Effects of sacubitril-valsartan on aging-related cardiac dysfunction.

Heart failure (HF) remains a huge medical burden worldwide, with aging representing a major risk factor. Here, we report the effects of sacubitril/valsartan, an approved drug for HF with reduced EF, in an experimental model of aging-related HF with preserved ejection fraction (HFpEF). Eighteen-month-old female Fisher 344 rats were treated for 12 weeks with sacubitril/valsartan (60 mg/kg/day) or with valsartan (30 mg/kg/day). Three-month-old rats were used as control. No differential action of sacubitril/valsartan versus valsartan alone, either positive or negative, was observed. The positive effects of both sacubitril/valsartan and valsartan on cardiac hypertrophy was evidenced by a significant reduction of wall thickness and myocyte cross-sectional area. Contrarily, myocardial fibrosis in aging heart was not reduced by any treatment. Doppler echocardiography and left ventricular catheterization evidenced diastolic dysfunction in untreated and treated old rats. In aging rats, both classical and non-classical renin-angiotensin-aldosterone system (RAAS) were modulated. In particular, with respect to untreated animals, both sacubitril/valsartan and valsartan showed a partial restoration of cardioprotective non-classical RAAS. In conclusion, this study evidenced the favorable effects, by both treatments, on age-related cardiac hypertrophy. The attenuation of cardiomyocyte size and hypertrophic response may be linked to a shift towards cardioprotective RAAS signaling. However, diastolic dysfunction and cardiac fibrosis persisted despite of treatment and were accompanied by myocardial inflammation, endothelial activation, and oxidative stress.

Role of CES1 and ABCB1 Genetic Polymorphisms on Functional Response to Dabigatran in Patients with Atrial Fibrillation.

Background: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). Methods: A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and CES1 rs2244613, CES1 rs8192935 and ABCB1 rs4148738 SNP while on two different dabigatran doses (110 and 150 mg BID). Results: A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different CES1 rs2244613 and CES1 rs8192935 genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44-111) ng/mL in patients with the ABCB1 rs4148738 heterozygous CT genotype vs. 127 (85-147) ng/mL in the wild-type CC genotype vs. 110 (47-159) ng/mL in the mutant trait TT genotype (p = 0.048). In patients with the ABCB1 rs4148738 CT genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04-9.88 (p = 0.042). Conclusions: ABCB1 rs4148738 CT heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.

Voltage and propagation mapping: New tools to improve successful ablation of atrioventricular nodal reentry tachycardia.

INTRODUCTION: Mapping system is useful in ablation of atrioventricular nodal reentry tachycardia (AVNRT) and localization of anatomic variances. Voltage mapping identifies a low voltage area in the Koch triangle called low-voltage-bridge (LVB); propagation mapping identifies the collision point (CP) of atrial wavefront convergence. We conducted a prospective study to evaluate the relationship between LVB and CP with successful site of ablation and identify standard value for LVB. MATERIALS AND METHODS: Three-dimensional (3D) maps of the right atria were constructed from intracardiac recordings using the ablation catheter. Cut-off values on voltage map were adjusted until LVB was observed. On propagation map, atrial wavefronts during sinus rhythm collide in the site representing CP, indicating the area of slow pathway conduction. Ablation site was selected targeting LVB and CP site, confirmed by anatomic position on fluoroscopy and atrioventricular ratio. RESULTS: Twenty-seven consecutive patients were included. LVB and CP were present in all patients. Postprocedural evaluation identified standard cut-off of 0.3-1 mV useful for LVB identification. An overlap between LVB and CP was observed in 23 (85%) patients. Procedure success was achieved in all patient with effective site at first application in 22 (81%) patients. There was a significant correlation between LVB, CP, and the site of effective ablation (p = .001). CONCLUSION: We found correlation between LVB and CP with the site of effective ablation, identifying a voltage range useful for standardized LVB identification. These techniques could be useful to identify ablation site and minimize radiation exposure.

