Impact of the immune profiles of hypertensive patients with and without obesity on COVID-19 severity.

BACKGROUND: Comorbidities such as obesity, hypertension, and diabetes are associated with COVID-19 development and severity, probably due to immune dysregulation; however, the mechanisms underlying these associations are not clear. The immune signatures of hypertensive patients with obesity with COVID-19 may provide new insight into the mechanisms of immune dysregulation and progression to severe disease in these patients. METHODS: Hypertensive patients were selected prospectively from a multicenter registry of adults hospitalized with COVID-19 and stratified according to obesity (BMI ≥ 30 kg/m²). Clinical data including baseline characteristics, complications, treatment, and 46 immune markers were compared between groups. Logistic regression was performed to identify variables associated with the risk of COVID-19 progression in each group. RESULTS: The sample comprised 213 patients (89 with and 124 without obesity). The clinical profiles of patients with and without obesity differed, suggesting potential interactions with COVID-19 severity. Relative to patients without obesity, patients with obesity were younger and fewer had cardiac disease and myocardial injury. Patients with obesity had higher EGF, GCSF, GMCSF, interleukin (IL)-1ra, IL-5, IL-7, IL-8, IL-15, IL-1ß, MCP 1, and VEGF levels, total lymphocyte counts, and CD8+ CD38+ mean fluorescence intensity (MFI), and lower NK-NKG2A MFI and percentage of CD8+ CD38+ T cells. Significant correlations between cytokine and immune cell expression were observed in both groups. Five variables best predicted progression to severe COVID-19 in patients with obesity: diabetes, the EGF, IL-10, and IL-13 levels, and the percentage of CD8+ HLA-DR+ CD38+ cells. Three variables were predictive for patients without obesity: myocardial injury and the percentages of B lymphocytes and HLA-DR+ CD38+ cells. CONCLUSION: Our findings suggest that clinical and immune variables and obesity interact synergistically to increase the COVID-19 progression risk. The immune signatures of hypertensive patients with and without obesity severe COVID-19 highlight differences in immune dysregulation mechanisms, with potential therapeutic applications.

New Insights on the Mechanisms of Myocardial Injury in Hypertensive Patients With COVID-19.

PURPOSE: Myocardial injury is common in hypertensive patients with 2019 coronavirus disease (COVID-19). Immune dysregulation could be associated to cardiac injury in these patients, but the underlying mechanism has not been fully elucidated. METHODS: All patients were selected prospectively from a multicenter registry of adults hospitalized with confirmed COVID-19. Cases had hypertension and myocardial injury, defined by troponin levels above the 99th percentile upper reference limit, and controls were hypertensive patients with no myocardial injury. Biomarkers and immune cell subsets were quantified and compared between the two groups. A multiple logistic regression model was used to analyze the associations of clinical and immune variables with myocardial injury. RESULTS: The sample comprised 193 patients divided into two groups: 47 cases and 146 controls. Relative to controls, cases had lower total lymphocyte count, percentage of T lymphocytes, CD8+CD38+ mean fluorescence intensity (MFI), and percentage of CD8+ human leukocyte antigen DR isotope (HLA-DR)+ CD38-cells and higher percentage of natural killer lymphocytes, natural killer group 2A (NKG2A)+ MFI, percentage of CD8+CD38+cells, CD8+HLA-DR+MFI, CD8+NKG2A+MFI, and percentage of CD8+HLA-DR-CD38+cells. On multivariate regression, the CD8+HLA-DR+MFI, CD8+CD38+MFI, and total lymphocyte count were associated significantly with myocardial injury. CONCLUSION: Our findings suggest that lymphopenia, CD8+CD38+MFI, and CD8+HLA-DR+MFI are immune biomarkers of myocardial injury in hypertensive patients with COVID-19. The immune signature described here may aid in understanding the mechanisms underlying myocardial injury in these patients. The study data might open a new window for improvement in the treatment of hypertensive patients with COVID-19 and myocardial injury.

