Clinical assessment of endothelial function in convalescent COVID-19 patients: a meta-analysis with meta-regressions.

BACKGROUND: Endothelial dysfunction has been proposed to play a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its post-acute sequelae. Flow-mediated dilation (FMD) is recognized as an accurate clinical method to assess endothelial function. Thus, we performed a meta-analysis of the studies evaluating FMD in convalescent COVID-19 patients and controls with no history of COVID-19. METHODS: A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the random effects method, differences between cases and controls were expressed as mean difference (MD) with 95% confidence intervals (95% CI). The protocol was registered on PROSPERO with reference number CRD42021289684. RESULTS: Twelve studies were included in the final analysis. A total of 644 convalescent COVID-19 patients showed significantly lower FMD values as compared to 662 controls (MD: -2.31%; 95% CI: -3.19, -1.44; p < 0.0001). Similar results were obtained in the sensitivity analysis of the studies that involved participants in either group with no cardiovascular risk factors or history of coronary artery disease (MD: -1.73%; 95% CI: -3.04, -0.41; p = 0.010). Interestingly, when considering studies separately based on enrolment within or after 3 months of symptom onset, results were further confirmed in both short- (MD: -2.20%; 95% CI: -3.35, -1.05; p < 0.0001) and long-term follow-up (MD: -2.53%; 95% CI: -4.19, -0.86; p = 0.003). Meta-regression models showed that an increasing prevalence of post-acute sequelae of COVID-19 was linked to a higher difference in FMD between cases and controls (Z-score: -2.09; p = 0.037). CONCLUSIONS: Impaired endothelial function can be documented in convalescent COVID-19 patients, especially when residual clinical manifestations persist. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.Key messagesThe mechanisms underlying the post-acute sequelae of coronavirus disease 2019 (COVID-19) have not been fully elucidated.Impaired endothelial function can be documented in convalescent COVID-19 patients for up to 1 year after infection, especially when residual clinical manifestations persist.Targeting endothelial dysfunction may represent an attractive therapeutic option in the post-acute phase of COVID-19.

Improving assessment and management of pain in hemophilia: an Italian Delphi consensus statement.

Comprehensive evidence-based guidelines and well-validated assessment scales for pain in people with hemophilia (PwH) are needed. Here, we report 28 statements covering five topics on pain assessment and management in pediatric and adult PwH that were developed by 60 Italian hemophilia specialists during a Delphi consensus process. Overall, a clear consensus was achieved for 19 of the 28 statements. Consensus was reached on all statements on the topic of pain assessment and quality of life (QoL), including the need for regular pain assessment on a quantitative scale, the importance of distinguishing between different pain types, and the need to evaluate the impact of pain on patient QoL. The other four topics concerned acute and chronic pain management in adults and in children. Consensus was reached on statements regarding non-pharmacologic treatment and the use of first-line paracetamol (acetaminophen). There was a lack of consensus regarding the use of non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, or opioids.

Clinical Assessment of Endothelial Function in Convalescent COVID-19 Patients Undergoing Multidisciplinary Pulmonary Rehabilitation.

BACKGROUND: Growing evidence points to a key role of endothelial dysfunction in the pathogenesis of COVID-19. In this study, we evaluated changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of convalescent COVID-19 patients undergoing pulmonary rehabilitation (PR). METHODS: After swab test negativization, convalescent COVID-19 patients referring to a post-acute care facility for PR were consecutively screened for inclusion. Study procedures were performed at the time of hospitalization and discharge. RESULTS: We enrolled 82 convalescent COVID-19 patients (85.4% males, mean age 60.4 years). After PR, a significant improvement in most pulmonary function tests and exercise capacity was documented. FMD changed from 2.48% ± 2.01 to 4.24% ± 2.81 (p < 0.001), corresponding to a 70.9% increase. Significantly higher changes in FMD were found in patients without a history of vascular events as compared to those with (+2.04% ± 2.30 vs. +0.61% ± 1.83, p = 0.013). Values of forced expiratory volume in 1 s (FEV1%), forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLCO%) significantly and directly correlated with FMD both at baseline and after PR. Patients with normal FEV1% (≥80% predicted) during the overall study period or those normalizing FEV1% after PR showed a more significant FMD change as compared to patients with persistently impaired FEV1% (<80% predicted) (p for trend = 0.029). This finding was confirmed in a multivariate analysis. CONCLUSIONS: Clinically evaluated endothelial function improves after PR in convalescent COVID-19 patients. A direct and persistent association between the severity of pulmonary and vascular disease can be hypothesized. Endothelial function testing may be useful in the follow-up of convalescent COVID-19 patients.