Left Atrial Strain to Predict Postoperative Atrial Fibrillation in Patients Undergoing Coronary Artery Bypass Grafting.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery being associated with poorer outcomes. Revealing before the operation of left atrial subtle structural/functional abnormalities may help to identify patients at increased risk of POAF. We investigated the role of left atrial strain parameters by preoperative speckle tracking echocardiography as independent predictors of POAF in patients undergoing coronary artery bypass graft. METHODS: Consecutive patients undergoing isolated coronary artery bypass graft were prospectively enrolled at three Italian centers. All patients underwent transthoracic echocardiography before the operation. The occurrence of POAF up to discharge was monitored. RESULTS: Overall, a total of 310 patients were included. POAF was demonstrated in 103 patients (33%). At receiver operating characteristic curve analysis, lower global peak atrial longitudinal strain (PALS) values significantly predicted the risk of POAF (area under the curve, 0.74; P<0.001). The optimal cutoff value for the arrhythmia prediction was a global PALS value <28%, with a specificity of 86% and a sensitivity of 36%. The incidence of POAF was 51% in patients with global PALS <28% versus 14% in those with PALS ≥28% (P<0.001), with a POAF-free survival at Kaplan-Meier analysis of 45.4% and 85.7%, respectively (P<0.001). At multivariate analysis, a global PALS <28% carried a 3.6-fold higher risk of POAF (hazard ratio, 3.6 [95% CI, 2.2-5.9]; P<0.001). The risk increase was even higher when PALS <28% was associated with age ≥70 years (adjusted hazard ratio, 11.2 [4.7-26.6], P<0.001). CONCLUSIONS: A presurgery global PALS <28% is a specific parameter to stratify patients at increased risk of POAF after coronary artery bypass graft. This assessment can be useful to identify patients at higher arrhythmic risk in whom perioperative preventive strategies and stricter monitoring aimed at early diagnosing and treating POAF may be applied.

Ticagrelor Enhances the Cardioprotective Effects of Ischemic Preconditioning in Stable Patients Undergoing Percutaneous Coronary Intervention: the TAPER-S Randomized Study.

BACKGROUND: Ticagrelor improves clinical outcomes in patients with acute coronary syndrome compared with clopidogrel. Ticagrelor also inhibits cell uptake of adenosine and has been associated with cardioprotective effects in animal models. We sought to investigate the potential cardioprotective effects of ticagrelor, as compared with clopidogrel, in stable patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: This was a Prospective Randomized Open Blinded End-points (PROBE) trial enrolling stable patients with coronary artery disease (CAD) requiring fractional flow reserve (FFR)-guided PCI of intermediate epicardial coronary lesions. ST-segment elevation at intracoronary (IC)-ECG during a two-step sequential coronary balloon inflations in the reference vessel during PCI was used as an indirect marker of cardioprotection induced by ischemic preconditioning. The primary endpoint of the study was the comparison of the delta (Δ) (difference) ST-segment elevation measured by intracoronary-ECG during two-step sequential coronary balloon inflations. RESULTS: Fifty-three patients were randomized to either clopidogrel or ticagrelor. The study was stopped earlier because the primary endpoint was met at a pre-specified interim analysis. ΔST-segment elevation was significantly higher in ticagrelor as compared to clopidogrel arms (p<0.0001). Ticagrelor was associated with lower angina score during coronary balloon inflations. There was no difference in coronary microvascular resistance between groups. Adenosine serum concentrations were increased in patients treated with ticagrelor as compared to those treated with clopidogrel. CONCLUSIONS: Ticagrelor enhances the cardioprotective effects of ischemic preconditioning compared with clopidogrel in stable patients with CAD undergoing PCI. Further studies are warranted to fully elucidate the mechanisms through which ticagrelor may exert cardioprotective effects in humans. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique Identifier: NCT02701140.

Statins as preventive therapy for anthracycline cardiotoxicity: a meta-analysis of randomized controlled trials.

