SARS-CoV-2 uses ACE2, an inhibitor of the Renin-Angiotensin-Aldosterone System (RAAS), for cellular entry. Studies indicate that RAAS imbalance worsens the prognosis in COVID-19. We present a consecutive retrospective COVID-19 cohort with findings of frequent pulmonary thromboembolism (17%), high pulmonary artery pressure (60%) and lung MRI perfusion disturbances. We demonstrate, in swine, that infusing angiotensin II or blocking ACE2 induces increased pulmonary artery pressure, reduces blood oxygenation, increases coagulation, disturbs lung perfusion, induces diffuse alveolar damage, and acute tubular necrosis compared to control animals. We further demonstrate that this imbalanced state can be ameliorated by infusion of an angiotensin receptor blocker and low-molecular-weight heparin. In this work, we show that a pathophysiological state in swine induced by RAAS imbalance shares several features with the clinical COVID-19 presentation. Therefore, we propose that severe COVID-19 could partially be driven by a RAAS imbalance.

BackgroundMyocardial native T1 measurements are likely influenced by intramyocardial blood. Since blood T1 is both variable and longer compared to myocardial T1, this will degrade the precision of myocardial T1 measurements. Precision could be improved by correction, but the amount of correction and the optimal blood T1 variables to correct with are unknown. We hypothesized that an appropriate correction would reduce the standard deviation (SD) of native myocardial T1.MethodsConsecutive patients (n = 400) referred for CMR with known or suspected heart disease were split into a derivation cohort for model construction (n = 200, age 51 ± 18 years, 50% male) and a validation cohort for assessing model performance (n = 200, age 48 ± 17 years, 50% male). Exclusion criteria included focal septal abnormalities. A Modified Look-Locker inversion recovery sequence (MOLLI, 1.5 T Siemens Aera) was used to acquire T1 and T1* maps. T1 and T1* maps were used to measure native myocardial T1, and blood T1 and T1*. A multivariate linear regression correction model was implemented using blood measurement of R1 (1/T1), R1* (1/T1*) or hematocrit. The correction model from the derivation cohort was applied to the validation cohort, and assessed for reduction in variability with the F-test.ResultsBlood [LV + RV] mean R1, mean R1* and hematocrit correlated with myocardial T1 (Pearson’s r, range 0.37 to 0.45, p < 0.05 for all) in both the derivation and validation cohorts respectively, suggesting that myocardial T1 measurements are influenced by intramyocardial blood. Mean myocardial native T1 did not differ between the derivation and validation cohorts (1030 ± 42.6 ms and 1023 ± 45.2 ms respectively, p = 0.07). In the derivation cohort, correction using blood mean R1 and mean R1* yielded a decrease in myocardial T1 SD (45.2 ms to 36.6 ms, p = 0.03).When the model from the derivation cohort was applied to the validation cohort, the SD reduction was maintained (39.3 ms, p = 0.049). This 13% reduction in measurement variability leads to a 23% reduction in sample size to detect a 50 ms difference in native myocardial T1.ConclusionsCorrecting native myocardial T1 for R1 and R1* of blood improves the precision of myocardial T1 measurement by ~13%, and could consequently improve disease detection and reduce sample size needs for clinical research.

Sahlén A, Abdula G, Norman M, Manouras A, Brodin LÅ, Lund LH, Shahgaldi K, Winter R. Arterial vasodilatory and ventricular diastolic reserves determine the stroke volume response to exercise in elderly female hypertensive patients.