Applications of Three-Dimensional Printing in the Management of Complex Aortic Diseases.

The use of three-dimensional (3D) printing is gaining considerable success in many medical fields, including surgery; however, the spread of this innovation in cardiac and vascular surgery is still limited. This article reports our pilot experience with this technology, applied as an additional tool for 20 patients treated for complex vascular or cardiac surgical diseases. We have analyzed the feasibility of a "3D printing and aortic diseases project," which helps to obtain a more complete approach to these conditions. 3D models have been used as a resource to improve preoperative planning and simulation, both for open and endovascular procedures; furthermore, real 3D aortic models were used to develop doctor-patients communication, allowing better knowledge and awareness of their disease and of the planned surgical procedure. A 3D printing project seems feasible and applicable as an adjunctive tool in the diagnostic-therapeutic path of complex aortic diseases, with the need for future studies to verify the results.

Sex-Related Differences in Long-Term Outcomes After Early-Onset Myocardial Infarction.

Importance: There is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure. Methods: A nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, n = 1,778 (88.9%). Patients were followed up for a median of 19.9 years (IQR 18.1-22.6). The primary composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial re-infarction or non-fatal stroke, and the secondary endpoint of hospitalization for revascularisation by means of a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Results: ST-elevation MI was the most frequent presentation among both men and women (85.1 vs. 87.4%, p = ns), but the men had a greater baseline coronary atherosclerotic burden (median Duke Coronary Artery Disease Index: 48 vs. 23; median Syntax score 9 vs. 7; both p < 0.001). The primary composite endpoint occurred less frequently among women (25.7% vs. 37.0%; adjusted hazard ratio: 0.69, 95% CI 0.52-0.91; p = 0.01) despite being less likely to receive treatment with most secondary prevention medications during follow up. Conclusions: There are significant sex-related differences in baseline risk factors and outcomes among patients with early-onset MI: women present with a lower atherosclerotic disease burden and, although they are less frequently prescribed secondary prevention measures, experience better long-term outcomes. Trial Registration: 4272/98 Ospedale Niguarda, Ca' Granda 03/09/1998.

Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease (MINOCA).

BACKGROUND: Acute myocardial infarction with non-obstructive coronary artery disease (MINOCA) is frequent in patients experiencing an early-onset MI, but data concerning its long-term prognosis are limited and conflicting. METHODS: The Italian Genetic Study on Early-onset MI enrolled 2000 patients experiencing a first MI before the age of 45 years, and had a median follow-up of 19.9 years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalisation for coronary revascularisation. RESULTS: MINOCA occurred in 317 patients (15.9%) and, during the follow-up, there was no significant difference in MACE rates between them and the patients with obstructive coronary artery disease (MICAD: 27.8% vs 37.5%; adjusted hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.57-1.09;p = 0.15). The CV death rate was lower in the MINOCA group (4.2% vs 8.4%, HR 0.26, 95%CI 0.08-0.86;p = 0.03), whereas the rates of non-fatal reinfarction (17.3% vs 25.4%; HR 0.76, 95%CI 0.52-1.13;p = 0.18), non-fatal ischemic stroke (9.5% vs 3.7%; HR 1.79, 95%CI 0.87-3.70;p = 0.12), and all-cause mortality (14.1% vs 20.7%, HR 0.73, 95%CI 0.43-1.25;p = 0.26) were not significantly different in the two groups. The rate of rehospitalisation for coronary revascularisation was lower among the MINOCA patients (6.7% vs 27.7%; HR 0.27, 95% CI 0.15-0.47;p < 0.001). CONCLUSIONS: MINOCA is frequent and not benign in patients with early-onset MI. Although there is a lower likelihood of CV death,the long-term risk of MACE and overall mortality is not significantly different from that of MICAD patients.

In-hospital Heart Rate Reduction With Beta Blockers and Ivabradine Early After Recovery in Patients With Acute Decompensated Heart Failure Reduces Short-Term Mortality and Rehospitalization.

