Targeting Collagen Pathways as an HFpEF Therapeutic Strategy.

Heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous clinical syndrome. The prevalence is expected to increase in the coming years, resulting in heart failure with reduced ejection fraction (HFrEF). This condition poses a burden to the global health care system as the number of patients affected by this condition is constantly increasing due to a rising average lifespan. The absence of validated drugs effective in reducing hospitalization rates and mortality may reflect the impossibility of applying a one size fits all approach as in HFrEF, heading for a personalized approach. Available evidence demonstrated the link between collagen quantity and quality alterations, and cardiac remodeling. In the context of fibrosis, collagen cross-linking is strictly involved, displaying two types of mechanisms: enzymatic and non-enzymatic. In the murine model, enzymatic inhibition of fibrosis-inducing protease-activated receptor-1 (PAR1) and transforming growth factor (TGF)-ß signaling appeared to reduce cardiac fibrosis. On the other hand, in the case of non-enzymatic cross-linking, sodium glucose co-transporter type 2 inhibitors (SGLT2is), appeared to counteract the deposition of advanced glycation end-products (AGEs), which in turn contributed to ventricular remodeling. In this review, we address the mechanisms associated with collagen alterations to identify potential targets of cardiac fibrosis in HFpEF patients.

Microbial signature of plaque and gut in acute coronary syndrome.

Gut microbiota is an emerging editable cardiovascular risk factor. We aim to investigate gut and coronary plaque microbiota, using fecal samples and angioplasty balloons from patients with acute coronary syndrome (ACS), chronic coronary syndrome (CCS) and control subjects. We examined bacterial communities in gut and coronary plaques by 16S rRNA sequencing and we performed droplet digital PCR analysis to investigate the gut relative abundance of the bacterial genes CutC/CntA involved in trimethylamine N-oxide synthesis. Linear discriminant analysis effect size (LEfSe) at the genus and species levels displayed gut enrichment in Streptococcus, Granulicatella and P. distasonis in ACS compared with CCS and controls; Roseburia, C. aerofaciens and F. prausnitzii were more abundant in controls than in patients. Principal component analysis (PCA) of 41 differentially abundant gut taxa showed a clustering of the three groups. In coronary plaque, LEfSe at the genus level revealed an enrichment of Staphylococcus and Streptococcus in ACS, and Paracoccus in CCS, whereas PCA of 15 differentially abundant plaque taxa exhibited clustering of ACS and CCS patients. CutC and CntA genes were more abundant in ACS and CCS than in controls while no significant difference emerged between ACS and CCS. Our results indicate that ACS and CCS exhibit a different gut and plaque microbial signature, suggesting a possible role of these microbiotas in coronary plaque instability.

Cardiovascular adverse events-related to GnRH agonists and GnRH antagonists: analysis of real-life data from Eudra-Vigilance and Food and Drug Administration databases entries.

INTRODUCTION AND OBJECTIVES: GnRH agonists and GnRH antagonists are two of the mainstays of hormonal therapy (HT) for prostate cancer (PCa). These drugs are at increased risk of cardiovascular (CV) adverse events (AEs). Aim of our study was to compare real-life data on AEs associated with GnRH agonists and GnRH antagonists based on Eudra-Vigilance (EV) and Food and Drug Administration (FDA) reported AEs. MATERIALS AND METHODS: EV and FDA databases were queried and the number of CV adverse events (AEs) for degarelix, buserelin, goserelin, leuprorelin, triptorelin until September 2021 were recorded. Specific CV AEs were recorded and data were analyzed per age and severity. pooled relative risk (PRR) was used to compare data between drugs. RESULTS: CV events were reported in 315/5128 (6%) for Degarelix, in 55/628 for Buserelin (9%), in 843/12,145 (7%) for Goserelin, in 3395/71,160 (5%) for Leuprorelin and in 214/4969 (5%) for Triptorelin. In terms of specific CV disorders, Degarelix presented lower risk of hypertension (PRR 0.60 (95% CI 0.37-0.98), p = 0.04), of myocardial infarction (PRR 0.05 (95% CI 0.01-0.39), p < 0.01) and thrombosis (PRR 0.14 (0.02-1.07), p = 0.06) when compared to GnRH agonists. Overall, younger patients (<65 years) presented a very low risk of CV AEs. Side effects were classified as serious in 90-96% of the cases. Fatal AEs were 5-20% over the CV AEs and 0.2-1% over the total AEs. CONCLUSIONS: Real-life data are consistent with registry studies regarding side effects related to HT. Real-life data suggest GnRH agonists are associated with higher CV AEs when compared to GnRH antagonists. Clinicians should consider these data when prescribing HT especially in patients with CV comorbidities.