Clinical assessment of endothelial function in heart failure with preserved ejection fraction: A meta-analysis with meta-regressions.

BACKGROUND: Endothelial dysfunction is a key mechanism in the development of cardiac remodelling and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are noninvasive methods to assess endothelial function. We performed a meta-analysis evaluating the impact of HFpEF on FMD and NMD. METHODS: PubMed, Web of Science, Scopus and EMBASE databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences were expressed as mean difference (MD) with 95% confidence intervals (95%CI). The random effects method was used. RESULTS: A total of seven studies were included in the final analysis, 7 with data on FMD (326 HFpEF patients and 417 controls) and 3 on NMD (185 HFpEF patients and 271 controls). Compared to controls, HFpEF patients showed significantly lower FMD (MD: -1.929; 95%CI: -2.770, -1.088; P < .0001) and NMD values (MD: -2.795; 95%CI: -3.876, -1.715; P < .0001). Sensitivity analyses substantially confirmed results. Meta-regression models showed that increasing differences in E/A ratio (Z-score: -2.002; P = .045), E/E' ratio (Z-score: -2.181; P = .029) and left atrial diameter (Z-score: -1.951; P = .050) were linked to higher differences in FMD values between cases and controls. CONCLUSIONS: Impaired endothelial function can be documented in HFpEF, with the possibility of a direct association between the severity of diastolic and endothelial dysfunction. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.

Risk Assessment and Antithrombotic Strategies in Antiphospholipid Antibody Carriers.

Antiphospholipid antibodies (aPL) are a cluster of autoantibodies directed against plasma proteins with affinity for membrane phospholipids. The most frequently tested aPL are lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), and anti-ß2-glycoprotein I antibodies (anti-ß2GPI). aPL play a key pathogenic role in the development of the antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by recurrent thrombotic and/or pregnancy complications in patients with persistent aPL. However, aPL positivity is occasionally documented in patients with no previous history of thrombotic or pregnancy morbidity. LA activity, multiple aPL positivity, high-titer aPL, and a concomitant systemic autoimmune disease are recognized risk factors for future thrombotic events in asymptomatic carriers. Moreover, an accelerated atherosclerosis with increased cardiovascular (CV) risk has also been associated with aPL positivity, thus exposing aPL carriers to fatal complications and chronic disability requiring cardiac rehabilitation. Overall, an accurate risk stratification is recommended for aPL-positive subjects in order to prevent both venous and arterial thrombotic complications. In this review, we provide an overview of the main antithrombotic and risk assessment strategies in aPL carriers.