Objective: In the past years, heart rate (HR) has emerged as a highly relevant modifiable risk factor for heart failure (HF) patients. However, most of the clinical trials so far evaluated the role of HR in stable chronic HF cohorts. The aim of this multi-center, prospective observational study was to assess the association between HR and therapy with HR modulators (beta blockers, ivabradine, or a combination of ivabradine and beta blockers) at hospital discharge with patients' cardiovascular mortality and re-hospitalization at 6 months in acutely decompensated HF patients. Materials and Methods: We recruited 289 HF patients discharged alive after admission for HF decompensation from 10 centers in northern Italy over 9 months (from April 2017 to January 2018). The primary endpoint was the combination of cardiovascular mortality or re-hospitalizations for HF at 6 months. Results: At 6 months after discharge, 64 patients were readmitted (32%), and 39 patients died (16%). Multivariate analysis showed that HR at discharge ≥ 90 bpm (OR = 8.47; p = 0.016) independently predicted cardiovascular mortality, while therapy with beta blockers at discharge was found to reduce the risk of the composite endpoint. In patients receiving HR modulators the event rates for the composite endpoint, all-cause mortality, and cardiovascular mortality were lower than in patients not receiving HR modulators. Conclusions: Heart rate at discharge ≥90 bpm predicts cardiovascular mortality, while therapy with beta blockers is negatively associated with the composite endpoint of cardiovascular mortality and hospitalization at 6 months in acutely decompensated HF patients. Patients receiving a HR modulation therapy at hospital discharge showed the lowest rate of cardiovascular mortality and re-hospitalization.

Sacubitril/Valsartan to Treat Heart Failure in a Patient with Relapsing Hairy Cell Leukaemia: Case Report.

Experience with angiotensin-receptor neprilysin inhibitors (ARNI) in oncologic patients with heart failure (HF) is limited. We report a case of ARNI started as first-choice therapy in a patient with relapsing hairy cell leukaemia (HCL) and HF with depressed left ventricular ejection fraction (LVEF). A middle-aged male, previously treated with rituximab for HCL, was scheduled for cardiologic screening before starting a new antineoplastic therapy for cancer relapse. The patient had symptomatic HF with reduced LVEF and high NT-proBNP levels. In this patient, early ARNI treatment was well tolerated and produced a rapid and durable improvement of symptoms, LVEF and NT-proBNP levels. Consequently, the oncologic team could start an experimental treatment with obinutuzumab, with complete HCL remission. In conclusion, in this patient with HCL and HF, ARNI therapy was safe and effective, contributing to undelayed cancer treatment.

A Random Shuffle Method to Expand a Narrow Dataset and Overcome the Associated Challenges in a Clinical Study: A Heart Failure Cohort Example.

Heart failure (HF) affects at least 26 million people worldwide, so predicting adverse events in HF patients represents a major target of clinical data science. However, achieving large sample sizes sometimes represents a challenge due to difficulties in patient recruiting and long follow-up times, increasing the problem of missing data. To overcome the issue of a narrow dataset cardinality (in a clinical dataset, the cardinality is the number of patients in that dataset), population-enhancing algorithms are therefore crucial. The aim of this study was to design a random shuffle method to enhance the cardinality of an HF dataset while it is statistically legitimate, without the need of specific hypotheses and regression models. The cardinality enhancement was validated against an established random repeated-measures method with regard to the correctness in predicting clinical conditions and endpoints. In particular, machine learning and regression models were employed to highlight the benefits of the enhanced datasets. The proposed random shuffle method was able to enhance the HF dataset cardinality (711 patients before dataset preprocessing) circa 10 times and circa 21 times when followed by a random repeated-measures approach. We believe that the random shuffle method could be used in the cardiovascular field and in other data science problems when missing data and the narrow dataset cardinality represent an issue.

Patent Foramen Ovale Closure Versus Medical Therapy in Cryptogenic Strokes and Transient Ischemic Attacks: A Meta-Analysis of Randomized Trials.

Cryptogenic strokes account for about 25% to 40% of total ischemic strokes, and 1 of the 3 of these have a patent foramen ovale (PFO). A meta-analysis concerning the effectiveness and safety of PFO closure in cryptogenic strokes or transient ischemic attacks (TIAs) was performed. We systematically searched Medline, Embase, and the Cochrane Library through April 2018. Eligible studies were randomized clinical trials. Primary and secondary end points were, respectively, stroke or TIA and stroke recurrences. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for all end points using fixed- and random-effects meta-analyses. Data were included from 6 trials involving 3560 patients. In the pooled analysis, PFO closure was superior to medical treatment for both primary (RR: 0.39; 95% CI: 0.18-0.82; P < .02) and secondary end points (RR: 0.58; 95% CI: 0.44-0.76; P < .001). Transcatheter closure significantly increased the risk of new-onset atrial fibrillation (AF; RR: 5.74; P < .001). Percutaneous closure is superior to medical treatment in reducing stroke and TIA recurrence, even if with a significant risk increasing for new-onset AF. These findings suggest that transcatheter closure is indicated in patients with cryptogenic strokes and large PFO.

Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry.

BACKGROUND: There is controversy about the outcome of patients with acute myocarditis (AM), and data are lacking on how patients admitted with suspected AM are managed. We report characteristics, in-hospital management, and long-term outcome of patients with AM based on a retrospective multicenter registry from 19 Italian hospitals. METHODS: A total of 684 patients with suspected AM and recent onset of symptoms (<30 days) were screened between May 2001 and February 2017. Patients >70 years of age and those >50 years of age without coronary angiography were excluded. The final study population comprised 443 patients (median age, 34 years; 19.4% female) with AM diagnosed by either endomyocardial biopsy or increased troponin plus edema and late gadolinium enhancement at cardiac magnetic resonance. RESULTS: At presentation, 118 patients (26.6%) had left ventricular ejection fraction <50%, sustained ventricular arrhythmias, or a low cardiac output syndrome, whereas 325 (73.4%) had no such complications. Endomyocardial biopsy was performed in 56 of 443 (12.6%), and a baseline cardiac magnetic resonance was performed in 415 of 443 (93.7%). Cardiac mortality plus heart transplantation rates at 1 and 5 years were 3.0% and 4.1%. Cardiac mortality plus heart transplantation rates were 11.3% and 14.7% in patients with complicated presentation and 0% in uncomplicated cases (log-rank P<0.0001). Major AM-related cardiac events after the acute phase (postdischarge death and heart transplantation, sustained ventricular arrhythmias treated with electric shock or ablation, symptomatic heart failure needing device implantation) occurred in 2.8% at the 5-year follow-up, with a higher incidence in patients with complicated forms (10.8% versus 0% in uncomplicated AM; log-rank P<0.0001). ß-Adrenoceptor blockers were the most frequently used medications both in complicated (61.9%) and in uncomplicated forms (53.8%; P=0.18). After a median time of 196 days, 200 patients had follow-up cardiac magnetic resonance, and 8 of 55 (14.5%) with complications at presentation had left ventricular ejection fraction <50% compared with 1 of 145 (0.7%) of those with uncomplicated presentation. CONCLUSIONS: In this contemporary study, overall serious adverse events after AM were lower than previously reported. However, patients with left ventricular ejection fraction <50%, ventricular arrhythmias, or low cardiac output syndrome at presentation were at higher risk compared with uncomplicated cases that had a benign prognosis and low risk of subsequent left ventricular systolic dysfunction.

Ambient air pollution and cardiovascular diseases: From bench to bedside.

Air pollution has a great impact on health, representing one of the leading causes of death worldwide. Previous experimental and epidemiological studies suggested the role of pollutants as risk factors for cardiovascular diseases. For this reason, international guidelines included specific statements regarding the contribution of particulate matter exposure to increase the risk of these events. In this review, we summarise the main evidence concerning the mechanisms involved in the processes linking air pollutants to the development of cardiovascular diseases.

Heart rate as a prognostic marker and therapeutic target in acute and chronic heart failure.

Since increased heart rate (HR) is associated with higher mortality in several cardiac disorders, HR is considered not only a physiological indicator but also a prognostic and biological marker. In heart failure (HF), it represents a therapeutic target in chronic phase. The use or up-titration of beta-blockers, a milestone in HF with reduced left ventricular ejection fraction (LVEF) treatment, is at times limited by patients' hemodynamic profile or intolerance. Ivabradine, a HR-lowering drug inhibiting the f-current in pacemaker cells, has been shown to improve outcome in patients with chronic HF, in sinus rhythm with increased HR beyond beta-blocker therapy. The rationale for this review is to update the role of HR as a prognostic biomarker and a potential therapeutic target in other scenarios than chronic HF; namely, in patients with coexisting atrial fibrillation (AF), in HF with preserved LVEF (HFpEF), in acute HF, and in patients discharged after an episode of acute HF. Preliminary studies and case reports that evaluated the use of ivabradine in the setting of acute HF will be summarized. Recent results of HR reduction in the setting of HFpEF with ivabradine will be presented. Finally, data from large registries and trials that evaluated the prognostic impact of HR in patients with acute HF and sinus rhythm or AF will be reviewed, showing that only patients in sinus rhythm may benefit from HR reduction.