Human skin processing affects clinical outcome in allograft recipients.

Skin allografts represent a milestone in burn patient treatment. However, skin procurement is still burdened by high rates of contamination, and validation procedures have not yet been standardized. In addition, it is not clear if tissue viability affects allograft skin outcomes. In 2120 skin samples from 610 donors, a retrospective analysis was performed to identify donor and procurement variables associated with bacterial contamination and tissue viability. Post-processing contamination was associated significantly with the donor type, cause of death, length of hospitalization, procurement site, surgeon, interval between procurement and banking, and decontamination method. Tissue viability appeared to be negatively associated with freezing. In two series of skin allograft recipients (155 and 195 patients), we evaluated the role of skin characteristics and procurement variables on clinical outcomes. We found that the length of hospitalization was associated significantly with donor age. Procalcitonin and PCR values in allograft recipients were correlated with the decontamination method. No significant associations were observed between tissue viability and clinical outcomes (length of hospitalization, cause of donor death, or inflammatory parameters) after allograft transplantation. In these large case series, we identified donor and procurement variables that may affect allograft skin recipients. The decontamination method appeared to be a critical step for skin allograft requiring better standardization.

Restricted T-Cell Repertoire in the Epicardial Adipose Tissue of Non-ST Segment Elevation Myocardial Infarction Patients.

Aims: Human epicardial adipose tissue, a dynamic source of multiple bioactive factors, holds a close functional and anatomic relationship with the epicardial coronary arteries and communicates with the coronary artery wall through paracrine and vasocrine secretions. We explored the hypothesis that T-cell recruitment into epicardial adipose tissue (EAT) in patients with non-ST segment elevation myocardial infarction (NSTEMI) could be part of a specific antigen-driven response implicated in acute coronary syndrome onset and progression. Methods and Results: We enrolled 32 NSTEMI patients and 34 chronic coronary syndrome (CCS) patients undergoing coronary artery bypass grafting (CABG) and 12 mitral valve disease (MVD) patients undergoing surgery. We performed EAT proteome profiling on pooled specimens from three NSTEMI and three CCS patients. We performed T-cell receptor (TCR) spectratyping and CDR3 sequencing in EAT and peripheral blood mononuclear cells of 29 NSTEMI, 31 CCS, and 12 MVD patients. We then used computational modeling studies to predict interactions of the TCR beta chain variable region (TRBV) and explore sequence alignments. The EAT proteome profiling displayed a higher content of pro-inflammatory molecules (CD31, CHI3L1, CRP, EMPRINN, ENG, IL-17, IL-33, MMP-9, MPO, NGAL, RBP-4, RETN, VDB) in NSTEMI as compared to CCS (P < 0.0001). CDR3-beta spectratyping showed a TRBV21 enrichment in EAT of NSTEMI (12/29 patients; 41%) as compared with CCS (1/31 patients; 3%) and MVD (none) (ANOVA for trend P < 0.001). Of note, 11/12 (92%) NSTEMI patients with TRBV21 perturbation were at their first manifestation of ACS. Four patients with the first event shared a distinctive TRBV21-CDR3 sequence of 178 bp length and 2/4 were carriers of the human leukocyte antigen (HLA)-A*03:01 allele. A 3D analysis predicted the most likely epitope able to bind HLA-A3*01 and interact with the TRBV21-CDR3 sequence of 178 bp length, while the alignment results were consistent with microbial DNA sequences. Conclusions: Our study revealed a unique immune signature of the epicardial adipose tissue, which led to a 3D modeling of the TCRBV/peptide/HLA-A3 complex, in acute coronary syndrome patients at their first event, paving the way for epitope-driven therapeutic strategies.