A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH), the severest form of familial hypercholesterolemia (FH), is characterized by very high LDL-cholesterol levels and a high frequency of coronary heart disease. The disease is caused by the presence of either a pathogenic variant at homozygous status or of two pathogenic variants at compound heterozygous status in the LDLR, APOB, PCSK9 genes. We retrospectively analyzed data of 23 HoFH patients (four children and 19 adults) identified during the genetic screening of 724 FH patients. Genetic screening was performed by sequencing FH causative genes and identifying large rearrangements of LDLR. Among the HoFH patients, four out of 23 (17.4%) were true homozygotes, whereas 19 out of 23 (82.6%) were compound heterozygotes for variants in the LDLR gene. Basal LDL-cholesterol was 12.9 ± 2.9 mmol/L. LDL-cholesterol levels decreased to 7.2 ± 1.8 mmol/L when treated with statin/ezetimibe and to 5.1 ± 3.1 mmol/L with anti-PCSK9 antibodies. Homozygous patients showed higher basal LDL-cholesterol and a poorer response to therapy compared with compound heterozygotes. Since 19 unrelated patients were identified in the Campania region (6,000,000 inhabitants) in southern Italy, the regional prevalence of HoFH was estimated to be at least 1:320,000. In conclusion, our results revealed a worse phenotype for homozygotes compared with compound heterozygotes, thereby highlighting the role of genetic screening in differentiating one genetic status from the other.

Clinical assessment of endothelial function in patients with chronic obstructive pulmonary disease: a systematic review with meta-analysis.

Patients with chronic obstructive pulmonary disease (COPD) have an increased cardiovascular morbidity and mortality. Flow-mediated (FMD) and nitrate-mediated dilatation (NMD) are considered non-invasive methods to assess endothelial function and surrogate markers of subclinical atherosclerosis. We performed a systematic review with meta-analysis and meta-regression to evaluate the impact of COPD on FMD and NMD. Studies were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. The random-effect method was used to take into account the variability among included studies. A total of eight studies were included in the final analysis, eight with data on FMD (334 COPD patients) and two on NMD (104 COPD patients). Compared to controls, COPD patients show a significantly lower FMD (MD -3.15%; 95% CI -4.89, -1.40; P < 0.001) and NMD (MD -3.53%; 95% CI -7.04, -0.02; P = 0.049). Sensitivity analyses substantially confirms the results. Meta-regression models show that a more severe degree of airway obstruction is associated with a more severe FMD impairment in COPD patients than in controls. Regression analyses confirm that the association between COPD and endothelial dysfunction is independent of baseline smoking status and most traditional cardiovascular risk factors. In conclusion, COPD is significantly and independently associated with endothelial dysfunction. These findings may be useful to plan adequate cardiovascular prevention strategies in this clinical setting, with particular regard to patients with a more severe disease.

Assessment of Hemophilic Arthropathy by Ultrasound: Where Do We Stand?

Joint hemorrhages represent the most common type of bleeding episode in persons with hemophilia, and recurrent hemarthrosis triggers chronic arthropathy, which is the most frequent chronic complication in these patients. In recent years, in the frame of a comprehensive care approach, a growing attention has been given to the periodic assessment of the joint status in hemophilia patients with the aim to identify early arthropathic changes and to prevent the development of a clinically overt arthropathy. Besides clinical examination, X-ray and magnetic resonance imaging (MRI) are currently used to evaluate joint status and to monitor the disease progression in hemophilia. Considering the limitations of X-ray and MRI, growing interest has been given to ultrasound (US) as a possible tool to assess joint status and identify early arthropathic changes in hemophilia patients. In the present review, we summarize major literature evidence on the use of joint US for the evaluation of markers of disease activity (joint effusion and synovial hypertrophy) and of degenerative damages (osteochondral changes) in patients with hemophilia. On the whole, being able to identify the presence of intra- or extra-articular fluid, US examination is the fastest and most reliable technique to identify acute conditions, such as hemarthrosis. In addition, the information on joint involvement provided by US in the patient follow-up may influence treatment decisions on a personalized basis. The use of US as part of a routine clinical examination by hemophilia experts may optimize the diagnostic workflow, avoiding additional costs and long waiting lists for patients referred to imaging departments. In the frame of a comprehensive care approach, US might represent a strategy to early detect and monitor synovial hypertrophy and osteochondral changes in hemophilia, thus extending the clinical examination and helping identify joints to be studied with a second-level examination such as MRI.

Clinical assessment of endothelial function in patients with rheumatoid arthritis: A meta-analysis of literature studies.

