Combined peripheral and central ultrasound for the diagnosis of PAH-SSc patients.

BACKGROUND: Systemic Sclerosis (SSc), an intricate autoimmune disease causing tissue fibrosis, introduces cardiovascular complexities, notably pulmonary hypertension (PH), affecting both survival and quality of life. This study centers on evaluating echocardiographic parameters and endothelial function using flow-mediated dilatation (FMD) in SSc patients, aiming to differentiate those with and without pulmonary arterial hypertension (PAH). The emphasis lies in early detection, given the heightened vulnerability of the right ventricle (RV) in the presence of PH. METHODS: Fifty-nine SSc patients and 48 healthy subjects participated, undergoing clinical examinations, echocardiography, FMD assessments, blood analyses, and right heart catheterization (RHC) according to the ESC/ERS guidelines for diagnosis and treatment of PH. RESULTS: SSc-PAH patients displayed lower FMD, higher frequency of TAPSE < 18 mm, RA area > 18 cm2, act RVOT < 105 ms and TRV > 280 cm/s compared to those without PAH and healthy controls. Resting resistivity index (RI) was higher in SSc patients, with no significant difference between those with and without PAH. Lower FMD% serves as a predictive marker for adverse cardiovascular outcomes in both SSc and SSc-PAH patients. Stratification by TRV levels and PAH presence reveals notable FMD% variations, emphasizing its potential utility. CONCLUSIONS: Early identification of endothelial dysfunction and impaired RV echocardiographic parameters, such as TAPSE and TRV, could aid in predicting right ventricular dysfunction and PAH in SSc patients.

Vascular and metabolic effects of SGLT2i and GLP-1 in heart failure patients.

Alterations of endothelial function, inflammatory activation, and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure. Metabolic alterations have been studied in the myocardium of heart failure (HF) patients; alterations in ketone body and amino acid/protein metabolism have been described in patients affected by HF, as well as mitochondrial dysfunction and other modified metabolic signaling. However, their possible contributions toward cardiac function impairment in HF patients are not completely known. Recently, sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have emerged as a new class of drugs designed to treat patients with type 2 diabetes (T2D), but have also been shown to be protective against HF-related events and CV mortality. To date, the protective cardiovascular effects of these drugs in patients with and without T2D are not completely understood and several mechanisms have been proposed. In this review, we discuss on vascular and metabolic effects of SGLT2i and GLP-1 in HF patients.

The Evolving Phenotypes of Cardiovascular Disease during COVID-19 Pandemic.

COVID-19 pandemic has negatively impacted the management of patients with acute and chronic cardiovascular disease: acute coronary syndrome patients were often not timely reperfused, heart failure patients not adequately followed up and titrated, atrial arrhythmias not efficaciously treated and became chronic. New phenotypes of cardiovascular patients were more and more frequent during COVID-19 pandemic and are expected to be even more frequent in the next future in the new world shaped by the pandemic. We therefore aimed to briefly summarize the main changes in the phenotype of cardiovascular patients in the COVID-19 era, focusing on new clinical challenges and possible therapeutic options.

Network meta-analysis of medical therapy efficacy in more than 90,000 patients with heart failure and reduced ejection fraction.

BACKGROUND: Following the availability of new drugs for chronic heart failure (HF) with reduced ejection fraction (HFrEF), we sought to provide an updated and comparative synthesis of the evidence on HFrEF pharmacotherapy efficacy. METHODS: We performed a Bayesian network meta-analysis of phase 2 and 3 randomized controlled trials (RCTs) of medical therapy in HFrEF patient cohorts with more than 90% of the participants with left ventricular ejection fraction less than 45% and all-cause mortality reported. RESULTS: Sixty-nine RCTs, accounting for 91,741 subjects, were evaluated. The step-wise introduction of new drugs progressively decreased the risk of all-cause death, up to reaching a random-effects hazard ratio (HR) of 0.43 (95% credible intervals [CrI] 0.27-0.63) with beta blockers (BB), angiotensin-converting enzyme inhibitors (ACEi), and mineralocorticoid receptor antagonist (MRA) versus placebo. The risk was further reduced by adding sodium-glucose cotransporter-2 inhibitors (SGLT2i; HR 0.38, 95% CrI 0.22-0.60), ivabradine (HR 0.39, 95% CrI 0.21-0.64), or vericiguat (HR 0.40, 95% CrI 0.22-0.65) to neurohormonal inhibitors, and by angiotensin receptor-neprilysin inhibitor (ARNI), BB, and MRA (HR 0.36, 95% CrI 0.20-0.60). In a sensitivity analysis considering the ARNI and non-ARNI subgroups of SGLT2i RCTs, the combination SGLT2i + ARNI + BB + MRA was associated with the lowest HR (0.28, 95% CrI 0.16-0.45 vs. 0.40, 95% CrI 0.24-0.60 for SGLT2i + BB + ACEi + MRA). Consistent results were obtained in sensitivity analyses and by calculating surface under the cumulative ranking area, as well as for cardiovascular mortality (information available for 56 RCTs), HF hospitalization (45 RCTs), and all-cause hospitalization (26 RCTs). CONCLUSIONS: Combination medical therapy including neurohormonal inhibitors and newer drugs, especially ARNI and SGLT2i, confers the maximum benefit with regard to HFrEF prognosis.

Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure.

PURPOSE: The use of sodium-glucose-cotransporter-type-2 inhibitors (SGLT2i) was associated in previous studies with an improved vascular function in non-human experimental models. We therefore sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with chronic heart failure (CHF) and type-2 diabetes mellitus (T2DM), switching from other oral hypoglycemic agents to SGLT2i in an observational study. METHODS: Twenty-two consecutive outpatients with CHF and T2DM were enrolled after switching to SGLT2i therapy, and compared with 23 consecutive controls from the same registry comparable for principal clinical characteristics. In all patients, endothelial function was assessed by FMD at baseline and after 3 months of follow-up. RESULTS: Three months of therapy with SGLT2i were associated with a statistically significant improvement in endothelial function (19.0 ± 5.7% vs 8.5 ± 4.1%, p < 0.0001); baseline levels of FMD were comparable between groups (p n.s.). Therapy with SGLT2i was significantly associated to improved FMD levels even at multivariable stepwise regression analysis (p < 0.001). CONCLUSIONS: Switch to SGLT2i in patients with CHF and T2DM was associated in an observational non-randomized study with an improved endothelial function.

Revascularization rates with coronary angioplasty and mortality in type 2 myocardial infarction: A meta-regression analysis.

BACKGROUND: Percutaneous coronary intervention (PCI) represents the best therapeutic option for type-1 myocardial infarction (T1MI) in the majority of clinical settings; its role in the treatment of type-2 myocardial infarction (T2MI), however, remains unclear. We therefore sought to assess in a meta-regression analysis the impact of PCI rates on mortality in patients with T2MI according to available observational studies. METHODS: We performed a meta-regression analysis including all the studies involving in-patients affected by T2MI. We excluded studies not reporting the rate of T2MI patients undergoing PCI and not specifying absolute in-hospital or 1-year all-cause mortality. In the meta-regression analysis we used the in-hospital mortality and 1-year mortality as dependent variables and the rate of PCI as independent; regression was weighted for studies' size. RESULTS: After careful examination, 8 studies were selected for the assessment of in-hospital mortality and 8 for 1-year-mortality. We included 3155 and 3756 in-patients for in-hospital and 1-year mortality respectively. At meta-regression analysis, a borderline correlation between PCI rate and in-hospital mortality (p 0.05) and a statistically significant correlation with 1-year mortality (p < 0.01) in T2MI patients were found. CONCLUSIONS: In a meta-regression analysis higher rates of PCI on T2MI in-patients were associated with lower mortality rates both in-hospital and at 1 year. Whether this association is related to the direct effect of PCI or better general conditions of T2MI patients undergoing a PCI still remains unclear.

Infection, atherothrombosis and thromboembolism beyond the COVID-19 disease: what similar in physiopathology and researches.

The recent Sars-Cov-2 pandemic (COVID-19) has led to growing research on the relationship between thromboembolism and Sars-Cov-2 infection. Nowadays, endothelial dysfunction, platelet activation, coagulation, and inflammatory host immune response are the subject of extensive researches in patients with COVID-19 disease. However, studies on the link between microorganisms or infections and thrombotic or thromboembolic events met fluctuating interest in the past. We, therefore, aimed to briefly summarize previous evidence on this topic, highlighting common points between previous data and what experienced today with SARS-COV2 infections.

Delirium in heart failure.