Troponin in COVID-19: To Measure or Not to Measure? Insights from a Prospective Cohort Study.

Myocardial injury (MI), defined by troponin elevation, has been associated with increased mortality and adverse outcomes in patients with coronavirus disease 2019 (COVID-19), but the role of this biomarker as a risk predictor remains unclear. Data from adult patients hospitalized with COVID-19 were recorded prospectively. A multiple logistic regression model was used to quantify associations of all variables with in-hospital mortality, including the calculation of odds ratios (ORs) and confidence intervals (CI). Troponin measurement was performed in 1476 of 4628 included patients, and MI was detected in 353 patients, with a prevalence of 23.9%; [95% CI, 21.8-26.1%]. The total in-hospital mortality rate was 10.9% [95% CI, 9.8-12.0%]. The mortality was much higher among patients with MI than among those without MI, with a prevalence of 22.7% [95% CI, 18.5-27.3%] vs. 5.5% [95% CI, 4.3-7.0%] and increased with each troponin level. After adjustment for age and comorbidities, the model revealed that the mortality risk was greater for patients with MI [OR = 2.99; 95% CI, 2.06-4.36%], and for those who did not undergo troponin measurement [OR = 2.2; 95% CI, 1.62-2.97%], compared to those without MI. Our data support the role of troponin as an important risk predictor for these patients, capable of discriminating between those with a low or increased mortality rate. In addition, our findings suggest that this biomarker has a remarkable negative predictive value in COVID-19.

NKG2A Expression among CD8 Cells Is Associated with COVID-19 Progression in Hypertensive Patients: Insights from the BRACE CORONA Randomized Trial.

Cardiovascular comorbidities and immune-response dysregulation are associated with COVID-19 severity. We aimed to explore the key immune cell profile and understand its association with disease progression in 156 patients with hypertension that were hospitalized due to COVID-19. The primary outcome was progression to severe disease. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and immune cell subsets associated with the primary outcome. Obesity; diabetes; oxygen saturation; lung involvement on computed tomography (CT) examination; the C-reactive protein concentration; total lymphocyte count; proportions of CD4+ and CD8+ T cells; CD4/CD8 ratio; CD8+ HLA-DR MFI; and CD8+ NKG2A MFI on admission were all associated with progression to severe COVID-19. This study demonstrated that increased CD8+ NKG2A MFI at hospital admission, in combination with some clinical variables, is associated with a high risk of COVID-19 progression in hypertensive patients. These findings reinforce the hypothesis of the functional exhaustion of T cells with the increased expression of NKG2A in patients with severe COVID-19, elucidating how severe acute respiratory syndrome coronavirus 2 infection may break down the innate antiviral immune response at an early stage of the disease, with future potential therapeutic implications.

IL-10 and IL-12 (P70) Levels Predict the Risk of Covid-19 Progression in Hypertensive Patients: Insights From the BRACE-CORONA Trial.

Background: Cardiovascular comorbidities such as hypertension and inflammatory response dysregulation are associated with worse COVID-19 prognoses. Different cytokines have been proposed to play vital pathophysiological roles in COVID-19 progression, but appropriate prognostic biomarkers remain lacking. We hypothesized that the combination of immunological and clinical variables at admission could predict the clinical progression of COVID-19 in hypertensive patients. Methods: The levels of biomarkers, including C-reactive protein, lymphocytes, monocytes, and a panel of 29 cytokines, were measured in blood samples from 167 hypertensive patients included in the BRACE-CORONA trial. The primary outcome was the highest score during hospitalization on the modified WHO Ordinal Scale for Clinical Improvement. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and biomarkers associated significantly with the primary outcome. Results: During hospitalization, 13 (7.8%) patients showed progression to more severe forms of COVID-19, including three deaths. Obesity, diabetes, oxygen saturation, lung involvement on computed tomography examination, the C-reactive protein level, levels of 15 cytokines, and lymphopenia on admission were associated with progression to severe COVID-19. Elevated levels of interleukin-10 and interleukin-12 (p70) combined with two or three of the abovementioned clinical comorbidities were associated strongly with progression to severe COVID-19. The risk of progression to severe disease reached 97.5% in the presence of the five variables included in our model. Conclusions: This study demonstrated that interleukin-10 and interleukin-12 (p70) levels, in combination with clinical variables, at hospital admission are key biomarkers associated with an increased risk of disease progression in hypertensive patients with COVID-19.

Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial.

Importance: It is unknown whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have a positive, neutral, or negative effect on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Objective: To determine whether discontinuation compared with continuation of ACEIs or ARBs changed the number of days alive and out of the hospital through 30 days. Design, Setting, and Participants: A randomized clinical trial of 659 patients hospitalized in Brazil with mild to moderate COVID-19 who were taking ACEIs or ARBs prior to hospitalization (enrolled: April 9-June 26, 2020; final follow-up: July 26, 2020). Interventions: Discontinuation (n = 334) or continuation (n = 325) of ACEIs or ARBs. Main Outcomes and Measures: The primary outcome was the number of days alive and out of the hospital through 30 days. Secondary outcomes included death, cardiovascular death, and COVID-19 progression. Results: Among 659 patients, the median age was 55.1 years (interquartile range [IQR], 46.1-65.0 years), 14.7% were aged 70 years or older, 40.4% were women, and 100% completed the trial. The median time from symptom onset to hospital admission was 6 days (IQR, 4-9 days) and 27.2% of patients had an oxygen saturation of less than 94% of room air at baseline. In terms of clinical severity, 57.1% of patients were considered mild at hospital admission and 42.9% were considered moderate. There was no significant difference in the number of days alive and out of the hospital in patients in the discontinuation group (mean, 21.9 days [SD, 8 days]) vs patients in the continuation group (mean, 22.9 days [SD, 7.1 days]) and the mean ratio was 0.95 (95% CI, 0.90-1.01). There also was no statistically significant difference in death (2.7% for the discontinuation group vs 2.8% for the continuation group; odds ratio [OR], 0.97 [95% CI, 0.38-2.52]), cardiovascular death (0.6% vs 0.3%, respectively; OR, 1.95 [95% CI, 0.19-42.12]), or COVID-19 progression (38.3% vs 32.3%; OR, 1.30 [95% CI, 0.95-1.80]). The most common adverse events were respiratory failure requiring invasive mechanical ventilation (9.6% in the discontinuation group vs 7.7% in the continuation group), shock requiring vasopressors (8.4% vs 7.1%, respectively), acute myocardial infarction (7.5% vs 4.6%), new or worsening heart failure (4.2% vs 4.9%), and acute kidney failure requiring hemodialysis (3.3% vs 2.8%). Conclusions and Relevance: Among patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications. These findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with mild to moderate COVID-19 if there is an indication for treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04364893.

Heart failure and endothelial nitric oxide synthase G894T gene polymorphism frequency variations within ancestries.

The G894T polymorphism in endothelial nitric oxide synthase enzyme gene plays an important role in heart failure (HF) and its frequency varies among populations. We investigated this association in highly admixed samples in terms of ancestry. The cohort included 210 HF patients and 106 healthy individuals. Self-reported race and NYHA class were analyzed for HF patients. G894T polymorphism was analyzed by polymerase chain reaction (PCR) and by restriction fragment length polymorphism technique. Ancestry was estimated using a PCR reaction containing 46 autosomal ancestry informative markers and an analysis by capillary electrophoresis. The GG homozygous genotype had a higher frequency in HF patients (63.8%) than in healthy individuals (48.1%), showing an increased chance (odds ratio 1.90, 95% confidence interval 1.18-3.05). The ancestry profiles in patients and controls were similar, with a major European contribution (57.1% and 63.2%), followed by African (30.2% and 24.0%) and Native American (12.7% and 12.8%), without a significant difference between both samples (p = 0.28). The GG genotype is associated to HF prognosis, and this association remains present in highly admixed sample groups.

