICU (55.4% vs. 40.2%, P=0.04) and for a longer period of time (13 days IQR 6 to 22 vs. 3 days IQR 2 to 8.3, P=0.02) than those affected by other types of ARDS. In comparison to the non-COVID-19 group, the COVID-19 group's median total hospital stay was more lasting (15 days IQR 6 to 30.5 vs. 7 days IQR 3 to 16.3, P<0.0001), and its death rate, higher (27.7% vs. 14.7%, P=0.03), as shown in Table 2. With respect to coagulation markers (Table 3), activated partial thromboplastin time and C-reactive protein levels were greater in COVID-19 than in non-COVID-19 patients, while the latter presented higher median platelet counts. There was no statistically significant difference between both study groups in regards to prothrombin time, fibrinogen, and D-dimer levels (COVID-19: 1488 ng/mL IQR 726.5 to 3476; non-COVID-19: 1773 ng/mL IQR 807.5 to 4153.8, P=0.57). Although thromboprophylaxis was more commonly administered to COVID-19 (76.2%) than non-COVID-19 patients (41.2%, P<0.0001), the incidence of thromboembolic events confirmed by imaging examination was similar between groups even after adjusting for multiple factors (age, sex, thromboprophylaxis use, arterial hypertension, and cancer): there were 7 confirmed events in 7 non-COVID-19 patients, and 13 confirmed events in 9 COVID-19 patients (adjusted OR 0.74, 95% CI 0.24-2.25, P=0.59). Table 4 demonstrates the characteristics of such thrombotic manifestations. By analyzing patients hospitalized in the same time period, we have found that although high, the thromboembolic risk in COVID-19 is similar to that in other types of ARDS, indicating that a hypercoagulable state is inherent to ARDS in general. Additionally, the obtained results show that the use of thromboprophylaxis was significantly higher among COVID-19 patients, and that there was no statistically relevant difference between COVID-19 and non-COVID-19 patients' D-dimer levels, a commonly used coagulation marker. Such findings provide a better understanding of the thromboembolic risk associated with SARS-CoV-2 infection, and suggest that previous evidence of higher thrombosis rates in COVID-19 suffered bias from the use of historical cohorts. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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