Overview of mitral valve replacement versus mitral valve repair due to ischemic papillary muscle rupture: A meta-analysis inspired by a case report.

BACKGROUND: Papillary muscle rupture (PMR) is an infrequent but catastrophic complication after myocardial infarction (MI). Surgical procedure is considered the optimal treatment, despite high risk. However, the gold standard technique is still a major dilemma. Therefore, a meta-analysis was carried out to assess and provide an overview comparing mitral valve replacement (MVR) and mitral valve repair (MVr) for PMR post-MI. METHODS: A systematic literature search was performed. Data were extracted and verified using a standardized data extraction form. Meta-analysis was realized mainly using RevMan 5.4 software. RESULTS: From four observational studies 1640 patients were identified; 81% underwent MVR and 19% MVr. Operative mortality results were significantly higher in MVR group than the MVr group. MVR was performed under emergency conditions and patients admitted in cardiogenic shock or who required the use of mechanical cardiac support underwent MVR. MVr had shorter time of hospitalization and similar incidence of postoperative complications than MVR. No significant differences existed between the two procedures regarding cardiopulmonary bypass time. CONCLUSIONS: Mitral valve repair appears to be a viable alternative to MVR for post-MI PMR, given that it has lower operative mortality, shorter time of hospitalization and similar incidence of short-term postoperative complications than MVR. However, it needs to be pointed out that MVR was associated with the most critical clinical condition following PMR. There is uncertainty regarding the overall survival and improvement of the quality of life between the procedures. Nevertheless, further completed investigation is required.

Advances and Challenges in Biomarkers Use for Coronary Microvascular Dysfunction: From Bench to Clinical Practice.

Coronary microvascular dysfunction (CMD) is related to a broad variety of clinical scenarios in which cardiac microvasculature is morphologically and functionally affected, and it is associated with impaired responses to vasoactive stimuli. Although the prevalence of CMD involves about half of all patients with chronic coronary syndromes and more than 20% of those with acute coronary syndrome, the diagnosis of CMD is often missed, leading to the underestimation of its clinical importance. The established and validated techniques for the measurement of coronary microvascular function are invasive and expensive. An ideal method to assess endothelial dysfunction should be accurate, non-invasive, cost-effective and accessible. There are varieties of biomarkers available, potentially involved in microvascular disease, but none have been extensively validated in this heterogeneous clinical population. The investigation of potential biomarkers linked to microvascular dysfunction might improve the assessment of the diagnosis, risk stratification, disease progression and therapy response. This review article offers an update about traditional and novel potential biomarkers linked to CMD.

In systemic sclerosis, the TAPSE/sPAP ratio can be used in addition to the DETECT algorithm for pulmonary arterial hypertension diagnosis.