Short-term air pollution exposure and cardiovascular events: A 10-year study in the urban area of Como, Italy.

BACKGROUND: In the last years several studies have investigated the effects of some air pollutants on cardiovascular diseases (CVD), but the results are not conclusive. Aim of this study was to investigate the association between short-term exposure to ambient air pollution and CVD events in a long-term observational period. METHODS: All CVD events (myocardial infarction - MI and ischemic stroke - IS) which occurred in residents of Como between January 2005 and December 2014 were included. Demographics and main vascular risk factors were registered for each patient. Principal meteorological variables and four ambient particles (O3, SO2, NO2, PM10) were recorded. Statistical analysis was performed using linear regression (GLM) and a generalized additive model (GAM) estimating Poisson distribution and adjusted for the main risk factors and ambient meteorological variables. RESULTS: A total of 4110 events were registered with a mild prevalence of MI (51.6%). In GLM analysis we observed a continuative association between CVD events and SO2 (p<0.05), while PM10 was associated with CVD occurrences at two-day lag time (p<0.05). Using GAM we observed a positive association between CVD and PM10 at the same day and at three- and four-day lag time with HRs ranging between 1.025 and 1.039 (p<0.001). These results were observed for both MI and IS, with an earlier effect for MI than for IS. CONCLUSIONS: These data confirm a possible association between some ambient air pollutants and CVD events, precisely MI and IS, with different temporal and cumulative effect.

[New oral anticoagulants (NOAC) in nephrology]. / I nuovi Anti-Coagulanti Orali (NOAC): cosa deve sapere un Nefrologo.

The new or direct oral anticoagulants [new oral anticoagulants (NOAC) or direct oral anticoagulants (DOAC)] were launched in the Italian market in 2013. Although these compounds share common pharmacological indications with vitamin K antagonists (warfarin or acenocumarol), they have different mechanisms of action, do not require a constant anticoagulant monitoring but are more efficacious and safer than vitamin K antagonists. The use of these molecules (Dabigatran, Apixaban, Rivaroxaban, Betrixaban, Edoxaban) is constantly rising in daily practice. However, while available data suggest that NOAC/DOAC use is safe, dosage should be adjusted based on renal or liver function. It should be acknowledged that commonly available blood tests [Prothrombin Time (PT) and partial thromboplastin time (PTT)] are not indicated to monitor the anticoagulant activity of these compounds. With the exception of dabigatran, we currently lack of an antidote to reverse the anticoagulant effect of NOAC/DOAC. We herein review available evidence on NOAC/DOAC pharmacokinetic, risk factors for bleeding, interventions to reverse the anticoagulant activity in case of hemorrhages or need of urgent surgery and/or NOAC/DOAC overdose or side effects.

[Heart rate and outcome in patients with acute and chronic heart failure]. / La frequenza cardiaca e la prognosi nello scompenso cardiaco acuto e cronico.

Heart rate (HR) is not only a physical sign but also a biomarker. High HR in several cardiac disorders is associated with increased mortality. In heart failure (HF), HR represents an important therapeutic target, both in the acute and chronic phase. Beta-blockers are a milestone of recommended treatments in HF patients with reduced ejection fraction. However, hemodynamic profile or intolerance may limit the use or the optimization of beta-blocker treatment, both during hospitalization and outpatient follow-up. More recently, ivabradine has become available, a drug that lowers HR by blocking the I(f) current in the pacemaker cells at the sinoatrial node level. In the SHIFT trial, ivabradine was shown to improve the outcome of patients with chronic HF, in sinus rhythm, with HR >70 b/min while on beta-blockers. Preliminary data have shown that this drug has a good safety profile and lowers effectively HR even during hospitalization due to worsening HF. However, further studies are warranted to understand if an earlier administration of ivabradine can lead to a better prognosis beyond symptom control and improved hemodynamics. In patients with atrial fibrillation and HF, the target is the restoration of sinus rhythm, alternatively rate control should be pursued with beta-blockers, amiodarone or digitalis, even if there is no clear evidence of an association between ventricular rate response in patients with atrial fibrillation at discharge after an HF hospitalization and major cardiovascular events. In this review, the studies that point to a role of HR both as a biomarker and a therapeutic target in patients with acute and chronic HF are described. In addition, the proportions of patients who do not reach target HR values at discharge after an acute decompensated HF episode or in the chronic phase are evaluated based on the Italian registries.

