SARS-CoV-2 Aiming for the Heart: A Multicenter Italian Perspective About Cardiovascular Issues in COVID-19.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the high fatality rate of coronavirus disease 2019 (COVID-19) have been putting a strain on the world since December 2019. Infected individuals exhibit unpredictable symptoms that tend to worsen if age is advanced, a state of malnutrition persists, or if cardiovascular comorbidities are present. Once transmitted, the virus affects the lungs and in predisposed individuals can elicit a sequela of fatal cardiovascular consequences. We aim to present the pathophysiology of COVID-19, emphasizing the major cellular and clinical manifestations from a cardiological perspective. As a roaming viral particle or more likely via the Trojan horse route, SARS-CoV-2 can access different parts of the body. Cardiovascular features of COVID-19 can count myocardial injuries, vasculitis-like syndromes, and atherothrombotic manifestations. Deviations in the normal electrocardiogram pattern could hide pericardial effusion or cardiac inflammation, and dispersed microthrombi can cause ischemic damages, stroke, or even medullary reflex dysfunctions. Tailored treatment for reduced ejection fraction, arrhythmias, coronary syndromes, macrothrombosis and microthrombosis, and autonomic dysfunctions is mandatory. Confidently, evidence-based therapies for this multifaceted nevertheless purely cardiological COVID-19 will emerge after the global assessment of different approaches.

Healthy Promotion for Fighting Metabolic Syndrome: Insights from Multi-Center HeRO-FiT Cohort.

We know that metabolic syndrome (MS) is a modern cardiovascular (CV) "epidemic", especially in western populations. MS is indeed strictly related to the risk of developing CV diseases (CVD) and/or diabetes. Therefore, the aim of our multi-center study was to promote a "healthy style" for fighting MS. Each participating center analyzed its own database of outpatients and globally we have pulled out 100 volunteers to participate in the study. Before starting, we collected their written consent. Enrolled subjects have not any history of overt CVD and/or diabetes, but they matched National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATP) criteria for MS. After enrolment (t0), subjects were randomly divided into two homogeneous groups: a) only diet suggestions; b) both diet and exercise prescription. Later, we measured for each subject: blood pressure (BP), heart rate (HR), height, weight, body mass index (BMI), waist circumference (WC), waist hip ratio (WHR), six-minute walking test (WT6M), distance and common blood tests such as fasting plasma glucose, high-density lipoproteins (HDL) and triglycerides (T1 assessments). At six months (T2), the same parameters were measured and then statistical comparisons were performed. Attention to diet caused significant changes only in WC and WHR, whilst a coupling of exercise and diet revealed a statistically significant improvement in HR, BP, BMI, blood samplings and WT6M too. In conclusion, a healthy lifestyle should be more encouraged by physicians and/or collaborators (such as dieticians) operating in preventive settings. Diet and physical activity may be early useful strategies in the "battle" against MS even before any medication choices. Further studies will be necessary in order to better address the topic.

Noninvasive imaging methods for evaluating cardiovascular involvement in patients with rheumatoid arthritis before and after anti-TNF drug treatment.

AIM: To use 2D speckle-tracking echocardiography, and conventional and tissue Doppler echocardiography to detect subclinical left ventricular myocardial dysfunction in patients with rheumatoid arthritis (RA). METHODS: Thirty RA outpatients were assessed before and after 18 months of treatment with anti-TNF drugs, along with 30 healthy controls. Cardiovascular risk was assessed by means of ultrasound carotid assessment and comprehensive echocardiographic evaluation (conventional and speckle-tracking calculation). RESULTS: The speckle-tracking analyses were significantly different between the two groups, with global longitudinal strain deformation in the apical four-chamber view being significantly lower in the RA patients (median: 18.78%, interquartile range [IQR]: 15.80-20.82% vs 20.16%, IQR: 19.03-21.89%; [p < 0.05]). After 18 months of biological treatment, global longitudinal strain showed a significant improvement (18.78%, IQR: 15.80-20.82 vs 19.24%, IQR: 18.23-19.98; [p < 0.01]), such as for DAS28 (4.80, IQR: 4.65-5.22 vs 2.78; IQR: 2.52-2.99; [p < 0.01]). CONCLUSION: Speckle-tracking echocardiography showed that left ventricular myocardial longitudinal strain was impaired in the RA patients.

Correction of hypovitaminosis D improved global longitudinal strain earlier than left ventricular ejection fraction in cardiovascular older adults after orthopaedic surgery.