BACKGROUND: Cardiotoxicity occurs in 5-20% of cancer patients who receive anthracyclines. The aim of this study was to pool all the randomized controlled trials (RCTs) investigating the cardio-protective role of statins in patients treated with anthracyclines. METHODS: PubMed and Scopus electronic databases were scanned for eligible studies up to May 3rd, 2023. A total of 5 RCTs with 808 patients were included. Efficacy endpoints were the rate of anthracycline-mediated cardiotoxicity, the incidence of hospitalization for heart failure (HF), left ventricular ejection fraction (LVEF) value after anthracycline treatment, and ∆LVEF calculated as the difference in LVEF before and after anthracycline therapy. Safety endpoints [i.e., the incidence of muscle pain and serious adverse events (SAE)] were also assessed. RESULTS: On pooled analysis, the statin-treated group had a lower incidence of cardiotoxicity compared to the placebo group [risk ratio (RR) 0.52, 95% confidence Interval (CI) 0.33-0.83, P = 0.01; I2 = 0%], as well as higher mean LVEF [Mean difference (MD) 1.88, 95% CI 0.66-3.1, P < 0.01; I2 = 57.3%)] and a more favorable ∆LVEF during follow-up (MD 2.38, 95% CI -0.03 - +4.79, P = 0.05; I2 = 99%), despite no significant difference in terms of hospitalization for HF and rate of adverse events. Of note, severe heterogeneity affected the analyses for both LVEF and ΔLVEF. CONCLUSIONS: The current meta-analysis of all RCTs conducted so far shows an overall beneficial effect of statins on the risk of anthracyclines-induced cardiotoxicity and LVEF preservation. No difference was observed in the rate of HF hospitalization. More powered RCTs are needed to fully investigate the impact of statins on prognosis in patients receiving anthracyclines therapy.

Massive myocardial infiltration by primary anaplastic T-cell lymphoma: a case report.

Background: Myocardial infiltration by primary cardiac neoplasm is a rare entity, providing diagnostic and therapeutic challenges. The pathological spectrum includes more frequently benign forms. Refractory heart failure, pericardial effusion, and arrhythmias due to infiltrative mass are the most common clinical manifestations. Case summary: We describe the case of a 35-year-old man complaining of shortness of breath and weight loss in the last 2 months. A previous acute myeloid leukaemia treated with allogenic bone marrow transplant was reported. Transthoracic echocardiography revealed an apical thrombus in the left ventricle, with inferior and septal hypokinesia conditioning a mildly reduced ejection fraction, circumferential pericardial effusion, and abnormal right ventricular thickening. Cardiac magnetic resonance confirmed diffuse thickening of the right ventricular free wall due to myocardial infiltration. Positron emission tomography showed the presence of neoplastic tissue with increased metabolic activity. A pericardiectomy was performed showing a widespread cardiac neoplastic infiltration. Histopathological analysis done on right ventricular pathological samples obtained during cardiac surgery revealed the presence of a rare and aggressive cardiac anaplastic T-cell non-Hodgkin lymphoma. Few days after the operation, the patient developed refractory cardiogenic shock and unluckily died before initiating an adequate antineoplastic therapy. Discussion: Primary cardiac lymphoma is not frequent, and the lack of specific symptoms makes the diagnosis extremely challenging and often limited to autopsy findings. Our case highlights the importance of an appropriate diagnostic algorithm, requiring non-invasive multimodality assessment imaging and then invasive cardiac biopsy. This approach may allow an early diagnosis and an adequate therapy for this otherwise fatal pathology.

Echocardiography vs. CMR in the Quantification of Chronic Mitral Regurgitation: A Happy Marriage or Stormy Divorce?

Quantification of chronic mitral regurgitation (MR) is essential to guide patients' clinical management and define the need and appropriate timing for mitral valve surgery. Echocardiography represents the first-line imaging modality to assess MR and requires an integrative approach based on qualitative, semiquantitative, and quantitative parameters. Of note, quantitative parameters, such as the echocardiographic effective regurgitant orifice area, regurgitant volume (RegV), and regurgitant fraction (RegF), are considered the most reliable indicators of MR severity. In contrast, cardiac magnetic resonance (CMR) has demonstrated high accuracy and good reproducibility in quantifying MR, especially in cases with secondary MR; nonholosystolic, eccentric, and multiple jets; or noncircular regurgitant orifices, where quantification with echocardiography is an issue. No gold standard for MR quantification by noninvasive cardiac imaging has been defined so far. Only a moderate agreement has been shown between echocardiography, either with transthoracic or transesophageal approaches, and CMR in MR quantification, as supported by numerous comparative studies. A higher agreement is evidenced when echocardiographic 3D techniques are used. CMR is superior to echocardiography in the calculation of the RegV, RegF, and ventricular volumes and can provide myocardial tissue characterization. However, echocardiography remains fundamental in the pre-operative anatomical evaluation of the mitral valve and of the subvalvular apparatus. The aim of this review is to explore the accuracy of MR quantification provided by echocardiography and CMR in a head-to-head comparison between the two techniques, with insight into the technical aspects of each imaging modality.

