Exposome in ischaemic heart disease: beyond traditional risk factors.

Ischaemic heart disease represents the leading cause of morbidity and mortality, typically induced by the detrimental effects of risk factors on the cardiovascular system. Although preventive interventions tackling conventional risk factors have helped to reduce the incidence of ischaemic heart disease, it remains a major cause of death worldwide. Thus, attention is now shifting to non-traditional risk factors in the built, natural, and social environments that collectively contribute substantially to the disease burden and perpetuate residual risk. Of importance, these complex factors interact non-linearly and in unpredictable ways to often enhance the detrimental effects attributable to a single or collection of these factors. For this reason, a new paradigm called the 'exposome' has recently been introduced by epidemiologists in order to define the totality of exposure to these new risk factors. The purpose of this review is to outline how these emerging risk factors may interact and contribute to the occurrence of ischaemic heart disease, with a particular attention on the impact of long-term exposure to different environmental pollutants, socioeconomic and psychological factors, along with infectious diseases such as influenza and COVID-19. Moreover, potential mitigation strategies for both individuals and communities will be discussed.

Intracoronary Imaging of Coronary Atherosclerotic Plaque: From Assessment of Pathophysiological Mechanisms to Therapeutic Implication.

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality worldwide. Several cardiovascular risk factors are implicated in atherosclerotic plaque promotion and progression and are responsible for the clinical manifestations of coronary artery disease (CAD), ranging from chronic to acute coronary syndromes and sudden coronary death. The advent of intravascular imaging (IVI), including intravascular ultrasound, optical coherence tomography and near-infrared diffuse reflectance spectroscopy has significantly improved the comprehension of CAD pathophysiology and has strengthened the prognostic relevance of coronary plaque morphology assessment. Indeed, several atherosclerotic plaque phenotype and mechanisms of plaque destabilization have been recognized with different natural history and prognosis. Finally, IVI demonstrated benefits of secondary prevention therapies, such as lipid-lowering and anti-inflammatory agents. The purpose of this review is to shed light on the principles and properties of available IVI modalities along with their prognostic significance.

Corticosteroid use, myocardial injury and in-hospital cardiovascular events in patients with community-acquired pneumonia.

BACKGROUND AND PURPOSE: Corticosteroids are often prescribed to community-acquired pneumonia (CAP) patients, but the relationship with major cardiovascular events (MACEs) is unclear. EXPERIMENTAL APPROACH: 541 CAP patients were recruited (334 males, mean age 71.9 ± 16.2 years). High-sensitivity troponin T (hs-cTnT) was measured at admission, during the hospital stay and at discharge. MACE occurrence was registered during a long-term follow-up. KEY RESULTS: Overall, 318 patients (59%) showed hs-cTnT elevation >99th percentile (>0.014 µg/L). Age, heart failure and the increasing quintiles of hs-cTnT (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.82-2.58, P < .001) predicted MACEs. Among patients with hs-cTnT >0.014 µg/L at admission, 102 patients (31%) were on corticosteroids and showed lower hs-cTnT increase (P = .021), (NADPH) oxidase-2 (Nox2) activation (P = .005) and incidence of MACEs than untreated ones (HR 0.64, 95% CI 0.41-0.97, P = .038); no effect of corticosteroids on MACEs was observed in CAP patients with normal troponin. In vitro study showed that glucocorticoids have an antioxidant effect via downregulation of Nox2 activity. CONCLUSION AND IMPLICATIONS: The study provides evidence that corticosteroid use is associated with lower increase of hs-cTnT and incidence of MACEs in CAP patients.

Low-voltage bridge strategy to guide cryoablation of typical and atypical atrioventricular nodal re-entry tachycardia in children: mid-term outcomes in a large cohort of patients.