Atherothrombotic disease, traditional risk factors, and 4-year mortality in a Latin American population: the REACH Registry.

BACKGROUND: Atherothrombosis is becoming the leading cause of chronic morbidity in developing countries. This epidemiological transition will represent an unbearable socioeconomic burden in the near future. We investigated factors associated with 4-year all-cause mortality in a Latin American population at high risk. HYPOTHESIS: Largely modifiable risk factors as well as polyvascular disease are the main predictors of 4-year all-cause and cardiovascular mortality in this Latin American cohort. METHODS: We analyzed 1816 Latin American stable outpatients (62.3% men, mean age 67 years) with symptomatic atherothrombosis (87.1%) or with multiple risk factors only (12.9%), in the Reduction of Atherothrombosis for Continued Health registry. RESULTS: Of patients with symptomatic atherothrombosis, 57.3% had coronary artery disease, 32% cerebrovascular disease, and 11.7% peripheral artery disease at baseline (9.1% polyvascular). The main risk factors were hypertension (76%), hypercholesterolemia (60%), and smoking (52.3%) in patients with established atherothrombosis; and hypertension (89.7%), diabetes (80.8%), and hypercholesterolemia (73.9%) in those with risk factors only. Four-year all-cause mortality steeply increased with none (6.8%), 1 (9.2%), 2 (15.5%), and 3 (29.2%) symptomatic arterial disease locations. In patients with only 1 location, cardiovascular mortality was significantly higher with peripheral artery disease (11.3%) than with cerebrovascular disease (6%) or coronary artery disease (5.1%). Significant baseline predictors of 4-year all-cause mortality were congestive heart failure (hazard ratio [HR]: 3.81), body mass index <20 (HR: 2.32), hypertension (HR: 1.84), polyvascular disease (HR: 1.69), and age ≥ 65 years (HR: 1.47), whereas statin use (HR: 0.49) and body mass index ≥ 30 (HR: 0.58) were associated with a reduced risk. CONCLUSIONS: Hypertension was the main modifiable risk factor for atherothrombosis and all-cause mortality in this Latin American cohort. Nearly one-third of the population with 3 symptomatic vascular-disease locations died at 4-year follow-up.

Prognostic value of CT angiography in patients with inconclusive functional stress tests.

OBJECTIVES: We attempted to determine the prognostic value of coronary computed tomographic angiography (CTA) in patients with inconclusive functional stress tests. BACKGROUND: Patients with suspected coronary artery disease (CAD) and inconclusive noninvasive cardiac stress tests represent a frequent management challenge. METHODS: We examined 529 consecutive patients with suspected CAD and prior inconclusive functional stress tests. All patients underwent a coronary CTA scan using a 64-slice multidetector row scanner. CAD severity by coronary CTA was categorized as: 1) no evidence of CAD; 2) nonobstructive coronary plaques (< 30%); 3) mild stenosis (30% to 49%); 4) moderate stenosis (50% to 69%); and 5) severe stenosis (≥ 70%). Patients were also categorized according to a modified Duke prognostic CAD index. Survival analyses were performed using Cox proportional hazards models adjusted for baseline risk factors and coronary artery calcium score. The primary outcome of the study was the combined endpoint of all-cause mortality and nonfatal myocardial infarction. RESULTS: Among patients with inconclusive stress tests, the large majority (69%) did not demonstrate significant CAD by coronary CTA. During a mean follow-up of 30.1 ± 11.1 months, there were 20 (3.8%) deaths and 17 (3.2%) nonfatal myocardial infarctions. Multivariable Cox regression analysis revealed that the presence of increasing degrees of obstructive CAD by CTA was an independent predictor of adverse events (hazard ratio [HR]: 1.66 [95% confidence interval (CI): 1.23 to 2.23], p = 0.001). Indeed, the presence of ≥ 50% coronary stenosis was associated with an increased risk of events (HR: 3.15 [95% CI: 1.26 to 7.89], p = 0.01). Likewise, the Duke prognostic CAD index was also found to be an independent predictor of events (HR: 1.54 [95% CI: 1.20 to 1.97], p = 0.001). CONCLUSIONS: Among patients with inconclusive functional stress tests, the noninvasive assessment of CAD severity by coronary CTA has been shown to provide incremental prognostic information beyond the evaluation of traditional risk factors and coronary artery calcium score.