Safety and efficacy of very low LDL-cholesterol intensive lowering: a meta-analysis and meta-regression of randomized trials.

AIMS: We performed a study-level meta-analysis to provide more robust evidence on safety of very low LDL-cholesterol (LDL-C) levels. BACKGROUND: Concerns on the safety of LDL-C values achieved with potent lipid-lowering therapies have been raised. METHODS AND RESULTS: We searched randomized trials reporting clinical outcomes with intensive lipid-lowering treatments leading to very low (<40 mg/dL) LDL-C levels vs. a control group with higher LDL-C levels. Only studies with follow-up duration ≥ 3 months were considered. Primary endpoint was the incidence of various safety measures. A total of 10 randomized trials were overall included, with 38 427 patients being in the very low LDL-C group vs. 70 668 in the control group. Median follow-up duration was 28.8 months. The incidence of all safety outcomes was similar in the two groups: non-cardiovascular death: OR 1.13, 95% CI 0.87-1.45; P = 0.36; any adverse events: OR 1.00, 0.90-1.11, P = 0.94; adverse events leading to drug discontinuation: OR 1.00, 0.87-1.15, P = 0.99; cancer: OR 1.02, 0.95-1.10, P = 0.57; haemorrhagic stroke OR 0.89, 0.66-1.20, P = 0.44; new-onset diabetes: OR 1.16, 0.91-1.47, P = 0.23; neurocognitive disorders: OR 0.97, 0.91-1.04, P = 0.41; haepatobiliary disorders: OR 0.99, 0.83-1.18, P = 0.93; muscle disorders: OR 0.94, 0.77-1.13, P = 0.49; cataract: OR 1.28, 0.78-2.10, P = 0.34. The rates of major adverse cardiovascular events were significantly lower in the very low LDL-C group: OR 0.82, 0.72-0.94, P = 0.005. CONCLUSION: This meta-analysis indicates that very low LDL-C levels on intensive lipid-lowering treatments are not associated with any adverse event and maintain a persistent reduction of cardiovascular events.

Prediction of congestive state in acute and chronic heart failure: The association between NT-proBNP and left atrial strain and its prognostic value.

BACKGROUND: The relief of congestion is crucial to improve heart failure (HF) patient's quality of life and prognosis. N-terminal-pro-brain natriuretic peptide (NT-proBNP) is a well-known marker of congestion, although with limited specificity. Peak atrial longitudinal strain (PALS) by speckle tracking echocardiography (STE) is an index of intracardiac pressure and HF prognosis. We aimed to determine the association between NT-proBNP and PALS and its prognostic implications in patients with HF. METHODS: Patients hospitalized for de-novo or recurrent HF and outpatients with chronic HF were included in this retrospective study. Patients with missing data, previous cardiac surgery, non-feasible STE were excluded. Clinical, laboratory and echocardiographic data were collected. STE was performed on echocardiographic records. Primary endpoint was a combination of all-cause death and HF hospitalization. RESULTS: Overall, 388 patients were included (172 acute HF, 216 chronic HF, mean age = 65 ± 12 years, 37% female). Mean LV ejection fraction = 31 ± 9%. Global PALS showed a significant inverse correlation with NT-proBNP in acute and chronic HF (all p < 0.001). During a median follow-up of 4 years, 180 patients reached the combined endpoint. NT-proBNP (AUC = 0.87) and global PALS (AUC = 0.82) were good predictors of the combined endpoint. Global PALS was the only independent predictor of the combined endpoint. Optimal risk stratification for the composite endpoint was provided combining PALS ≤15% and NTproBNP ≥874.5 ng/l. CONCLUSIONS: Global PALS is associated with NT-proBNP in acute and chronic HF and may be used as additional index of congestion to optimize therapeutic management. The combination of global PALS and NT-proBNP could enhance the prognostic stratification of HF.

