Antecedent use of renin-angiotensin system inhibitors is associated with reduced mortality in elderly hypertensive Covid-19 patients.

OBJECTIVES: The effect of renin-angiotensin system inhibitors (RASIs) on mortality in patients with coronavirus disease (Covid-19) is debated. From a cohort of 1352 consecutive patients admitted with Covid-19 to Papa Giovanni XXIII Hospital in Bergamo, Italy, between February and April 2020, we selected and studied hypertensive patients to assess whether antecedent (prior to hospitalization) use of RASIs might affect mortality from Covid-19 according to age. METHODS AND RESULTS: Arterial hypertension was present in 688 patients. Overall mortality (in-hospital or shortly after discharge) was 35% (N = 240). After adjusting for 26 medical history variables via propensity score matching, antecedent use of RASIs (N = 459, 67%) was associated with a lower mortality in older hypertensive patients (age above the median of 68 years in the whole series), whereas no evidence of a significant effect was found in the younger group of the same population (P interaction = 0.001). In an analysis of the subgroup of 432 hypertensive patients older than 68 years, we considered two RASI drug subclasses, angiotensin-converting enzyme inhibitors (ACEIs, N = 156) and angiotensin receptor blockers (ARBs, N = 140), and assessed their respective effects by taking no-antecedent-use of RASIs as reference. This analysis showed that both antecedent use of ACEIs and antecedent use of ARBs were associated with a lower Covid-19 mortality (odds ratioACEI = 0.57, 95% confidence interval 0.36--0.91, P = 0.018) (odds ratioARB = 0.49, 95% confidence interval 0.29--0.82, P = 0.006). CONCLUSION: In the population of over-68 hypertensive Covid-19 patients, antecedent use of ACEIs or ARBs was associated with a lower all-cause mortality, whether in-hospital or shortly after discharge, compared with no-antecedent-use of RASIs.

Effects of Simulated COVID-19 Cytokine Storm on Stent Thrombogenicity.

BACKGROUND: Cytokine storm-related hypercoagulation may be important in the pathogenesis of stent thrombosis in patients with SARS-CoV-2. Whether stent polymers behave differently under such conditions has never been explored. METHODS: Fluorinated polymer-nanocoated and uncoated COBRA stents (CeloNova), BioLinx-polymer-coated Resolute Onyx stents (Medtronic), and Synergy stents (Boston Scientific), which are abluminally coated with a bioabsorbable polymer, were exposed to human blood from healthy donors which was supplemented with 400 pg/mL IL-6 and 100 pg/mL TNF-α, similar to what is seen in cytokine storm caused by SARS-CoV-2. Platelet adhesion and neutrophil activation, assessed by immunofluorescence, were compared under cytokine storm and control conditions (untreated blood) (n = 4 experimental runs). RESULTS: Platelet adhesion values, defined as %platelet-covered area x staining intensity, were significantly lower in coated and uncoated COBRA and in Resolute Onyx than in Synergy under control conditions (1.28 × 107 ± 0.43 × 107 vs. 2.92 × 107 ± 0.49 × 107 vs. 3.57 × 107 ± 0.73 × 107 vs. 9.94 × 107 ± 0.99 × 107; p ≤0.0001). In cytokine storm, platelet adhesion values remained low in coated COBRA-PzF (1.78 × 107 ± 0.38 × 107) compared to all other devices (uncoated COBRA: 5.92 × 107 ± 0.96 × 107; Resolute Onyx: 7.27 × 107 ± 1.82 × 107; Synergy: 11.28 × 107 ± 1.08 × 107; p ≤ 0.0001). Although cytokine storm conditions significantly increased neutrophil activation in all stents, it was significantly less in coated and uncoated COBRA, and in Resolute Onyx than in Synergy. CONCLUSIONS: Blood-biomaterials interactions may determine the thrombogenic potential of stents. Under simulated cytokine storm conditions, fluoropolymer-coated stents showed the most favorable anti-thrombogenic and anti-inflammatory properties.

Covid-19 and gender: lower rate but same mortality of severe disease in women-an observational study.

BACKGROUND: Gender-related factors might affect vulnerability to Covid-19. The aim of this study was to describe the role of gender on clinical features and 28-day mortality in Covid-19 patients. METHODS: Observational study of Covid-19 patients hospitalized in Bergamo, Italy, during the first three weeks of the outbreak. Medical records, clinical, radiological and laboratory findings upon admission and treatment have been collected. Primary outcome was 28-day mortality since hospitalization. RESULTS: 431 consecutive adult patients were admitted. Female patients were 119 (27.6%) with a mean age of 67.0 ± 14.5 years (vs 67.8 ± 12.5 for males, p = 0.54). Previous history of myocardial infarction, vasculopathy and former smoking habits were more common for males. At the time of admission PaO2/FiO2 was similar between men and women (228 [IQR, 134-273] vs 238 mmHg [150-281], p = 0.28). Continuous Positive Airway Pressure (CPAP) assistance was needed in the first 24 h more frequently in male patients (25.7% vs 13.0%; p = 0.006). Overall 28-day mortality was 26.1% in women and 38.1% in men (p = 0.018). Gender did not result an independent predictor of death once the parameters related to disease severity at presentation were included in the multivariable analysis (p = 0.898). Accordingly, the Kaplan-Meier survival analysis in female and male patients requiring CPAP or non-invasive ventilation in the first 24 h did not find a significant difference (p = 0.687). CONCLUSION: Hospitalized women are less likely to die from Covid-19; however, once severe disease occurs, the risk of dying is similar to men. Further studies are needed to better investigate the role of gender in clinical course and outcome of Covid-19.