Efficacy, safety and tolerability of sildenafil in Brazilian hypertensive patients on multiple antihypertensive drugs.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of sildenafil among Brazilian patients with hypertension treated with combinations of anti-hypertensive drugs. MATERIALS AND METHODS: One hundred twenty hypertensive men aged 30 to 81 years old under treatment with 2 or more anti-hypertensive drugs and with erectile dysfunction (ED) lasting for at least 6 months were enrolled at 7 research centers in Brazil. Patients were randomized to receive treatment with either sildenafil or placebo taken 1 hour before sexual intercourse (initial dose of 50 mg, adjusted to 25 mg or 100 mg according to efficacy and toxicity). During the following 8 weeks, patients were evaluated regarding vital signs, adverse events, therapeutic efficacy, satisfaction with treatment and use of concurrent medications. RESULTS: The primary evaluation of efficacy, which was based on responses to questions 3 and 4 of the International Index of Erectile Function, showed significant differences regarding treatment with sildenafil (p = 0.0002 and p < 0.0001, respectively). In the assessment of global efficacy, 87% of the patients treated with sildenafil reported improved erections, as compared with 37% of patients given placebos (p < 0.0001). The other secondary evaluations supported the results favoring sildenafil. The most frequent adverse events among patients treated with sildenafil were headaches (11.4%), vasodilation (11.4%) and dyspepsia (6.5%). There were no significant changes in blood pressure measurements in both groups. CONCLUSION: Sildenafil is efficacious and safe for the treatment of hypertensive patients with ED who receive concurrent combinations of anti-hypertensive drugs.

Efficacy, safety and tolerability of sildenafil in Brazilian hypertensive patients on multiple antihypertensive drugs

OBJECTIVE: To evaluate the efficacy, safety and tolerability of sildenafil among Brazilian patients with hypertension treated with combinations of anti-hypertensive drugs. MATERIALS AND METHODS: One hundred twenty hypertensive men aged 30 to 81 years old under treatment with 2 or more anti-hypertensive drugs and with erectile dysfunction (ED) lasting for at least 6 months were enrolled at 7 research centers in Brazil. Patients were randomized to receive treatment with either sildenafil or placebo taken 1 hour before sexual intercourse (initial dose of 50 mg, adjusted to 25 mg or 100 mg according to efficacy and toxicity). During the following 8 weeks, patients were evaluated regarding vital signs, adverse events, therapeutic efficacy, satisfaction with treatment and use of concurrent medications. RESULTS: The primary evaluation of efficacy, which was based on responses to questions 3 and 4 of the International Index of Erectile Function, showed significant differences regarding treatment with sildenafil (p = 0.0002 and p < 0.0001, respectively). In the assessment of global efficacy, 87 percent of the patients treated with sildenafil reported improved erections, as compared with 37 percent of patients given placebos (p < 0.0001). The other secondary evaluations supported the results favoring sildenafil. The most frequent adverse events among patients treated with sildenafil were headaches (11.4 percent), vasodilation (11.4 percent) and dyspepsia (6.5 percent). There were no significant changes in blood pressure measurements in both groups. CONCLUSION: Sildenafil is efficacious and safe for the treatment of hypertensive patients with ED who receive concurrent combinations of anti-hypertensive drugs.