Safety and efficacy of different P2Y12 inhibitors in patients with acute coronary syndromes stratified by the PRAISE risk score: a multicentre study.

AIMS: To establish the safety and efficacy of different dual antiplatelet therapy (DAPT) combinations in patients with acute coronary syndrome (ACS) according to their baseline ischaemic and bleeding risk estimated with a machine learning derived model [machine learning-based prediction of adverse events following an acute coronary syndrome (PRAISE) score]. METHODS AND RESULTS: Incidences of death, re-acute myocardial infarction (re-AMI), and Bleeding Academic Research Consortium 3-5 bleeding with aspirin plus different P2Y12 inhibitors (clopidogrel or potent P2Y12 inhibitors: ticagrelor or prasugrel) were appraised among patients of the PRAISE data set grouped in four subcohorts: low-to-moderate ischaemic and bleeding risk; low-to-moderate ischaemic risk and high bleeding risk; high ischaemic risk and low-to-moderate bleeding risk; and high ischaemic and bleeding risk. Hazard ratios (HRs) for the outcome measures were derived with inverse probability of treatment weighting adjustment. Among patients with low-to-moderate bleeding risk, clopidogrel was associated with higher rates of re-AMI in those at low-to-moderate ischaemic risk [HR 1.69, 95% confidence interval (CI) 1.16-2.51; P = 0.006] and increased risk of death (HR 3.2, 1.45-4.21; P = 0.003) and re-AMI (HR 2.23, 1.45-3.41; P < 0.001) in those at high ischaemic risk compared with prasugrel or ticagrelor, without a difference in the risk of major bleeding. Among patients with high bleeding risk, clopidogrel showed comparable risk of death, re-AMI, and major bleeding vs. potent P2Y12 inhibitors, regardless of the baseline ischaemic risk. CONCLUSION: Among ACS patients with non-high risk of bleeding, the use of potent P2Y12 inhibitors is associated with a lower risk of death and recurrent ischaemic events, without bleeding excess. Patients deemed at high bleeding risk may instead be safely addressed to a less intensive DAPT strategy with clopidogrel.

New echocardiographic indices of shift to biventricular failure to optimize risk stratification of chronic heart failure.

AIMS: The present study investigated the prognostic impact of either isolated left atrial (LA) impairment, or its association with right ventricular (RV) failure, in heart failure (HF) with reduced ejection fraction (HFrEF), using basic and speckle tracking echocardiography (STE). METHODS AND RESULTS: One hundred and six outpatients with HFrEF were enrolled in this prospective observational study. Patients with primary lung diseases, non-sinus rhythm, previous cardiac surgery, and poor acoustic window were excluded. After clinical examination and basic echocardiography, STE was used to measure peak atrial longitudinal strain (PALS) and a new marker of RV performance and pulmonary circulation relation: free-wall RV longitudinal strain (fwRVLS)/systolic pulmonary artery pressure (sPAP). Patients were followed for all-cause/cardiovascular death and HF hospitalization. Of 84 eligible patients (60.1 ± 11.5 years; 82% male patients), 48 reached the combined endpoint (cardiovascular death and/or HF hospitalization). Population was divided into three groups: Group 1 (PALS ≥ 15 and fwRVLS/sPAP ≤ -0.5), Group 2 (PALS ≤ 15 and fwRVLS/sPAP ≤ -0.5), and Group 3 (PALS ≤ 15 and fwRVLS/sPAP > -0.5). Mean follow up was 3.5 ± 0.3 years. The higher severity groups were associated with higher LA volume index (P < 0.0001), New York Heart Association class (P = 0.02), mitral regurgitation (P = 0.0004) and tricuspid regurgitation grades (P < 0.0001), lower left ventricular (LV) ejection fraction (P = 0.0003), LV global longitudinal strain (P < 0.0001), PALS (P < 0.0001), tricuspid annular plane systolic excursion (P < 0.007), sPAP (P < 0.0001), and RV strain (P < 0.0001). Reduced PALS and fwRVLS/sPAP were independent predictors of the combined endpoint with adjusted Cox models (hazard ratio = 9.54; 95% confidence interval = 2.95-30.92; P = 0.0002 for Group 3 vs. Group 1). Kaplan-Meier curves showed early and persistent divergence between the three groups for the prediction of the combined endpoint and of all-cause death (P < 0.0001). CONCLUSIONS: The combination of LA and right heart damage entails worse prognosis in patients with HFrEF. The evaluation of PALS and fwRVLS/sPAP could aid risk stratification of HFrEF patients to provide them early treatment.