Effect of Respiratory Impairment on the Outcomes of Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction and Coronavirus Disease-2019 (COVID-19).

BACKGROUND: Coronavirus Disease-2019 (COVID-19) may impair outcomes of patients with ST-segment elevation myocardial infarction (STEMI). The extent of this phenomenon and its mechanisms are unclear.Methods and Results:This study prospectively included 50 consecutive STEMI patients admitted to our center for primary percutaneous coronary intervention (PCI) at the peak of the Italian COVID-19 outbreak. At admission, a COVID-19 test was positive in 24 patients (48%), negative in 26 (52%). The primary endpoint was in-hospital all-cause mortality. Upon admission, COVID-19 subjects had lower PO2/FiO2 (169 [100-425] vs. 390 [302-477], P<0.01), more need for oxygen support (62.5% vs. 26.9%, P=0.02) and a higher rate of myocardial dysfunction (ejection fraction <30% in 45.8% vs. 19.2%, P=0.04). All patients underwent emergency angiography. In 12.5% of COVID-19 patients, no culprit lesions were detected, thus PCI was performed in 87.5% and 100% of COVID-19 positive and negative patients, respectively (P=0.10). Despite a higher rate of obstinate thrombosis in the COVID-19 group (47.6% vs. 11.5%, P<0.01), the PCI result was similar (TIMI 2-3 in 90.5% vs. 100%, P=0.19). In-hospital mortality was 41.7% and 3.8% in COVID-19 positive and negative patients, respectively (P<0.01). Respiratory failure was the leading cause of death (80%) in the COVID-19 group, frequently associated with severe myocardial dysfunction. CONCLUSIONS: In-hospital mortality of COVID-19 patients with STEMI remains high despite successful PCI, mainly due to coexisting severe respiratory failure. This may be a critical factor in patient management and treatment selection.

At the peak of COVID-19 age and disease severity but not comorbidities are predictors of mortality: COVID-19 burden in Bergamo, Italy.

BACKGROUND: Findings from February 2020, indicate that the clinical spectrum of COVID-19 can be heterogeneous, probably due to the infectious dose and viral load of SARS-CoV-2 within the first weeks of the outbreak. The aim of this study was to investigate predictors of overall 28-day mortality at the peak of the Italian outbreak. METHODS: Retrospective observational study of all COVID-19 patients admitted to the main hospital of Bergamo, from February 23 to March 14, 2020. RESULTS: Five hundred and eight patients were hospitalized, predominantly male (72.4%), mean age of 66±15 years; 49.2% were older than 70 years. Most of patients presented with severe respiratory failure (median value [IQR] of PaO2/FiO2: 233 [149-281]). Mortality rate at 28 days resulted of 33.7% (N.=171). Thirty-nine percent of patients were treated with continuous positive airway pressure (CPAP), 9.5% with noninvasive ventilation (NIV) and 13.6% with endotracheal intubation. 9.5% were admitted to Semi-Intensive Respiratory Care Unit, and 18.9% to Intensive Care Unit. Risk factors independently associated with 28-day mortality were advanced age (≥78 years: odds ratio [OR], 95% confidence interval [CI]: 38.91 [10.67-141.93], P<0.001; 70-77 years: 17.30 [5.40-55.38], P<0.001; 60-69 years: 3.20 [1.00-10.20], P=0.049), PaO2/FiO2<200 at presentation (3.50 [1.70-7.20], P=0.001), need for CPAP/NIV in the first 24 hours (8.38 [3.63-19.35], P<0.001), and blood urea value at admission (1.01 [1.00-1.02], P=0.015). CONCLUSIONS: At the peak of the outbreak, with a probable high infectious dose and viral load, older age, the severity of respiratory failure and renal impairment at presentation, but not comorbidities, are predictors of 28-day mortality in COVID-19.

Microthrombi as a Major Cause of Cardiac Injury in COVID-19: A Pathologic Study.