BACKGROUND: Cardiovascular diseases and insufficient levels of vitamin D are risk factors for adverse surgical outcomes, and they are both commonly present among older adults undergoing orthopaedic surgery. Giving the cardiovascular effects of vitamin D, pre-operative diagnosis of hypovitaminosis D would be a valuable step for the implementation of supplementation protocols. We investigated if the normalization of serum 25 [OH] D could ameliorate cardiac performance of older adults suffering from cardiovascular diseases. METHODS: We enrolled 47 older adults scheduled for major orthopaedic surgery and suffering from hypovitaminosis D. Patients underwent 6-months calcifediol supplementation with a starting dose at first post-operative day of 50 µg/die in liquid preparation. Down-titration to 20 µg/die at 3-months assessment was planned. Cardiac performance was evaluated by measuring left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) during pre-operative assessments and at 1-month, 3-months, 6-months follow-ups. RESULTS: Six months of calcifediol supplementation were associated with a significant improvement of both LVEF (+ 3.94%; 95% CI: -4.0789 to -0.8232; P < 0.01) and GLS (+ 18.56%; Z = -5.895; P < 0.0001). CONCLUSIONS: Calcifediol supplementation normalized serum 25 [OH] D concentration after 1-month treatment. GLS offered better insights into myocardial contractile amelioration than LVEF, thus being useful for detecting earlier subclinical changes that may anticipate hemodynamic modifications.

Foot and Soccer Referees': A Pilot Study Searching "Performance" Throughout Prevention.

Soccer refereeing is a "not-conventional" sport in which aerobic workload is prevalent. Along the years, several studies have attempted to define best markers of referees' performance. Many studies focused their attention on field tests and their relationship with aerobic power. Instead, in this study, starting by a medical assessment satisfying the FIFA 11+ criteria for injuries prevention, we have investigated the foot of soccer referees and we have also wanted to find possible and/or unexpected improvements in performance. As performance marker, we have used the referral field test for soccer referees that is internationally validated and known as Yo-Yo test (YYiR1). While standardized foot posture index (FPI) questionnaire was used for screening foot referees conditions (40 young, all men by sex, with mean age 23.47 ± 4.36). Analyzing collected data, we have demonstrated by means of Read-Cressie Chi square test that neutral FPI is an important favor item affecting YYiR1 results. Further studies will be necessary in order to confirm our pilot investigation.

Cardiovascular Imaging Techniques in Systemic Rheumatic Diseases.

The risk of cardiovascular (CV) events and mortality is significantly higher in patients with systemic rheumatic diseases than in the general population. Although CV involvement in such patients is highly heterogeneous and may affect various structures of the heart, it can now be diagnosed earlier and promptly treated. Various types of assessments are employed for the evaluation of CV risk such as transthoracic or transesophageal echocardiography, magnetic resonance imaging (MRI), and computed tomography (CT) to investigate valve abnormalities, pericardial disease, and ventricular wall motion defects. The diameter of coronary arteries can be assessed using invasive quantitative coronarography or intravascular ultrasound, and coronary flow reserve can be assessed using non-invasive transesophageal or transthoracic ultrasonography (US), MRI, CT, or positron emission tomography (PET) after endothelium-dependent vasodilation. Finally, peripheral circulation can be measured invasively using strain-gauge plethysmography in an arm after the arterial infusion of an endothelium-dependent vasodilator or non-invasively by means of US or MRI measurements of flow-mediated vasodilation of the brachial artery. All of the above are reliable methods of investigating CV involvement, but more recently, introduced use of speckle tracking echocardiography and 3-dimensional US are diagnostically more accurate.

Left ventricular longitudinal strain in soccer referees.

Along the years, the analysis of soccer referees perfomance has interested the experts and we can find several types of studies in literature using in particular cardiac imaging. The aim of this retrospective study was to observe relationship between VO2max uptake and some conventional and not-conventional echocardiographic parameters. In order to perform this evaluation, we have enrolled 20 referees, belonging to Italian Soccer Referees' Association and we have investigated cardiovascular profile of them. We found a strong direct relationship between VO2max and global longitudinal strain of left ventricle assessed by means of speckle tracking echocardiographic analysis (R2=0.8464). The most common classic echocardiographic indexes have showed mild relations (respectively, VO2max vs EF: R2=0.4444; VO2max vs LV indexed mass: R2=0.2268). Therefore, our study suggests that longitudinal strain could be proposed as a specific echocardiographic parameter to evaluate the soccer referees performance.