OBJECTIVE: Early detection of pulmonary arterial hypertension (PAH) is crucial for improving patient outcomes. The aim of this study was to compare the positive predictive value (PPV) of the echocardiography-derived tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio with that of the DETECT algorithm for PAH screening in a cohort of SSc patients. METHODS: Fifty-one SSc patients were screened for PAH using the DETECT algorithm and echocardiography. RESULTS: Echocardiography was recommended by the DETECT algorithm step 1 in 34 patients (66.7%). Right heart catheterization (RHC) was recommended by the DETECT algorithm step 2 in 16 patients (31.4%). PAH was confirmed by RHC in 5 patients. The DETECT algorithm PPV was 31.3%. The TAPSE/sPAP ratio was higher in SSc patients not referred for RHC than in SSc patients referred for RHC according to the DETECT algorithm step 2 [0.83 (0.35-1.40) mm/mmHg vs 0.74 (0.12-1.09) mm/mmHg, P < 0.05]. Using a cut-off of 0.60 mm/mmHg, 8 (15.7%) SSc patients had a TAPSE/sPAP ratio of ≤0.60 mm/mmHg. PAH was confirmed by RHC in 5 patients. The PPV of TAPSE/sPAP was 62.5%. In multiple regression analysis, TAPSE/sPAP was associated with age [ß coefficient = -0.348 (95% CI: -0.011, -0.003); P < 0.01], DETECT algorithm step 1 [ß coefficient = 1.023 (95% CI: 0.006, 0.024); P < 0.01] and DETECT algorithm step 2 (ß coefficient = -1.758 [95% CI: -0.059, -0.021]; P < 0.0001). CONCLUSION: In SSc patients with a DETECT algorithm step 2 total score of >35, the TAPSE/sPAP ratio can be used to further select patients requiring RHC to confirm PAH diagnosis.

The prognostic role of the echocardiographic tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/sPAP) ratio and its relationship with NT-proANP plasma level in systemic sclerosis.

Background: The tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/sPAP) ratio is an echocardiographic estimation of the right ventricle to pulmonary artery (RV/PA) coupling, with a validated prognostic role in different clinical settings. Systemic sclerosis (SSc) patients without evident cardiovascular involvement frequently display subtle RV impairment. The amino-terminal atrial natriuretic peptide (NT-proANP) plasma level relates to SSc disease progression and mortality. We aimed to assess the prognostic value of the TAPSE/sPAP ratio and its relationship with NT-proANP plasma level in SSc patients without overt cardiovascular involvement. Methods: We retrospectively analysed 70 SSc consecutive patients, with no clinical evidence of cardiovascular involvement or pulmonary hypertension (PH), and 30 healthy controls (HC) in a retrospective, single-centre study. All SSc patients underwent recurrent clinical and echocardiographic assessments and NT-proANP plasma level was assessed at baseline. SSc-related cardiovascular events and deaths were extracted during a 6-year follow-up. The complete work-up for the diagnosis, treatment and management of PH performed along the 6 years of follow-up referred to the 2015 European Society of Cardiology guidelines. Results: Systemic sclerosis patients showed lower TAPSE/sPAP ratio at baseline compared to HC [SSc median value = 0.71 mm/mmHg, (IQR 0.62-0.88) vs. HC median value = 1.00 mm/mmHg, (IQR 0.96-1.05); p < 0.001]. Multivariable Cox analysis revealed TAPSE/sPAP ratio as an independent predictor for SSc-related cardiovascular events [HR = 3.436 (95% CI 1.577-7.448); p = 0.002] and mortality [HR = 3.653 (95% CI 1.712-8.892); p = 0.014]. The value of TAPSE/sPAP ratio < 0.7 mm/mmHg was identified as an optimal cut-off for predicting adverse outcomes (p < 0.001) by receiver operating characteristic (ROC) analyses. NT-proANP level significantly related to TAPSE/sPAP ratio (r = 0.52, p < 0.001). TAPSE/sPAP ratio combined with NT-proANP showed an overall significant prognostic role in this SSc population, confirmed by Kaplan-Meier analysis (Log rank p < 0.001). Conclusion: The TAPSE/sPAP ratio, as an index of RV/PA coupling, is an affordable predictor of cardiovascular events and mortality in SSc and, combined with NT-proANP level, may improve the clinical phenotyping and prognostic stratification of SSc patients.

A Novel Monocyte Subset as a Unique Signature of Atherosclerotic Plaque Rupture.