Determinants of long COVID among adults hospitalized for SARS-CoV-2 infection: A prospective cohort study.

Rationale: Factors associated with long-term sequelae emerging after the acute phase of COVID-19 (so called "long COVID") are unclear. Here, we aimed to identify risk factors for the development of COVID-19 sequelae in a prospective cohort of subjects hospitalized for SARS-CoV-2 infection and followed up one year after discharge. Methods: A total of 324 subjects underwent a comprehensive and multidisciplinary evaluation one year after hospital discharge for COVID-19. A subgroup of 247/324 who consented to donate a blood sample were tested for a panel of circulating cytokines. Results: In 122 patients (37.8%) there was evidence of at least one persisting physical symptom. After correcting for comorbidities and COVID-19 severity, the risk of developing long COVID was lower in the 109 subjects admitted to the hospital in the third wave of the pandemic than in the 215 admitted during the first wave, (OR 0.69, 95%CI 0.51-0.93, p=0.01). Univariable analysis revealed female sex, diffusing capacity of the lungs for carbon monoxide (DLCO) value, body mass index, anxiety and depressive symptoms to be positively associated with COVID-19 sequelae at 1 year. Following logistic regression analysis, DLCO was the only independent predictor of residual symptoms (OR 0.98 CI 95% (0.96-0.99), p=0.01). In the subgroup of subjects with normal DLCO (> 80%), for whom residual lung damage was an unlikely explanation for long COVID, the presence of anxiety and depressive symptoms was significantly associated to persistent symptoms, together with increased levels of a set of pro-inflammatory cytokines: interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-12, IL-1ß, IL-17. In logistic regression analysis, depressive symptoms (p=0.02, OR 4.57 [1.21-17.21]) and IL-12 levels (p=0.03, OR 1.06 [1.00-1.11]) 1-year after hospital discharge were independently associated with persistence of symptoms. Conclusions: Long COVID appears mainly related to respiratory sequelae, prevalently observed during the first pandemic wave. Among patients with little or no residual lung damage, a cytokine pattern consistent with systemic inflammation is in place.

Speckle tracking echocardiography in primary mitral regurgitation: should we reconsider the time for intervention?

Thanks to the improvement in mitral regurgitation (MR) diagnostic and therapeutic management, with the introduction of minimally invasive techniques which have considerably reduced the individual surgical risk, the optimization of the timing for MR "open" or percutaneous surgical treatment has become a main concern which has highly raised scientific interest. In fact, the current indications for intervention in MR, especially in asymptomatic patients, rely on echocardiographic criteria with high severity cut-offs that are fulfilled only when not only mitral valve apparatus but also the cardiac chambers' structure and function are severely impaired, which results in poor benefits for post-operative clinical outcome. This led to the need of new indices to redefine the optimal surgical timing in these patients. Speckle tracking echocardiography provides early markers of cardiac dysfunction due to subtle myocardial impairment; therefore, it could offer pivotal information in this setting. In fact, left ventricular and left atrial strains have already shown evidence about their usefulness in recognizing MR impact not only on symptoms and quality of life but also on cardiovascular events and new-onset atrial fibrillation in these patients. Moreover, right ventricular strain could be used to identify those patients with advanced cardiac damage and different grades of right ventricular dysfunction, which entails higher risks for cardiac surgery that could overweigh surgical benefits. This review aims to describe the importance of reconsidering the timing of intervention in MR and to analyze the potential additive value of speckle tracking echocardiography in this clinical setting.

Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering.

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February-May 2020). Patients' characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (p < 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.

Left atrial conduit flow rate at baseline and during exercise: an index of impaired relaxation in HFpEF patients.