BACKGROUND: Several studies reported an increased cardiovascular (CV) morbidity and mortality in patients with rheumatoid arthritis (RA). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are considered non-invasive methods to assess endothelial function and surrogate markers of subclinical atherosclerosis. METHODS: We performed a systematic review with meta-analysis and meta-regression of literature studies evaluating the impact of RA on FMD and NMD. Studies evaluating the relationship between RA and markers of CV risk (FMD and NMD) were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. The random-effect method was used for analyses and results were expressed as mean difference (MD). RESULTS: A total of 20 studies (852 RA patients, 836 controls) were included in the final analysis. In detail, 20 studies with data on FMD (852 cases, 836 controls) and 5 studies with data on NMD (207 cases, 147 controls) were analyzed. Compared to controls, RA patients showed a significantly lower FMD (MD: -2.16%; 95% CI: -3.33, -0.98; P=0.0003), with no differences in NMD (MD: -0.41%; 95% CI: -2.89, 2.06; P=0.74). Interestingly, a lower FMD (MD: -2.00%; 95% CI: -3.20, -0.80; P=0.001) and no differences in NMD (P=0.49) were confirmed when excluding data on patients with early-RA. Meta-regression models showed that a more severe inflammatory status was associated with a more significant impairment in FMD. CONCLUSIONS: RA patients show impaired FMD, which is currently considered an independent predictor of CV events. The presence of endothelial dysfunction in RA should be taken into account to plan adequate prevention strategies and therapeutic approaches.

Non-invasive assessment of arterial stiffness in patients with rheumatoid arthritis: a systematic review and meta-analysis of literature studies.

INTRODUCTION: Patients with rheumatoid arthritis (RA) have an increased cardiovascular (CV) morbidity and mortality. Pulse-wave velocity (PWV) and augmentation index (AIx) are non-invasive methods to assess arterial stiffness, a marker of CV risk. We performed a meta-analysis evaluating the impact of RA on aortic-PWV, brachial-PWV, brachial-ankle (ba-) PWV, AIx, and AIx normalized to a 75 beats/minute heart rate (AIx@75). MATERIALS AND METHODS: Studies evaluating the relationship between RA and aortic-PWV, brachial-PWV, ba-PWV, AIx, and AIx@75 were systematically searched. A total of 25 studies (1,472 RA patients, 1,583 controls) were included. RESULTS: Compared to controls, RA patients showed a significantly higher aortic-PWV (mean difference 1.32 m/s; 95% CI 0.77, 1.88; P < 0.00001), ba-PWV (MD 198.42 cm/s; 95% CI 45.79, 342.76; P = 0.01), AIx (MD 11.50%; 95% CI 5.15, 17.86; P = 0.0004), and AIx@75 (MD 6.99%; 95% CI 4.92, 9.06; P < 0.00001), with a trend toward a higher brachial-PWV (MD 0.34 m/s; 95% CI -0.03, 0.70; P = 0.07). When analyzing studies on early RA, the difference in aortic-PWV among RA patients and controls was even higher (MD 2.30 m/s; 95% CI 1.15, 3.45; P < 0.0001). CONCLUSION: Meta-regression showed that a more severe inflammatory status impacted on aortic-PWV, AIx, and AIx@75. Arterial stiffness, a recognized marker of CV risk, is increased in RA patients. This alteration is associated with the severity of the inflammatory status and is present even in early-stage disease.

Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery.