AIMS: In the current literature, results of the low-voltage bridge (LVB) ablation strategy for the definitive treatment of atrioventricular nodal re-entry tachycardia (AVNRT) seem to be encouraging also in children. The aims of this study were (i) to prospectively evaluate the mid-term efficacy of LVB ablation in a very large cohort of children with AVNRT, and (ii) to identify electrophysiological factors associated with recurrence. METHODS AND RESULTS: One hundred and eighty-four children (42% male, mean age 13 ± 4 years) with AVNRT underwent transcatheter cryoablation guided by voltage mapping of the Koch's triangle. Acute procedural success was 99.2% in children showing AVNRT inducibility at the electrophysiological study. The overall recurrence rate was 2.7%. The presence of two LVBs, a longer fluoroscopy time and the presence of both typical and atypical AVNRT, were found to be significantly associated with an increased recurrence rate during mid-term follow-up. Conversely, there was no significant association between recurrences and patient's age, type of LVB, lesion length, number of cryolesions or catheter tip size. CONCLUSION: The LVB ablation strategy is very effective in AVNRT treatment in children. Recurrences are related to the complexity of the arrhythmogenic substrate.

Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction.

AIMS: Low-grade endotoxaemia is detectable in human circulation but its role in thrombosis is still unclear. METHODS AND RESULTS: We measured serum lipopolysaccharide (LPS) concentration, soluble P-selectin (sP-selectin), a marker of platelet activation, and zonulin, a marker of gut permeability, in peripheral circulation, coronary thrombi, and intracoronary blood of patients with ST-elevation myocardial infarction (STEMI, n = 50) and stable angina (SA) (n = 50), respectively, and in controls (n = 50). Experimental study was carried out in mice to assess if Escherichia coli-LPS (E. coli-LPS) possess thrombotic property. Coronary thrombi from STEMI showed higher concentrations of LPS, sP-selectin vs. intracoronary blood of SA and peripheral blood of controls (P < 0.001). Zonulin was higher in STEMI compared to the other two groups [4.57 (3.34-5.22); 2.56 (0.41-4.36); 1.95 (1.22-2.65) ng/mL; P < 0.001] and correlated with LPS (Rs = 0.585; P < 0.001). Escherichia coli DNA was positive in 34% of STEMI vs. 12% of SA and 4% of controls (P < 0.001). In a subgroup of 12 STEMI, immunohistochemical analysis of coronary thrombi showed positivity for leucocyte Toll-like receptor 4 (TLR4), cathepsin G, and LPS from E. coli in 100%, 80%, and 25% of samples, respectively. E. coli-LPS injected in mice to reach LPS concentrations like those detected in coronary thrombi was associated with enhanced artery thrombosis and platelet activation, an effect blunted by TLR4 inhibitor co-administration. In vitro study demonstrated that LPS from E. coli enhanced platelet aggregation via TLR4-mediated leucocyte cathepsin G activation. CONCLUSION: ST-elevation myocardial infarction patients disclose an enhanced gut permeability that results in LPS translocation in human circulation and eventually thrombus growth at site of artery lesion via leucocyte-platelet interaction.

Use of a Pediatric Syncope Unit Improves Diagnosis and Lowers Costs: A Hospital-Based Experience.

OBJECTIVES: To assess the effect of a dedicated pediatric syncope unit on the diagnostic and therapeutic management of children with suspected syncope. We also evaluated the effectiveness of the pediatric syncope unit model in decreasing unnecessary tests and hospitalizations, minimizing social costs, and improving diagnostic yield. STUDY DESIGN: This single-center cohort observational, prospective study enrolled 2278 consecutive children referred to Bambino Gesù Children's Hospital from 2012 to 2017. Characteristics of the study population, number and type of admission examinations, and diagnostic findings before the pediatric syncope unit was implemented (2012-2013) and after the pediatric syncope unit was implemented (2014-2015 and 2016-2017) were compared. RESULTS: The proportion of undefined syncope, number of unnecessary diagnostic tests performed, and number of hospital stay days decreased significantly (P < .0001), with an overall decrease in costs. A multivariable logistic regression analysis, adjusted for confounding variables (age, sex, number of diagnostic tests), the period after pediatric syncope unit (2016-2017) resulted as the best independent predictor of effectiveness for a defined diagnosis of syncope (P < .0001). CONCLUSIONS: Pediatric syncope unit organization with fast-tracking access more appropriate diagnostic tests is effective in terms of accuracy of diagnostic yield and reduction of costs.

Glucocorticoids impair platelet thromboxane biosynthesis in community-acquired pneumonia.