Despite relative frequency of delirium in elderly hospitalized heart failure patients, skills and expertise in managing such complication are usually poor for physicians and nurses facing this clinical condition. International guidelines on heart failure do not provide detailed indication for such clinical condition, and evidence on this topic is limited. A multi-disciplinary approach (cardiologists, internists, geriatricians, psychologists, and psychiatrists) is often required; this review will therefore focus on diagnosis and clinical management of delirium in heart failure patients from a multidisciplinary point of view.

Lower Major Bleeding Rates with Direct Oral Anticoagulants in Catheter Ablation of Atrial Fibrillation: an Updated Meta-analysis of Randomized Controlled Studies.

INTRODUCTION: Catheter ablation (CA) of atrial fibrillation (AF) is an important rhythm control strategy for patients with drug-refractory AF. We aimed to perform an updated meta-analysis of direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs) as uninterrupted anticoagulation in patients undergoing AF ablation to assess safety and efficacy of DOAC, after the publication of recent data on edoxaban in CA of AF. METHODS: We performed a meta-analysis of RCTs enrolling patients undergoing AF ablation. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% CIs for thromboembolic events, major bleeding (MB), and non-major bleeding (NMB). RESULTS: A total of 2118 patients have been included in the analysis. Compared with patients receiving VKA, patients receiving DOACs had a lower, although non-significant, risk of thromboembolic events (RR, 0.40; 95% CI, 0.09-1.76; P = 0.23). MB rates in patients treated with DOACs were statistically significantly lower than VKA (RR, 0.61; 95% CI, 0.39-0.93, P = 0.02). The incidence of NMB was not significantly different (RR, 0.98; 95% CI, 0.83-1.57, p n.s.). CONCLUSIONS: In a meta-analysis of RCTs, an uninterrupted DOACs strategy for CA of AF appears to be superior to uninterrupted VKA in terms of safety; a non-significant trend favoring DOACs in terms of efficacy is also evident.

Direct oral anticoagulants more effective than low-molecular-weight heparin for venous thrombo-embolism in cancer: an updated meta-analysis of randomized trials.

In the recent past, low-molecular-weight heparin (LMWH) was the first choice in the treatment of cancer related venous thrombo-embolism (VTE). Evidence supporting the preferential use of direct anticoagulants (DOACs) in patients with cancer, instead, is less robust so far. We therefore aimed to assess in an updated meta-analysis of randomized controlled trials whether the use of DOACs may be associated with a more favorable profile when compared to LMWH. We performed a meta-analysis of RCTs enrolling patients with VTE and cancer. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% CIs for recurrence of VTE, major bleeding, and mortality comparing subjects treated with DOACs with those with LMWH. After study selection, three RCTs (HOKUSAI-Cancer, SELECT-D and ADAM-VTE) were included for the analysis with an overall population of 1739 patients. DOACs patients had a lower incidence of 6-month recurrent VTE when compared to LMWHs (RR 0.56, 95% CI 0.40-0.79; p < 0.001). Incidence of major bleeding was not significantly different between DOACs and LMWH treated patients (RR 1.56, 95% CI 0.95-2.47, p = n.s.), and mortality rates were comparable (RR 1.03, 95% CI 0.91-2.47, p = n.s.). In a meta-analysis of RCTs therapy with DOACs was superior to LMWH in terms of efficacy and lower recurrence of VTE with a comparable safety profile in terms of bleeding events and complications.

Advanced heart failure: non-pharmacological approach.

Patients with advanced heart failure have poor prognosis despite traditional pharmacological therapies. The early identification of these subjects would allow them to be addressed on time in dedicated centers to select patients eligible for heart transplantation or ventricular assistance. In this article we will report the current management of these patients based on latest international guidelines, underlining some critical aspects, with reference to future perspectives.

Drug-Induced Pulmonary Arterial Hypertension: Mechanisms and Clinical Management.

Pulmonary arterial hypertension is a rare disease, with drug-induced causes even more uncommon, accounting for only 10% of cases in large registry series. Predisposing factors for drug-induced PAH have not been completely defined. This review summarizes drugs with definite, possible, or likely association to pulmonary hypertension and possible mechanisms involved in the occurrence of pulmonary hypertension. Controversies on mechanisms and on their role in pathophysiology were also shown. The possible synergism between drug abuse and HIV was discussed and the possible interactions of antiretroviral therapy in HIV subjects were analyzed. Furthermore, we reported clinical findings and possible management, specific for each class of drugs, in case of drug-induced PAH. Finally, we summarized into a unified algorithm possible management of drug-induced PAH.