Interaction between polyphenols intake and PON1 gene variants on markers of cardiovascular disease: a nutrigenetic observational study.

BACKGROUND: Paraoxonase 1 (PON1) gene polymorphisms and polyphenols intake have been reported independently associated to lipid profile and susceptibility to atherosclerosis and cardiovascular disease. However, the interaction between these factors remains to be investigated. We performed an observational nutrigenetic study to examine whether the interaction between polyphenols and anthocyanins intake and PON1 genetic variants can modulate biomarkers of cardiovascular health in an Italian healthy population. METHODS: We recruited 443 healthy volunteers who participated in the EC funded ATHENA project (AnThocyanin and polyphenols bioactive for Health Enhancement through Nutritional Advancement). Data collection included detailed demographic, clinical, dietary, lifestyle, biochemical and genetic data. Polyphenols and anthocyanins intake was measured by 24 h dietary recall repeated three times a year in order to get seasonal variations. We tested the interaction between 18 independent tagging SNPs in PON1 gene and polyphenols intake on HDL, LDL, cholesterol, triglycerides and atherogenic index of plasma. RESULTS: Without considering the genetic background, we could not observe significant differences in the lipid profile between high and low polyphenols and anthocyanins intake. Using a nutrigenetic approach, we identified protective genotypes in four independent polymorphisms that, at Bonferroni level (p ≤ 0.0028), present a significant association with increased HDL level under high polyphenols and anthocyanins intake, compared to risk genotypes (rs854549, Beta = 4.7 per C allele; rs854552, Beta = 5.6 per C allele; rs854571, Beta = 3.92 per T allele; rs854572, Beta = 3.94 per C allele). CONCLUSIONS: We highlight the protective role of genetic variants in PON1 towards cardiovascular risk under high polyphenols and anthocyanins consumption. PON1 variants could represent novel biomarkers to stratify individuals who might benefit from targeted dietary recommendation for health promotion and strategies of preventive medicine.

Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: cause for concern?

There are now five anti-TNF drugs available for clinical use, and it will not be long before they are joined by biosimilar drugs. Some patients treated with selective TNF drugs may develop adverse events such as infections, malignancies, acute infusion and injection reactions, autoimmunity and cardiovascular effects. Registry data consistently show that, particularly during the first 6 months, anti-TNF drugs slightly increase the risk of serious infections of the skin, soft tissues and joints, but it does not seem to increase the risk of cancer other than nonmelanoma skin cancers. A number of studies have shown that the administration of biological agents can lead to the formation of neutralizing and nonneutralizing antibodies. Lipid levels increase, but the atherogenic index remains stable and qualitative changes to lipid particles may reduce the risk of cardiovascular diseases. Patients treated with anti-TNF drugs therefore need to be monitored regularly.

Is atherosclerosis an autoimmune disease?

Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds ß2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that ß2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.

Silent cardiovascular involvement in patients with diffuse systemic sclerosis: a controlled cross-sectional study.

OBJECTIVE: An association between systemic autoimmune diseases and atherosclerosis has been described in many connective tissue diseases, and this association is known to lead to increased cardiovascular morbidity and mortality. Systemic sclerosis (SSc) is characterized by multisystem organ inflammation, endothelial wall damage, and vasculopathy. There are many markers of endothelial dysfunction and/or atherosclerotic risk, such as asymmetric dimethylarginine (ADMA), arterial stiffness parameters, carotid intima-media thickness (CIMT), and coronary flow reserve (CFR) assessed by transthoracic echocardiography. The aim of this pilot study was to use various endothelial and atherosclerosis markers to identify early cardiovascular involvement in a group of SSc patients. METHODS: The study involved 20 patients (2 men and 18 women with a mean ± SD age of 52.96 ± 12.51 years) with diffuse SSc who had no signs or symptoms of cardiovascular disease (CVD) and 20 age- and sex-matched controls. All subjects underwent a dipyridamole echocardiographic stress test that included a determination of CFR and an evaluation of CIMT, arterial stiffness, and plasma ADMA levels. RESULTS: All of the arterial wall measurements of the patients with diffuse SSc were significantly different from those of the controls, and both right and left CIMT, pulse wave velocity, and stiffness index (ß) were significantly elevated in the SSc patients compared to the healthy controls. Moreover, in patients with diffuse SSc, CFR was significantly lower (P = 0.0033) and plasma ADMA levels were higher (P < 0.0001) than in healthy controls. CONCLUSION: SSc patients without any clinical evidence of CVD seem to have had subclinical atherosclerosis, which was suggested by early impairment of coronary microcirculation and macrovascular involvement.