Previous reports suggest that community-acquired pneumonia (CAP) is associated with an enhanced risk of myocardial infarction (MI) and that enhanced platelet activation may play a role. Aims of this study were to investigate if urinary excretion of 11-dehydro-thromboxane (Tx) B2, a reliable marker of platelet activation in vivo, was elevated in CAP and whether glucocorticoid administration reduced platelet activation. Three-hundred patients hospitalized for CAP were recruited and followed-up until discharge. Within the first 2 days from admission, urinary 11-dehydro-TxB2 and serum levels of methylprednisolone and betamethasone were measured. 11-Dehydro-TxB2 was also measured in a control group of 150 outpatients, matched for age, sex, and comorbidities. Finally, in-vitro studies were performed to assess if glucocorticoids affected platelet activation, at the same range of concentration found in the peripheral circulation of CAP patients treated with glucocorticoids. Compared to controls, CAP patients showed significantly higher levels of 11-dehydro-TxB2 (110 [69-151] vs. 163 [130-225] pg/mg creatinine; p < 0.001). During the in-hospital stay, 31 patients experienced MI (10%). A COX regression analysis showed that 11-dehydro-TxB2 independently predicted MI (p = .005). CAP patients treated with glucocorticoids showed significantly lower levels of 11-dehydro-TxB2 compared to untreated ones (147 [120-201] vs. 176 [143-250] pg/mg creatinine; p < 0.001). In vitro, glucocorticoids-treated platelets showed a dose-dependent decrease of ADP-induced platelet aggregation, TxB2 production, cPLA2 phosphorylation and arachidonic acid release from the platelet membrane. In conclusion, platelet TxB2 is overproduced in CAP patients and may be implicated in MI occurrence. Glucocorticoids reduce platelet release of TxB2 in vitro and urinary excretion of 11-dehydro-TxB2 in vivo and may be a novel tool to decrease platelet activation in this setting.

Electroanatomic mapping-guided localization of alternative right ventricular septal pacing sites in children.

BACKGROUND: Alternative right ventricular (RV) sites (RVAPS) have been proposed to prevent or reduce RV pacing-induced left-ventricular (LV) dysfunction. Nonfluoroscopic 3D electroanatomic mapping systems (EAM) have been developed to guide cardiac catheter navigation and reduce fluoroscopy during electrophysiological procedures or pacemaker implantations. AIM: The aim of the study was to compare the results of EAM-guided permanent pacemaker implantation aiming at RVAPS with conventional fluoroscopic-guided implantation in RV apex (RVA) in children and adolescents. METHODS: A prospective, randomized analysis was performed on children/adolescents with complete atrioventricular block (CAVB) who underwent EAM-guided pacemaker and transvenous leads implantation into RVAPS (EAM-RVAPS) or conventional, fluoroscopic-guided implantation into RV apex (RVA). In EAM-RVAPS, a pacing map guided the implantation of ventricular leads in septal sites with narrower QRS. After implantation, LV contractility (ejection fraction [EF], Global Longitudinal Strain [GLS]) and synchrony were evaluated at 1-12 months. RESULTS: Twenty-one pediatric patients with CAVB, with (six patients) or without structural heart diseases, aged 4-16 (median 10.5) years, were divided in two groups: EAM-RVAPS (11 patients, four dual-chamber/DDD, seven single-chamber/VVIR pacemakers) and RVA (10 patients, one DDD/nine VVIR). The two groups did not show significant differences for preoperative parameters. EAM-RVAPS showed: preserved LVEF and synchrony (not significantly different than RVA), significantly lower GLS and radiation doses/exposures, in spite more complex procedures, significantly longer procedure times and narrower paced QRS than RVA. CONCLUSIONS: EAM-guided procedures have been useful to reduce radiation exposure and to localize RVAPS with narrower paced QRS and lower GLS than RVA.

Physiological pacing in young patients with complex congenital heart defects.