AIMS: In healthy subjects, adrenergic stimulation augments left ventricular (LV) long-axis shortening and lengthening, and increases left atrial (LA) to LV intracavitary pressure gradients in early diastole. Lower increments are observed in patients with heart failure with preserved ejection fraction (HFpEF). We hypothesized that exercise in HFpEF would further impair passive LV filling in early-mid diastole, during conduit flow from pulmonary veins. METHODS AND RESULTS: Twenty HFpEF patients (67.8 ± 9.8 years; 11 women), diagnosed using 2007 ESC recommendations, underwent ramped semi-supine bicycle exercise to submaximal target heart rate (∼100 bpm) or symptoms. Seventeen asymptomatic subjects (64.3 ± 8.9 years; 7 women) were controls. Simultaneous LA and LV volumes were measured from pyramidal 3D-echocardiographic full-volume datasets acquired from an apical window at baseline and during stress, together with brachial arterial pressure. LA conduit flow was computed from the increase in LV volume from its minimum at end-systole to the last frame before atrial contraction (onset of the P wave), minus the reduction in LA volume during the same time interval; the difference was integrated and expressed as average flow rate, according to a published formula. The slope of single-beat preload recruitable stroke work (PRSW) quantified LV inotropic state. 3D LV torsion (rotation of the apex minus rotation of the base divided by LV length) was also measurable, both at rest and during stress, in 10 HFpEF patients and 4 controls. There were divergent responses in conduit flow rate, which increased by 40% during exercise in controls (+17.8 ± 37.3 mL/s) but decreased by 18% in patients with HFpEF (-9.6 ± 42.3 mL/s) (P = 0.046), along with congruent changes (+1.77 ± 1.13°/cm vs. -1.94 ± 2.73°/cm) in apical torsion (P = 0.032). Increments of conduit flow rate and apical torsion during stress correlated with changes in PRSW slope (P = 0.003 and P = 0.006, respectively). CONCLUSIONS: In HFpEF, conduit flow rate decreases when diastolic dysfunction develops during exercise, in parallel with changes in LV inotropic state and torsion, contributing to impaired stroke volume reserve. Conduit flow is measurable using 3D-echocardiographic full-volume atrio-ventricular datasets, and as a marker of LV relaxation can contribute to the diagnosis of HFpEF.

[Zero-fluoroscopy transcatheter ablation and CRT-D implantation: new frontiers of electroanatomical mapping systems]. / Ablazione transcatetere e contestuale impianto di CRT-D "zero-fluoroscopy": nuove frontiere del mappaggio elettroanatomico.

In cardiac resynchronization therapy (CRT) implantation procedures, contrast-induced nephropathy risk and ionizing radiation exposure can be eliminated using electroanatomical mapping system (EAMS). Under EAMS guidance, it is possible to place the left ventricular catheter in the branch of the coronary sinus that presents the latest activation. The use of EAMS allows for both arrhythmic ablation and CRT implantation to be obtained in a single, "zero fluoroscopy" procedure. Here we report two cases of successful arrhythmia ablation and CRT-D implantation with "zero fluoroscopy" in a single procedure.

Incidence and Predictors of Stent Thrombosis in Patients Treated with Stents for Coronary Bifurcation Narrowing (From the BIFURCAT Registry).

Percutaneous coronary interventions performed at coronary bifurcations yield high rates of stent thrombosis (ST). The aim of the present study was to investigate the predictors of ST in contemporary coronary bifurcation percutaneous coronary interventions. We retrospectively investigated the BIFURCAT (comBined Insights From the Unified RAIN and COBIS bifurcAtion regisTries) registry on coronary bifurcations to assess the incidence and predictors of definite ST, which were the study primary endpoints. Predictors of ST among patients on dual antiplatelet therapy (DAPT) were also examined. A total of 5330 patients were included. After a mean 2-years follow-up, 64 (1.2%) patients experienced ST. 42 (65.6%) ST patients were on DAPT. At multivariable analysis, age (HR 1.02, CI 1.01 to 1.05, p = 0,027), smoking status (HR 2.57, CI 1.49 to 4.44, p = 0.001), chronic kidney disease (HR 2.26, CI 1.24 to 4.12, p = 0.007) and a 2-stent strategy (HR 2.38, CI 1.37 to 4.14, p = 0.002) were independent predictors of ST, whereas intracoronary imaging (HR 0.42, CI 0.23 to 0.78, p = 0.006) and final kissing balloon (FKB) (HR 0.48, CI 0.29 to 0.82, p = 0.007) were protective against ST. Among patients on DAPT, smoking status and a 2-stent strategy significantly increased the risk of ST, while intracoronary imaging and FKB reduced the risk. In conclusion, age, smoking status, chronic kidney disease and a 2-stent strategy were significant predictors of ST, whereas intracoronary imaging use and FKB had a protective effect. Only smoking status and a 2-stent strategy significantly predicted ST in DAPT subgroup, while intracoronary imaging and FKB had a protective role.