BACKGROUND: Cardiac injury is common in patients who are hospitalized with coronavirus disease 2019 (COVID-19) and portends poorer prognosis. However, the mechanism and the type of myocardial damage associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain uncertain. METHODS: We conducted a systematic pathological analysis of 40 hearts from hospitalized patients dying of COVID-19 in Bergamo, Italy, to determine the pathological mechanisms of cardiac injury. We divided the hearts according to presence or absence of acute myocyte necrosis and then determined the underlying mechanisms of cardiac injury. RESULTS: Of the 40 hearts examined, 14 (35%) had evidence of myocyte necrosis, predominantly of the left ventricle. Compared with subjects without necrosis, subjects with necrosis tended to be female, have chronic kidney disease, and have shorter symptom onset to admission. The incidence of severe coronary artery disease (ie, >75% cross-sectional narrowing) was not significantly different between those with and without necrosis. Three of 14 (21.4%) subjects with myocyte necrosis showed evidence of acute myocardial infarction, defined as ≥1 cm2 area of necrosis, whereas 11 of 14 (78.6%) showed evidence of focal (>20 necrotic myocytes with an area of ≥0.05 mm2 but <1 cm2) myocyte necrosis. Cardiac thrombi were present in 11 of 14 (78.6%) cases with necrosis, with 2 of 14 (14.2%) having epicardial coronary artery thrombi, whereas 9 of 14 (64.3%) had microthrombi in myocardial capillaries, arterioles, and small muscular arteries. We compared cardiac microthrombi from COVID-19-positive autopsy cases to intramyocardial thromboemboli from COVID-19 cases as well as to aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19-infected patients presenting with ST-segment-elevation myocardial infarction. Microthrombi had significantly greater fibrin and terminal complement C5b-9 immunostaining compared with intramyocardial thromboemboli from COVID-19-negative subjects and with aspirated thrombi. There were no significant differences between the constituents of thrombi aspirated from COVID-19-positive and -negative patients with ST-segment-elevation myocardial infarction. CONCLUSIONS: The most common pathological cause of myocyte necrosis was microthrombi. Microthrombi were different in composition from intramyocardial thromboemboli from COVID-19-negative subjects and from coronary thrombi retrieved from COVID-19-positive and -negative patients with ST-segment-elevation myocardial infarction. Tailored antithrombotic strategies may be useful to counteract the cardiac effects of COVID-19 infection.

Pathological Evidence for SARS-CoV-2 as a Cause of Myocarditis: JACC Review Topic of the Week.

To investigate whether severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-induced myocarditis constitutes an important mechanism of cardiac injury, a review was conducted of the published data and the authors' experience was added from autopsy examination of 16 patients dying of SARS-CoV-2 infection. Myocarditis is an uncommon pathologic diagnosis occurring in 4.5% of highly selected cases undergoing autopsy or endomyocardial biopsy. Although polymerase chain reaction-detectable virus could be found in the lungs of most coronavirus disease-2019 (COVID-19)-infected subjects in our own autopsy registry, in only 2 cases was the virus detected in the heart. It should be appreciated that myocardial inflammation alone by macrophages and T cells can be seen in noninfectious deaths and COVID-19 cases, but the extent of each is different, and in neither case do such findings represent clinically relevant myocarditis. Given its extremely low frequency and unclear therapeutic implications, the authors do not advocate use of endomyocardial biopsy to diagnose myocarditis in the setting of COVID-19.

Management of acute coronary syndromes during the COVID-19 outbreak in Lombardy: The "macro-hub" experience.

BACKGROUND: During the COVID-19 outbreak, healthcare Authorities of Lombardy modified the regional network concerning time-dependent emergencies. Specifically, 13 Macro-Hubs were identified to deliver timely optimal care to patients with acute coronary syndromes (ACS). Aim of this paper is to present the results of this experience. METHODS AND RESULTS: This is a multicenter, observational study. A total of 953 patients were included, presenting with STEMI in 57.7% of the cases. About 98% of patients received coronary angiography with a median since first medical contact to angiography of 79 (IQR 45-124) minutes for STEMI and 1262 (IQR 643-2481) minutes for NSTEMI.A total of 107 patients (11.2%) had SARS-CoV2 infection, mostly with STEMI (74.8%). The time interval from first medical contact to cath-lab was significant shorter in patients with COVID-19, both in the overall population and in STEMI patients (87 (IQR 41-310) versus 160 (IQR 67-1220) minutes, P = 0.001, and 61 (IQR 23-98) versus 80 (IQR 47-126) minutes, P = 0.01, respectively). In-hospital mortality and cardiogenic shock rates were higher among patients with COVID-19 compared to patients without (32% vs 6%, P < 0.0001, and 16.8% vs 6.7%, P < 0.0003, respectively). CONCLUSIONS: During the COVID-19 outbreak in Lombardy, the redefinition of ACS network according to enlarged Macro-Hubs allowed to continue with timely ACS management, while reserving a high number of intensive care beds for the pandemic. Patients with ACS and COVID-19 presented a worst outcome, particularly in case of STEMI.