AIM: Young patients with operated complex congenital heart defects (CHD) often develop sinus node dysfunction (SND) requiring permanent pacing with rate-responsive function. Activity-driven sensors cannot account for nonmovement stress and cannot modulate heart rate physiologically. Closed Loop Stimulation (CLS, Biotronik, Berlin, Germany) is a physiological rate-responsive pacemaker based on the indirect measure of ventricular contractility. No data are available on the effects of such pacing strategy in young patients. METHODS: We report a series of nine patients with CHD and SND who underwent single-chamber CLS-atrial pacing with endocardial or epicardial lead. During the first 30 days, the pacemaker was programmed in AAI pacing mode and then was switched to CLS-atrial pacing mode. An in-hospital control was scheduled 1-2 months later to evaluate the CLS response to neurovegetative stresses (i.e., nonmovement stress [Stroop color test, handgrip] and exercise stress test) and Holter monitor. CLS pacing was compared with rate-responsive accelerometer-driven pacing (AAIR). RESULTS: At telemetric interrogation, CLS pacing showed a more physiological pattern of 24-h heart rate trends than accelerometer sensors. The data obtained during nonmovement/exercise stress demonstrated a physiological increase in the pacing rate with CLS, in synergy with spontaneous events. The accelerometer sensor histogram, during nonmovement stress, showed a "nonresponse" behavior (only lower rate events), and during exercise test showed most events in lower rate range. Holter monitoring showed increase of average and maximum heart rate compared with AAIR. CONCLUSION: In young CHD patients, endocardial/epicardial CLS-atrial pacing demonstrated a physiological response of heart rate to neurovegetative and physical stresses.

Bradyarrhythmias in Repaired Atrioventricular Septal Defects: Single-Center Experience Based on 34 Years of Follow-Up of 522 Patients.

Atrioventricular Septal Defect (AVSD) is a rare congenital heart defect (CHD) often associated with genetic syndromes, most commonly Down syndrome (DS). Over the last four decades, surgical repair has increased survival and improved quality of life in these patients. The prevalence of bradyarrhythmias namely, atrioventricular block (AVB) and sinus node dysfunction (SND) in AVSD is partially known. 522 cases with both partial and complete AVSD (38.7% with DS), undergoing intracardiac repair from 1982 to 2016 at our institution, were reviewed from our system database. 38 (7.3%) patients received permanent PM implantation for AVB (early or late) or SND. On one hand, AVB requiring PM was found in 26 (4.98%). This was further subdivided into early-onset 14 (2.6%) and late-onset AVB 12 (2.2%) (median 4 [IQR 1-7] years). On the other hand, 12 (2.3%) experienced late SND requiring PM (median 11 [IQR 3.5-15.2] years). Early and late AVB were independent from the type of AVSD (partial or complete), whereas the late SND was remarkably observed in complete AVSD compared to partial AVSD (p = 0.017). We classified the cohort into two main categories: DS (202, 38.7%) and non-DS (320, 61.3%). At Kaplan-Meier survival analysis, DS was significantly associated with late-onset bradyarrhythmias (p = 0.024). At Cox regression analysis, we identified DS as an independent predictor of PM implantation (HR 2.17). In conclusion, about 7% of repaired AVSD patients need PM implantation during follow-up. There are no differences in early and late AVB occurrence according to the type of AVSD. There is a higher incidence of late SND in repaired complete AVSD, with a later timing onset in patients with associated DS. Moreover, DS seems to be an independent predictor of PM implantation.

Low-grade endotoxemia and clotting activation in the early phase of pneumonia.

BACKGROUND AND OBJECTIVE: Community-acquired pneumonia (CAP) is associated with an increased risk of arterial and venous thrombosis but the underlying pathophysiological mechanisms are still unclear. We investigated if, in patients with CAP, a pro-thrombotic state does exist and its relationship with serum levels of endotoxins. METHODS: A total of 104 consecutive patients with CAP were prospectively recruited and followed up until discharge. At admission and at discharge, serum endotoxins, systemic markers of clotting activation and zonulin, a marker of gut permeability, were analysed. Hospitalized patients matched for gender, age and comorbidities but without infections were used as control. RESULTS: At admission, CAP patients showed higher plasma levels of F1+2 , a marker of thrombin generation (P = 0.023), and lower levels of protein C (PC; P < 0.001) and activated PC (aPC) (P < 0.001) compared with controls. At discharge, plasma levels of both PC and aPC significantly increased while F1+2 significantly decreased (P < 0.001). Baseline serum endotoxins and zonulin were higher in CAP patients than controls (P < 0.001) and significantly decreased at discharge; a significant correlation between serum endotoxins and zonulin was detected (R = 0.575; P < 0.001) CONCLUSION: This study provides the first evidence that CAP patients disclose an ongoing pro-thrombotic state and suggests a role for endotoxemia in determining enhanced thrombin generation.