Validated methods for assessment of subclinical atherosclerosis in rheumatology.

Rheumatoid arthritis, as well as other types of arthritides and connective tissue diseases, is associated with accelerated atherosclerosis, and increased cardiovascular morbidity and mortality. The early signs of cardiovascular disease therefore need to be recognized in patients with these conditions so that effective cardiovascular protection can be introduced. This Review provides an overview of validated techniques that are currently available to determine subclinical atherosclerosis in patients with rheumatic conditions. Techniques for early assessment of endothelial dysfunction include brachial artery flow-mediated vasodilation and laser Doppler flowmetry. Coronary circulation can be assessed by measuring coronary flow reserve using CT, MRI or PET based techniques. The standard indicators of arterial stiffness are pulse-wave velocity and the augmentation index. Carotid atherosclerosis is determined by the common carotid intima-media thickness (ccIMT) measurement or by the assessment of plaques and plaque areas. The combination of ccIMT with plaque assessment is likely to increase the predictive value of this approach. The potential use of a multimarker approach to increase the diagnostic and prognostic value of these clinical assessments is also discussed.

Detection of preclinical impairment of myocardial function in rheumatoid arthritis patients with short disease duration by speckle tracking echocardiography.

BACKGROUND: Subclinical cardiac involvement diagnosis is important for long term management of rheumatoid arthritis (RA) patients. Recently, 2D speckle tracking echocardiography (STE) allows non invasive and angle-independent measurement of left ventricular (LV) dimensions and regional myocardial strain (ε). The aim of this study was to assess whether STE can be useful to detect subclinical cardiac involvement in RA patients. METHODS: We studied 22 RA patients (10 M, 12 F, aged 46 ± 12 years) without clinical evidence of coronary artery disease (CAD) and 20 healthy controls matched for age and sex by STE. LV end-systolic longitudinal and radial ε from apical 4-chamber view were analyzed using available software (QLAB 6.0). RESULTS: Standard echo and Doppler parameters did not differ between the 2 groups. Tissue Doppler Imaging (TDI) showed a significant reduction of S', E' and E'/A' ratio from the basal septum and lateral mitral annulus in RA patients. LV end-systolic radial and longitudinal ε of basal-lateral, basal- and mid-septal, mid-lateral and apical segments were significantly reduced compared to controls. CONCLUSIONS: Our data indicate that LV end-systolic radial and longitudinal ε are reduced in RA patients without CAD despite normal standard echo. Non invasive evaluation of LV function by STE appears to be useful to detect subclinical cardiac involvement in comparison to conventional 2D echoDoppler, representing a promising new modality to follow-up RA patients for cardiac involvement.

Non-stationarities significantly distort short-term spectral, symbolic and entropy heart rate variability indices.

The autonomic regulation is non-invasively estimated from heart rate variability (HRV). Many methods utilized to assess autonomic regulation require stationarity of HRV recordings. However, non-stationarities are frequently present even during well-controlled experiments, thus potentially biasing HRV indices. The aim of our study is to quantify the potential bias of spectral, symbolic and entropy HRV indices due to non-stationarities. We analyzed HRV series recorded in healthy subjects during uncontrolled daily life activities typical of 24 h Holter recordings and during predetermined levels of robotic-assisted treadmill-based physical exercise. A stationarity test checking the stability of the mean and variance over short HRV series (about 300 cardiac beats) was utilized to distinguish stationary periods from non-stationary ones. Spectral, symbolic and entropy indices evaluated solely over stationary periods were contrasted with those derived from all the HRV segments. When indices were calculated solely over stationary series, we found that (i) during both uncontrolled daily life activities and controlled physical exercise, the entropy-based complexity indices were significantly larger; (ii) during uncontrolled daily life activities, the spectral and symbolic indices linked to sympathetic modulation were significantly smaller and those associated with vagal modulation were significantly larger; (iii) while during uncontrolled daily life activities, the variance of spectral, symbolic and entropy rate indices was significantly larger, during controlled physical exercise, it was smaller. The study suggests that non-stationarities increase the likelihood to overestimate the contribution of sympathetic control and affect the power of statistical tests utilized to discriminate conditions and/or groups.

Cardiovascular injury in systemic autoimmune diseases: an update.