[New antiarrhythmic drugs for the treatment of atrial fibrillation]. / I nuovi farmaci antiaritmici per il trattamento della fibrillazione atriale.

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and a difficult-to-treat arrhythmia. Conventional antiarrhythmic drugs, including flecainide, propafenone, sotalol and amiodarone, have several limitations in terms of efficacy and tolerability, and have made new drug development crucial. In the last decade, intensive research was undertaken to find new pharmacological options for the treatment of AF, and two new drugs are now available. Vernakalant is an atrial-selective drug specifically designed to block sodium channels at the atrial level, and its intravenous formulation has recently been recommended for approval by the Food and Drug Administration for pharmacological conversion of AF. Dronedarone is a chemical derivative of amiodarone (though having a significantly different clinical profile) with effects on multiple ion channels that proved effective in reducing the rate of the combined endpoint of death from any cause and cardiovascular hospitalization in patients with non-permanent AF enrolled in the ATHENA study. The available evidence on the efficacy of dronedarone has led to approval for recommendation in many clinical situations in which rhythm control is desirable. The complexity of the mechanisms underlying AF and the large variability of associated comorbidities render the AF patient a unique entity, making the identification of patients who may benefit from these novel approaches challenging.

Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: In patients with idiopathic pulmonary hypertension (IPAH) progression of the disease and survival are related to the capability of the right ventricle to adapt to the chronically elevated pulmonary artery pressure. Although several echocardiographic variables have been associated with outcome in previous studies, a comparative evaluation of all right ventricular (RV) function indices obtainable at echocardiography has never been performed. METHODS: 59 patients consecutively admitted in a tertiary referral centre because of IPAH (22 males, mean age 46.3+/-16.1 years, 68% in WHO class III/IV at referral) underwent right heart catheterization and echocardiography. During a median follow-up period of 52 months, 21 patients died and 2 underwent lung transplantation in emergency conditions. RESULTS: The following parameters were associated with survival: tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, degree of tricuspid regurgitation, inferior vena cava collapsibility, superior vena cava flow velocity pattern, left ventricular diastolic eccentricity index. Patients with TAPSEor=1.7 had the highest event rate (51.7 per 100 person year); patients with TAPSE>15 mm and mild or no tricuspid regurgitation had the lowest event rate (2.6 per 100 person year). CONCLUSIONS: A comprehensive echocardiographic assessment of RV systolic and diastolic function based on TAPSE, left ventricular diastolic eccentricity index and degree of tricuspid regurgitation allows an accurate prognostic stratification of patients with IPAH.

Levels of circulating pro-angiogenic cells predict cardiovascular outcomes in patients with chronic heart failure.

BACKGROUND: Circulating pro-angiogenic cells (PACs) contribute to vascular and myocardial regeneration. A low level of PACs is associated with worse outcome in patients with coronary heart disease. However, little is known about PACs in heart failure (HF). METHODS AND RESULTS: Blood was sampled at baseline in 111 patients with HF, 67 from 5 Italian Centers and 44 from Frankfurt, Germany. In cultured mononuclear cells from peripheral blood, PACs were counted as double-stained by tetramethylindocarbocyanine-labeled acetylated LDL and fluorescein-5-isothiocyanate-labeled lectin. Mean age of the patients was 62 years, 12 were females, 66 had ischemic etiology, 26 were in New York Heart Association Class >II. Cutoffs for PACs were assessed by receiver operating characteristic curves, to identify the optimal cutoffs for PAC level in predicting outcomes. Mean level of PACs was 35+/-29 (mean+/-SD) cells/mm(2), 2- to 3-fold lower than in age-matched healthy volunteers, but unrelated to severity of HF, age, or sex. Over 2.5 years, 12 cardiovascular deaths and 47 first hospitalizations for cardiovascular reasons were recorded. After adjustment for demographic and clinical variables, elevated creatinine and natriuretic peptides, and PACs