Nox2 up-regulation is associated with an enhanced risk of atrial fibrillation in patients with pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) may be complicated by atrial fibrillation (AF) but the underlying mechanism is still unclear. Nox2-derived oxidative stress has been suggested to favour AF. METHODS: We consecutively enrolled 432 patients hospitalised for CAP. Nox2 activity, as assessed by serum levels of soluble Nox2 (sNox2-dp), was evaluated in each CAP patient. A 12-lead electrocardiography was repeated every 24 h. All patients were followed up until discharge. RESULTS: Forty-one patients with CAP (9.5%) experienced a new episode of AF within 24-72 h after hospital admission. Patients who experienced AF showed higher blood levels of sNox2-dp compared to those who did not (35.2±15.1 vs 27.0±12.5 pg/mL; p<0.001). Pneumonia Severity Index score (p=0.014), history of paroxysmal AF (p<0.001) and sNox2-dp (p=0.019) were independently associated with AF. At discharge, serum sNox2-dp levels were significantly decreased in the entire cohort (27.8±13.0 vs 21.9±6.8 pg/mL; p<0.001). Twenty-three out of 41 CAP patients with AF returned to sinus rhythm (56%); patients who remained in AF showed significantly higher baseline and discharge levels of sNox2-dp compared to those without AF (p<0.001) or with the 23 AF patients who returned to sinus rhythm (p<0.05). In vitro study showed that platelets or leucocytes incubated with endotoxin, at concentrations similar to those found in the circulation of CAP patients, elicited Nox2 up-regulation, suggesting endotoxin as a trigger of oxidative stress. CONCLUSIONS: AF may be detected in the early phase of CAP and is associated with Nox2 activation, suggesting a role for oxidative stress in promoting this cardiac arrhythmia. TRIAL REGISTRATION NUMBER: NCT01773863.

C2238 atrial natriuretic peptide molecular variant is associated with endothelial damage and dysfunction through natriuretic peptide receptor C signaling.

RATIONALE: C2238 atrial natriuretic peptide (ANP) minor allele (substitution of thymidine with cytosine in position 2238) associates with increased risk of cardiovascular events. OBJECTIVE: We investigated the mechanisms underlying the vascular effects of C2238-αANP. METHODS AND RESULTS: In vitro, human umbilical vein endothelial cell were exposed to either wild-type (T2238)- or mutant (C2238)-αANP. Cell survival and apoptosis were tested by Trypan blue, annexin V, and cleaved caspase-3 assays. C2238-αANP significantly reduced human umbilical vein endothelial cell survival and increased apoptosis. In addition, C2238-αANP reduced endothelial tube formation, as assessed by matrigel. C2238-αANP did not differentially modulate natriuretic peptide receptor (NPR)-A/B activity with respect to T2238-αANP, as evaluated by intracellular cGMP levels. In contrast, C2238-αANP, but not T2238-αANP, markedly reduced intracellular cAMP levels in an NPR-C-dependent manner. Accordingly, C2238-αANP showed higher affinity binding to NPR-C, than T2238-αANP. Either NPR-C inhibition by antisense oligonucleotide or NPR-C gene silencing by small interfering RNA rescued survival and tube formation of human umbilical vein endothelial cell exposed to C2238-αANP. Similar data were obtained in human aortic endothelial cell with NPR-C knockdown. NPR-C activation by C2238-αANP inhibited the protein kinase A/Akt1 pathway and increased reactive oxygen species. Adenovirus-mediated Akt1 reactivation rescued the detrimental effects of C2238-αANP. Overall, these data indicate that C2238-αANP affects endothelial cell integrity through NPR-C-dependent inhibition of the cAMP/protein kinase A/Akt1 pathway and increased reactive oxygen species production. Accordingly, C2238-αANP caused impairment of acetylcholine-dependent vasorelaxation ex vivo, which was rescued by NPR-C pharmacological inhibition. Finally, subjects carrying C2238 minor allele showed early endothelial dysfunction, which highlights the clinical relevance of our results. CONCLUSIONS: C2238-αANP reduces endothelial cell survival and impairs endothelial function through NPR-C signaling. NPR-C targeting represents a potential strategy to reduce cardiovascular risk in C2238 minor-allele carriers.