Two and Three-Dimensional Echocardiography in Primary Mitral Regurgitation: Practical Hints to Optimize the Surgical Planning.

Primary mitral regurgitation (MR) is the second most common valvular disease, characterized by a high burden in terms of quality of life, morbidity, and mortality. Surgical treatment is considered the best therapeutic strategy for patients with severe MR, especially if they are symptomatic. However, pre-operative echocardiographic evaluation is an essential step not only for surgical candidate selection but also to avoid post-operative complications. Therefore, a strong collaboration between cardiologists and cardiac surgeons is fundamental in this setting. A meticulous pre-operative echocardiographic exam, both with transthoracic or transesophageal echocardiography, followed by a precise report containing anatomical information and parameters should always be performed to optimize surgical planning. Moreover, intraoperative transesophageal evaluation is often required by cardiac surgeons as it may offer additive important information with different hemodynamic conditions. Three-dimensional echocardiography has recently gained higher consideration and availability for the evaluation of MR, providing more insights into mitral valve geometry and MR mechanism. This review paper aims to realize a practical overview on the main use of basic and advanced echocardiography in MR surgical planning and to provide a precise checklist with reference parameters to follow when performing pre-operative echocardiographic exam, in order to aid cardiologists to provide a complete echocardiographic evaluation for MR operation planning from clinical and surgical point-of-view.

[Concepts and preconceptions on the use of direct oral anticoagulants in Italy: a Delphi consensus panel of the Atherosclerosis Thrombosis, Vascular Biology Study Group (ATBV)]. / Concetti e preconcetti sull'uso degli anticoagulanti orali diretti in Italia: un comitato di consenso Delphi del Gruppo di Studio Aterosclerosi, Trombosi, Biologia Vascolare (ATBV).

In the last decade, direct oral anticoagulants (DOACs) have entered the clinical practice of different specialists for the prevention of cardioembolic stroke in patients with non-valvular atrial fibrillation (NVAF) and the prevention and treatment of venous thromboembolism (VTE). Owing to the persistent uncertainties about the use of DOACs in daily clinical scenarios not fully explored in the clinical trials, we conducted a national Delphi consensus regarding issues deemed interesting by the Italian Atherosclerosis, Thrombosis and Vascular Biology (ATBV) Study Group in relation to: (i) elderly and/or frail patients; (ii) chronic kidney disease; (iii) drug-drug interactions; (iv) lower doses and safety; (v) criteria for choosing individual drugs and compliance; (vi) VTE in the cancer patient. Eighty-four Italian clinicians (cardiologists, internists, geriatricians, neurologists and hematologists) expressed their level of agreement on each statement using a 5-point Likert scale (1: very much in disagreement, 2: disagreement, 3: partial agreement, 4: agreement, 5: very much in agreement). In particular, 1-2 selections were considered as disagreement, while 3-5 selections were considered as agreement. A ≥66% agreement between the participants for each statement was considered consensus. In general, a broad and general awareness and sharing of the methods of use of DOACs emerged from our initiative, and in particular their preferential indication in the elderly population and in frail patients or with renal insufficiency or oncological, always following the prescription indications and dose reduction criteria. The importance of being aware of drug-drug interactions has also been underlined in a concordant way, as well as simplicity of treatment in the multi-treated patient. In view of the persistent, albeit limited (12%), absence of consensus on some issues, with regard to the frail patient, drug-food interactions and availability of antidote, the acquisition of further evidence and a persistent educational effort are nonetheless indicated.