BACKGROUND: In people with haemophilia or other congenital bleeding disorders undergoing surgical interventions, haemostatic treatment is needed in order to correct the underlying coagulation abnormalities and minimise the bleeding risk. This treatment varies according to the specific haemostatic defect, its severity and the type of surgical procedure. The aim of treatment is to ensure adequate haemostatic coverage for as long as the bleeding risk persists and until wound healing is complete. OBJECTIVES: To assess the effectiveness and safety of different haemostatic regimens (type, dose and duration, modality of administration and target haemostatic levels) administered in people with haemophilia or other congenital bleeding disorders for preventing bleeding complications during and after surgical procedures. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of the last search: 20 November 2014. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing any hemostatic treatment regimen to no treatment or to another active regimen in children and adults with haemophilia or other congenital bleeding disorders undergoing any surgical intervention. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials (eligibility and risks of bias) and extracted data. Meta-analyses were performed on available and relevant data. MAIN RESULTS: Of the 16 identified trials, four (112 participants) were eligible for inclusion.Two trials evaluated 59 people with haemophilia A and B undergoing 63 dental extractions. Trials compared the use of a different type (tranexamic acid or epsilon-aminocaproic acid) and regimen of antifibrinolytic agents as haemostatic support to the initial replacement treatment. Neither trial specifically addressed mortality (one of this review's primary outcomes); however, in the frame of safety assessments, no fatal adverse events were reported. The second primary outcome of blood loss was assessed after surgery and these trials showed the reduction of blood loss and requirement of post-operative replacement treatment in people receiving antifibrinolytic agents compared with placebo. The remaining primary outcome of need for re-intervention was not reported by either trial.Two trials reported on 53 people with haemophilia A and B with inhibitors treated with different regimens of recombinant activated factor VII (rFVIIa) for haemostatic coverage of 33 major and 20 minor surgical interventions. Neither of the included trials specifically addressed any of the review's primary outcomes (mortality, blood loss and need for re-intervention). In one trial a high-dose rFVIIa regimen (90 µg/kg) was compared with a low-dose regimen (35 µg/kg); the higher dose showed increased haemostatic efficacy, in particular in major surgery, with shorter duration of treatment, similar total dose of rFVIIa administered and similar safety levels. In the second trial, bolus infusion and continuous infusion of rFVIIa were compared, showing similar haemostatic efficacy, duration of treatment and safety. AUTHORS' CONCLUSIONS: There is insufficient evidence from randomised controlled trials to assess the most effective and safe haemostatic treatment to prevent bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgical procedures. Ideally large, adequately powered, and well-designed randomised controlled trials would be needed, in particular to address the cost-effectiveness of such demanding treatments in the light of the increasing present economic constraints, and to explore the new challenge of ageing patients with haemophilia or other congenital bleeding disorders. However, performing such trials is always a complex task in this setting and presently does not appear to be a clinical and research priority. Indeed, major and minor surgeries are effectively and safely performed in these individuals in clinical practice, with the numerous national and international recommendations and guidelines providing regimens for treatment in this setting mainly based on data from observational, uncontrolled studies.

Thromboprophylaxis with low-molecular-weight heparins: an assessment of the methodological quality of studies.

Low-molecular-weight heparin (LMWH) represents the standard of care for prophylaxis of venous thromboembolism (VTE). We conducted a review of the evidence supporting the use of the different LMWHs employed in VTE prophylaxis, in different clinical settings, and analyzed its progression over time. To evaluate the standards of methodological quality of studies, we elaborated a quality assessment tool. By electronic databases, PubMed, MEDLINE, and Scopus databases, 249 articles deemed eligible for the analysis were selected. Several LMWHs did not have publications in all clinical settings. Extended duration of prophylaxis was documented only for a few LMWH. The quality score yielded statistically significant differences between the medians of the four settings (p = 0.0021) with a higher score in major orthopedic surgery (median, 16; 95% confidence interval [CI], 15-16) when compared with general surgery (median, 14; 95% CI, 13-14; p < 0.001). Median score for studies published after the year 1990 was higher than for those published earlier (p < 0.001). We conclude that the quality of the studies supporting LMWH for VTE prophylaxis in the different clinical settings is not homogeneous and inferior for studies performed before the year 1990. Clinical interchangeability of LMWHs in clinical practice remains a critical issue, and the selection of a product should be based on evidence available for each agent, and for each clinical indication derived from clinical trials.