Total adiponectin is inversely associated with platelet activation and CHA2DS2-VASc score in anticoagulated patients with atrial fibrillation.

BACKGROUND: Adiponectin (APN) possesses anti-inflammatory and antiatherogenic effects. Atrial fibrillation (AF) is burdened by enhanced systemic inflammation and platelet activation, as documented by increased blood levels of soluble CD40L (sCD40L). The interplay between APN and platelet activation in AF is still undefined. MATERIALS AND METHODS: Circulating levels of APN and sCD40L were measured in 257 anticoagulated nonvalvular AF patients. Exclusion criteria were as follows: prosthetic heart valves, cardiac revascularization in the previous year, severe cognitive impairment, chronic infectious or autoimmune diseases, and active cancer. RESULTS: Mean age was 72.9 (±8.7) years and 41.6% were female. Serum APN and plasmatic sCD40L were inversely correlated (R -0.626, P < 0.001). A progressive increase of sCD40L across tertiles of CHA2DS2-VASc score was observed (rS 0.473, P < 0.001), whilst APN was inversely correlated (rS -0.463, P < 0.001). A multivariable linear regression analysis showed that CHA2DS2-VASc score (B -0.227, P < 0.001) and sCD40L (B -0.524, P < 0.001) correlated to APN. CONCLUSIONS: AF patients at high risk of stroke disclose low and high levels of APN and sCD40L, respectively, suggesting a role for APN if it favors platelet activation in vivo in this clinical setting. Enhancing APN levels may be a future goal to reduce the risk of vascular outcomes in AF patients.

Low-grade endotoxemia is associated with cardiovascular events in community-acquired pneumonia.

OBJECTIVES: Community-acquired pneumonia (CAP) is associated with low-grade endotoxemia but its relationship with cardiovascular events (CVE) has not been investigated. METHODS: We evaluated the incidence of CVE including myocardial infarction, stroke, and cardiovascular death in 523 adult patients hospitalized for CAP. Serum lipopolysaccharide (LPS) and zonulin, a marker of gut permeability, were analyzed in the cohort, that was followed-up during hospitalization and up to 43 months thereafter. RESULTS: During the hospital-stay, 55 patients experienced CVE with a progressive increase from the lowest (0.6%) to highest LPS tertile (23.6%, p < 0.001). Logistic regression analyses showed that higher LPS tertile was independently associated with CVE; LPS significantly correlated with age, hs-CRP and zonulin. In a sub-group of 23 CAP patients, blood E. coli DNA was higher in patients compared to 24 controls and correlated with LPS. During the long-term follow-up, 102 new CVE were registered; the highest tertile of LPS levels was associated with incident CVE; Cox regression analysis showed that LPS tertiles, age, history of CHD, and diabetes independently predicted CVE. CONCLUSIONS: In CAP low-grade endotoxemia is associated to short- and long-term risk of CVE. Further study is necessary to assess if lowering LPS by non-absorbable antibiotics may result in improved outcomes.

Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease.

Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the ATP2A2 gene that causes an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far, although a high incidence of neuropsychiatric syndromes suggests an involvement of the central nervous system. We report that the pathogenic ATP2A2 gene variant c.118G>A may cause cardiac involvement in patients with DD, consisting of keratinocyte and cardiomyocyte disconnection. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsies because cardiac dilatation and dysfunction appeared several decades after skin manifestations. Keratinocyte disconnection was paralleled by cardiomyocyte separation at the lateral junction. Cardiomyocyte separation was associated with cell disarray, sarcoplasmic reticulum dilatation, and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules are associated with chest pain, severe muscle exhaustion, and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation. Cardiac pathologic changes are similar to those documented in the skin, including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors that enhance SERCA2 protein phosphorylation may substantially attenuate the symptoms.

Type and dimensions can predict ventricular arrhythmias and cardiac death in primary benign cardiac tumors in children.