The evaluation of monocyte subset distribution among acute coronary syndrome (ACS) patients according to culprit coronary plaque morphology has never been explored. We evaluated whether there were significant differences in frequency of circulating monocyte subsets isolated from ACS patients according to optical coherence tomography (OCT) investigation of plaque erosion and rupture. We enrolled 74 patients with non-ST-elevation ACS (NSTE-ACS), 21 of them underwent OCT investigation of the culprit coronary plaque and local macrophage infiltration (MØI) assessment. As control, we enrolled 30 chronic coronary syndrome (CCS) patients. We assessed the frequency of monocyte subsets in the whole study population, in reliance on their CD14 and CD16 expression (classical, CM: CD14++CD16-; intermediates, IM: CD14++CD16+; non-classical, NCM: CD14+CD16++). Then, we tested the effect of lipopolysaccharide (LPS) (a CD14 ligand) on peripheral blood mononuclear cells (PBMCs) of NSTE-ACS patients, quantifying the inflammatory cytokine levels in cell-culture supernatants. Our data proved that monocyte subsets isolated from NSTE-ACS patients represent a peculiar biological signature of the pathophysiological mechanism lying beneath atherosclerotic plaque with a ruptured fibrous cap (RFC) as compared with plaque erosion. Moreover, the magnitude of LPS-mediated effects on IL-1ß, IL-6, and IL-10 cytokine release in cell-culture supernatants appeared to be greater in NSTE-ACS patients with RFC. Finally, we described a fourth monocyte population never explored before in this clinical setting (pre-classical monocytes, PCM: CD14+CD16-) that was prevalent in NSTE-ACS patients as compared with CCS and, especially, in patients with RFC and culprit plaque with MØI.

Novel Biomarkers in Heart Failure: New Insight in Pathophysiology and Clinical Perspective.

Heart failure (HF) is a complex clinical syndrome with a huge social burden in terms of cost, morbidity, and mortality. Brain natriuretic peptide (BNP) appears to be the gold standard in supporting the daily clinical management of patients with HF. Novel biomarkers may supplement BNP to improve the understanding of this complex disease process and, possibly, to personalize care for the different phenotypes, in order to ameliorate prognosis. In this review, we will examine some of the most promising novel biomarkers in HF. Inflammation plays a pivotal role in the genesis and progression of HF and, therefore, several candidate molecules have been investigated in recent years for diagnosis, prognosis, and therapy monitoring. Noncoding RNAs are attractive as biomarkers and their potential clinical applications may be feasible in the era of personalized medicine. Given the complex pathophysiology of HF, it is reasonable to expect that the future of biomarkers lies in the application of precision medicine, through wider testing panels and "omics" technologies, to further improve HF care delivery.

Prevalence and characteristics of myocardial injury during COVID-19 pandemic: A new role for high-sensitive troponin.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic disease that is causing a public health emergency. Characteristics and clinical significance of myocardial injury remain unclear. METHODS: This retrospective single-center study analyzed 189 patients who received a COVID-19 diagnosis out of all 758 subjects with a high sensitive troponin I (Hs-TnI) measurement within the first 24 h of admission at the Policlinico A.Gemelli (Rome, Italy) between February 20th 2020 to April 09th 2020. RESULTS: The prevalence of myocardial injury in our COVID-19 population is of 16%. The patients with cardiac injury were older, had a greater number of cardiovascular comorbidities and higher values of acute phase and inflammatory markers and leucocytes. They required more frequently hospitalization in Intensive Care Unit (10 [32.3%] vs 18 [11.4%]; p = .003) and the mortality rate was significantly higher (17 [54.8%] vs. 15 [9.5%], p < .001). Among patients in ICU, the subjects with myocardial injury showed an increase need of endotracheal intubation (8 out of 9 [88%] vs 7 out of 19[37%], p = .042). Multivariate analyses showed that hs-TnI can significantly predict the degree of COVID-19 disease, the intubation need and in-hospital mortality. CONCLUSIONS: In this study we demonstrate that hs-Tn can significantly predict disease severity, intubation need and in-hospital death. Therefore, it may be reasonable to use Hs-Tn as a clinical tool in COVID-19 patients in order to triage them into different risk groups and can play a pivotal role in the detection of subjects at high risk of cardiac impairment during both the early and recovery stage.