It is well known in literature that systemic autoimmune diseases (SADs) are associated with enhanced atherosclerosis and impaired endothelial function early after the onset of the disease. Cardiovascular (CV) disease represents one of the leading causes of morbidity and mortality in SADs. There is considerable evidence suggesting a pathogenetic role of chronic inflammation and immune dysregulation for enhanced atherosclerosis in SADs, as demonstrated in several recent studies. Moreover, chronic inflammation, accelerated atherosclerosis and functional abnormalities of the endothelium suggest a subclinical CV involvement beginning rapidly soon after the onset of the disease and progressing with disease duration.

Coronary flow reserve and asymmetric dimethylarginine levels: new measurements for identifying subclinical atherosclerosis in patients with psoriatic arthritis.

OBJECTIVE: To identify the presence of subclinical atherosclerosis in patients with psoriatic arthritis (PsA) and healthy controls using intima-media thickness (IMT), coronary flow reserve (CFR), and the plasma concentration of asymmetric dimethylarginine (ADMA), to evaluate the correlations among ADMA, IMT, and CFR. METHODS: The study involved 22 patients who fulfilled the ClASsification of Psoriatic ARthritis study group criteria for PsA and a cohort of 35 healthy controls with no history or current signs of coronary artery disease (CAD). Common carotid IMT was measured using high-resolution B-mode ultrasonography. Dipyridamole transthoracic stress echocardiography was used to evaluate CFR. Blood samples were obtained to assess ADMA levels. The clinical manifestations were recorded. All patients were treated with disease-modifying antirheumatic drug, but none had received any biological or steroid therapy. RESULTS: Plasma ADMA levels were significantly higher in the patients with PsA (0.71 ± 0.07 µmol/l vs 0.48 ± 0.07 µmol/l; p = 0.00) and CFR was significantly reduced in that group (2.86 ± 0.70 vs 3.3 ± 0.43; p < 0.01) compared to controls. Common carotid IMT was greater in the patients with PsA, but the difference was not significant (0.64 ± 0.26 mm vs 0.62 ± 0.5 mm; p = 0.65). There was a significant correlation between CFR and plasma ADMA levels in the PsA group (R = 0.28; p < 0.01), but no correlation between plasma ADMA levels and IMT (R = 0.02; p = 0.32), Disease Activity Score 28 (p = 0.52), or Psoriasis Area and Severity Index (p = 0.98). CONCLUSION: Our patients with PsA showed a profile of subclinical atherosclerosis. ADMA may be a useful marker of endothelial dysfunction in PsA.

Robotic treadmill training improves cardiovascular function in spinal cord injury patients.

BACKGROUND: Body weight supported treadmill training (BWSTT) assisted with a robotic driven gait orthosis (DGO) is an emerging tool in rehabilitating patients with lost sensorimotor function. Few information about the effects of BWSTT on cardiovascular system are available. The purpose of this study was to determine the effects of BWSTT on: 1) left ventricular (LV) systo-diastolic function; 2) coronary flow reserve (CFR); 3) endothelial function in patients with lost sensorimotor function due to neurologic lesions. METHODS: Fourteen adults (males 10, age 50.6±17.1years) with motor incomplete spinal cord injuries (SCI) due to trauma or spondylotic diseases underwent standard echocardiographic examination, non invasive assessment of CFR by dipyridamole stress echo and determination of plasma asymmetric dimethylarginine (ADMA) levels at baseline and after 6weeks of BWSTT. RESULTS: At post training evaluation we observed lower LV end-diastolic (P=0.0164) and end-systolic volumes (P=0.0029) with increased ejection fraction (EF) (P=0.0266). We also observed a LV interventricular septum (IVS) (P=0.00469) increase. At the same time, we detected an improvement of LV diastolic function as witnessed by the reduction of isovolumic relaxation time (IVRT) (P=0.0404) and deceleration time (DT) (P=0.0405) with an increased E/A ratio (P=0.0040). Improved CFR (P=0.020) and reduced plasma ADMA levels (P=0.0005) have been observed too, in association with a reduction of the inflammatory status (C-reactive protein (CRP) (P=0.0022) and erythrocyte sedimentation rate (ESR) (P=0.0005)). CONCLUSION: For the first time, this study demonstrated that 6weeks of BWSTT improved not only the sensorimotor function but also systo-diastolic LV function, CFR and endothelial dysfunction associated with a reduction of the inflammatory status in patients with incomplete SCI.