Despite being extremely rare in children, primary benign cardiac tumors can cause malignant ventricular arrhythmias (VA) or even sudden cardiac death. To assess the predictors of cardiovascular death and malignant VAs, we designed a retrospective single-center study enrolling paediatric patients. We defined as primary outcome a composite of cardiovascular death, sustained VT, ventricular fibrillation and rapid, symptomatic non-sustained VT. Our secondary endpoint was to assess the prevalence of clinically significant arrhythmias in our population. METHODS AND RESULTS: We fitted a multivariate Cox regression model to assess the predictors of the primary outcome. Over a period of 38 years, a total of 97 children were enrolled in the study. Among them, there were 73 rhabdomyomas, 13 fibromas, 3 myxomas, 3 teratomas, 1 lipoma, 2 haemangiomas and 2 fibroelastomas. Over a median follow up of 10.53 years, 16 patients met the primary outcome. Kaplan Meier unadjusted survival estimates showed that tumor dimensions larger than 2.3 cm and diagnosis of fibroma predicted worse outcomes compared with smaller tumors or other histotypes, (log rank p < 0.0002 and < 0.0001 respectively). In multivariate Cox proportional hazards analysis, diagnosis of fibroma and tumor dimensions were independently associated to the primary endpoint (HR: 5.06, 95 %CI (1.3-19); and 1.26 • (1.05-11), respectively). Clinically significant arrhythmias were reported in 24.5 % of the study population. CONCLUSIONS: Among paediatric primary cardiac tumors, type and dimensions may predict the hazard of malignant VAs and cardiac death.

Left Ventricular Adverse Remodeling in Ischemic Heart Disease: Emerging Cardiac Magnetic Resonance Imaging Biomarkers.

Post-ischemic left ventricular (LV) remodeling is a biologically complex process involving myocardial structure, LV shape, and function, beginning early after myocardial infarction (MI) and lasting until 1 year. Adverse remodeling is a post-MI maladaptive process that has been associated with long-term poor clinical outcomes. Cardiac Magnetic Resonance (CMR) is the best tool to define adverse remodeling because of its ability to accurately measure LV end-diastolic and end-systolic volumes and their variation over time and to characterize the underlying myocardial changes. Therefore, CMR is the gold standard method to assess in vivo myocardial infarction extension and to detect the presence of microvascular obstruction and intramyocardial hemorrhage, both associated with adverse remodeling. In recent times, new CMR quantitative biomarkers emerged as predictive of post-ischemic adverse remodeling, such as T1 mapping, myocardial strain, and 4D flow. Additionally, CMR T1 mapping imaging may depict infarcted tissue and assess diffuse myocardial fibrosis by using surrogate markers such as extracellular volume fraction, which may predict functional recovery or risk stratification of remodeling. Finally, there is emerging evidence supporting the utility of intracavitary blood flow kinetic energy and hemodynamic features assessed by the 4D flow CMR technique as early predictors of remodeling.

Microvascular Complications Are Associated With Coronary Collateralization in Type 2 Diabetes and Chronic Occlusion.

CONTEXT: Coronary collateral (CC) vessel development appears to be protective with regard to adverse cardiovascular events and survival in patients with coronary chronic total occlusion (CTO). The influence of type 2 diabetes mellitus (T2DM) on CC growth has been controversial. In particular, the role of diabetic microvascular complications (DMC) in determining coronary collateralization has not been elucidated. OBJECTIVE: To investigate whether patients with DMC presented differences in CC vessel presence and grading as compared with patients without DMC. METHODS: We conducted a single-center observational study, including consecutive T2DM patients, without previous cardiovascular history, undergoing a clinically indicated coronary angiography for chronic coronary syndrome (CCS) and angiographic evidence of at least one CTO. Patients were subdivided into 2 study groups according to the presence/absence of at least one DMC (neuropathy, nephropathy, or retinopathy). The presence and grading of angiographically visible CC development from the patent vessels to the occluded artery were assessed using the Rentrop classification. RESULTS: We enrolled 157 patients (mean age 68.6 ± 9.8 years; 120 [76.4%] men). Patients with DMC (75 [47.8%]) had a higher prevalence of CC (69 [92.0%] vs 62 [75.6%], P = .006) and high-grade CC (55 [73.3%] vs 39 [47.6%], P = .001) compared with those without, and we found a positive association between the number of DMC in each patient and the prevalence of high-grade CC. CONCLUSION: Among T2DM patients with coronary CTO, the presence of DMC was associated with a high CC development.