Differences of myocardial systolic deformation and correlates of diastolic function in competitive rowers and young hypertensives: a speckle-tracking echocardiography study.

BACKGROUND: The aim of this study was to compare speckle-tracking echocardiography-derived left ventricular (LV) systolic mechanics and their relationships with LV diastolic properties in young patients with hypertension and in young competitive athletes in relation to their respective alterations of LV structure. METHODS: Nineteen sedentary controls, 22 top-level rowers, and 18 young newly diagnosed, never-treated patients with hypertension, all male, underwent Doppler echocardiography including pulsed tissue Doppler of the mitral annulus and speckle-tracking echocardiography. Peak longitudinal strain was calculated in apical long-axis, four-chamber, and two-chamber views, and values of the three views were averaged (global longitudinal strain [GLS]). Regional circumferential and radial strain were calculated at the LV basal, middle, and apical levels, and values were averaged (global circumferential strain and global radial strain). LV torsion was determined as the net difference in the mean rotation between the apical and basal levels. RESULTS: The three groups were comparable for age, whereas body mass index and blood pressure were higher in patients with hypertension, and heart rate was lower in rowers. LV mass index was higher in rowers and in patients with hypertension than in controls, without differences in relative wall thickness, ejection fraction, and midwall shortening. Left atrial volume index was greater in rowers than in controls and patients with hypertension. Annular systolic velocity (s') (P < .001) and early diastolic velocity (e') (P < .0001) were lower and the E/e' ratio was higher (P < .0001) in patients with hypertension. GLS was lower in patients with hypertension (-17.5 ± 2.8%) than in rowers (-22.2 ± 2.7%) and in controls (-21.1 ± 2.0%) (P < .0001). Global circumferential strain, global radial strain, and torsion were similar among the three groups. In the pooled population, GLS was an independent contributor to E/e' ratio (P < .0001) after adjusting for age, heart rate, meridional end-systolic stress, LV mass index and left atrial volume index. By receiver operating characteristic curve analyses, both GLS and E/e' ratio appeared to be accurate in discriminating patients with hypertension from healthy controls, with the E/e' ratio being more sensitive (77.8%) and GLS more specific (89.5%). CONCLUSIONS: The hearts of young patients with hypertension are characterized by reduced GLS, whereas global circumferential strain, global radial strain, and torsion are similar to those of athletes' hearts. The extent of GLS is strongly associated with LV diastolic function, independently of afterload changes and the degree of LV hypertrophy.

Troponin I and right ventricular dysfunction for risk assessment in patients with nonmassive pulmonary embolism in the Emergency Department in combination with clinically based risk score.

To determine whether troponin I (cTnI) and right ventricular (RV) dysfunction predict adverse in-hospital outcomes in patients admitted to the Emergency Department (ED) with definite nonmassive pulmonary embolism (PE) independent of and in addition to a recently validated clinical prognostic risk score. From a pool of 168 patients with suspected PE, 89 had nonmassive PE confirmed by spiral lung angio-computed tomography. By the clinical prognostic score, in our study sample, 14% had very low risk; 17% had low risk, 20% had intermediate risk, whereas high risk and very high risk were identified in 29 and 20%, respectively. Prevalence of elevated cTnI (>0.1 microg/L, 57%) at admission was comparable among patients grouped by clinical prognostic score (P = NS); echocardiographic RV dysfunction (54%) was more prevalent with intermediate or high clinical risk score (P < 0.02). Increased cTnI predicted primary end-point (development of hemodynamic instability, overall 33 cases, 37%) independent of and in addition to the clinical risk class and RV dysfunction (P < 0.01 for interaction). Fatal events (12 cases, 14%, 5 definite, 7 possible PE-related) were predicted by higher clinical risk score (P < 0.05). In patients with nonmassive central PE admitted to the ED, increased cTnI contributed to identifying those with increased risk of development of hemodynamic instability independent of and in addition to a validated clinically based risk score.