Cardiopulmonary exercise test predicts right heart catheterization.

BACKGROUND: Right heart catheterization (RHC) is usually required to confirm the diagnosis of pulmonary artery hypertension (PAH). As an invasive test, RHC may be associated with possible complications, so noninvasive parameters able to predict PAH at RHC would be extremely useful. AIM: To ascertain possible correlations between cardiopulmonary exercise testing (CPET) and hemodynamic parameters at RHC indicative of pulmonary hypertension (PH). METHODS: Thirty-six consecutive outpatients with suspect of PAH underwent CPET and RHC; the intercept of ventilation (VEint) on the VE vs carbon dioxide production (VE/VCO2 ) and VE/VCO2 slope at CPET and diastolic pressure gradient (DPG), trans-pulmonary pressure gradient (TPG), mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) at RHC were assessed and compared. RESULTS: Ventilation VCO2 slope was directly related to DPG (r: .41, P: .019), TPG (r: .45, P: .01), mean pulmonary arterial pressure (mPAP, r: .36, P: .031), PVR (r: .41, P: .029), VEint and VE/VCO2 slope inversely related to DPG (r: -.63, P < .001), TPG (r: -.67, P < .001), mPAP (r: -.68, P < .001) and PVR (r: -.5, P < .001). CONCLUSION: In patients with suspected PAH, VEint during exercise and the VE/VCO2 slope might provide useful information to predict results of RHC. Their correlations with PVR and with DPG may be helpful in discriminating patients with isolated postcapillary PH from those with combined postcapillary and precapillary.

Why do some Children Get Sick with Recurrent Respiratory Infections?

Respiratory tract infections (RTI) represent a frequent condition, particularly among preschool children, with an important burden on the affected children and their families. It has been estimated that recurrent RTIs affect up to 25% of children during the first 4 years of life. These infections are mainly caused by viruses and are generally self-limiting. Social and environmental factors have been studied in determining the incidence of recurrent RTIs and the mostly recognized are precocious day care attendance, tobacco exposure and pollution. Primary immune defects, local anatomical factors, and genetic disorders such as primary ciliary dyskinesia or cystic fibrosis, may be also involved in recurrent RTIs of a subgroup of children, typically characterized by more severe and chronic symptoms. However, there is increasing awareness that RTIs have a complex pathophysiology and that some underrecognized factors, including genetic susceptibility to infections, low levels of some micronutrients, and respiratory microbiota might shape the probability for the child to develop RTIs. The sum (i.e. the number) of these factors may help in explaining why some children get sick for RTIs whilst other not. In some children iatrogenic factors, including improper use of antibiotics and NSAIDS or glucocorticoids might also aggravate this condition, further weakening the host's immune response and the possibly of establishing a "vicious circle". The present review aims to focus on several possible factors involved in influencing RTIs and to propose a unifying hypothesis on pathophysiological mechanisms of unexplained recurrent RTIs in children.

Flow Mediated Dilation in Systemic Sclerosis: Association with clinical findings, capillaroscopic patterns and endothelial circulating markers.

AIM: Endothelial dysfunction represents a key feature of the pathological process underlying micro and macro-vascular damage in Systemic Sclerosis (SSc). This study aims to improve knowledge of the physiopathology of vascular damage in SSc through the assessment of the endothelial dysfunction by Flow Mediated Dilation (FMD) and serum levels of circulating endothelial dysfunction markers and the correlation of macrovascular damage with clinical findings and microvascular capillaroscopic patterns. METHODS: 57 SSc patients and 37 healthy subjects were recruited. All included subjects underwent radial artery FMD test and Nailfold Video-Capillaroscopy; serum levels of Vascular Endothelial Growth Factor (VEGF), Vascular Cell Adhesion Molecule-1 (VCAM-1) and angiopoietin-2 were evaluated. RESULTS: Compared to healthy subjects, in SSc patients lower FMD and higher time needed to obtain the maximal FMD responsewere observed, whereas serum levels of VEGF, VCAM-1, and angiopoietin-2 were significantly higher. The impairment of FMD values was associated with disease duration, pulmonary arterial hypertension, and digital ulcers and correlates with greater microvascular damage evaluated by Nailfold Video-Capillaroscopy… An inverse relationship between VEGF, angiopoietin-2, VCAM-1 levels and FMD was observed, but only VEGF and angiopoietin-2 were significantly higher in patients with digital ulcers and pulmonary arterial hypertension. CONCLUSIONS: FMD ultrasound test and circulating levels of endothelial dysfuncion markers could be useful as biomarkers of vasculopathy and could be a helpful tool in the overall assessment of vascular injury in Systemic Sclerosis patients.

Distinct Profiles and New Pharmacological Targets for Heart Failure with Preserved Ejection Fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial condition with a variety of pathophysiological causes and morphological manifestations. The inclusion criteria and patient classification have become overly simplistic due to the customary differentiation regarding the ejection fraction (EF) cutoff. EF is considered a measure of systolic function; nevertheless, it only represents a portion of the true contractile state and has been shown to have certain limits due to methodological and hemodynamic irregularities. Methods: As a result, broader randomized clinical trials have yet to incorporate the most recent criteria for HFpEF diagnosis, leading to a lack of data consistency and confusion in interpreting the results. The primary variations between the bigger clinical trials published in this context concerning patient selection and echocardiographic characteristics were analyzed. For all these reasons, we aim to clarify the main features and clinical impact of HFpEF in a study combining imaging, bio-humoral analysis, and clinical history to identify the specific subgroups that respond better to tailored treatment. Results: Disparate clinical characteristics and a lack of uniform diagnostic standards may cause suboptimal therapeutic feedback. To optimize treatment, we suggest shifting the paradigm from the straightforward EF measurement to a more comprehensive model that considers additional information, such as structural traits, related disorders, and biological and environmental data. Therefore, by evaluating certain echocardiographic and clinical factors, a stepwise diagnostic procedure may be useful in identifying patients at high risk, subjects with early HFpEF, and those with evident HFpEF. Conclusions: The present assessment underscores the significance of the precision medicine approach in guaranteeing optimal patient outcomes by providing the best care according to each distinct profile.

Endothelial Function in Pulmonary Arterial Hypertension: From Bench to Bedside.

Pulmonary arterial hypertension is a complex pathology whose etiology is still not completely well clarified. The pathogenesis of pulmonary arterial hypertension involves different molecular mechanisms, with endothelial dysfunction playing a central role in disease progression. Both individual genetic predispositions and environmental factors seem to contribute to its onset. To further understand the complex relationship between endothelial and pulmonary hypertension and try to contribute to the development of future therapies, we report a comprehensive and updated review on endothelial function in pulmonary arterial hypertension.

Circulating Biomarkers in Pulmonary Arterial Hypertension: An Update.

Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH.

Right ventricular dysfunction in chronic heart failure: clinical laboratory and echocardiographic characteristics. (the RIVED-CHF registry).

BACKGROUND: Right ventricular dysfunction (RVD) and pulmonary hypertension have been recognized as two important prognostic features in patients with left side heart failure. Current literature does not distinguish between right heart failure (RHF) and RVD, and the two terms are used indiscriminately to describe pulmonary hypertension and RVD as well as clinical sign of RHF. Therefore, the right ventricle (RV) adaptation across the whole spectrum of left ventricular ejection fraction (LVEF) values has been poorly investigated. METHODS: This is a multicenter observational prospective study endorsed by the Italian Society of Cardiology aiming to analyze the concordance between the signs and symptoms of RHF and echocardiographic features of RVD. The protocol will assess patients affected by chronic heart failure in stable condition regardless of the LVEF threshold by clinical, laboratory, and detailed echocardiographic study. During the follow-up period, patients will be observed by direct check-up visit and/or virtual visits every 6 months for a mean period of 3 years. All clinical laboratory and echocardiographic data will be recorded in a web platform system accessible for all centers included in the study. RESULTS: The main study goals are: to investigate the concordance and discordance between clinical signs of RHF and RVD measured by ultrasonographic examination; to evaluate prognostic impact (in terms of cardiovascular mortality and heart failure hospitalization) of RVD and RHF during a mean follow-up period of 3 years; to investigate the prevalence of different right ventricular maladaptation (isolated right ventricular dilatation, isolated pulmonary hypertension, combined pattern) and the related prognostic impact. CONCLUSIONS: With this protocol, we would investigate the three main RVD patterns according to heart failure types and stages; we would clarify different RVD and pulmonary hypertension severity according to the heart failure types. Additionally, by a serial multiparametric analysis of RV, we would provide a better definition of RVD stage and how much is it related with clinical signs of RHF (ClinicalTrials.gov Identifier: NCT06002321).