Background/aims: Myocarditis is an inflammatory disease with diverse clinical presentations. It is known that low-risk patients have a good prognosis compared to high-risk patients. There are few data regarding the prognosis of intermediate-risk patients. This study aimed to analyze the long-term outcomes of patients with acute myocarditis with different risk profiles at presentation, focusing on the intermediate risk one. Methods: A retrospective multicenter study was conducted, enrolling patients who met the diagnostic criteria for clinically suspected myocarditis with acute presentation. Patients were stratified into high, intermediate and low risk, according to the classification proposed by Sinagra and his team. Cardiovascular adverse events (AEs) were assessed after a median follow-up of 19 months. Echocardiographic and cardiac magnetic resonance (CMR) parameters predictive of adverse events have been reported. Results: We enrolled 127 patients (mean age 30 +/- 13 years; 103 men, 24 women). High-risk patients had a higher frequency of adverse events (80 %) compared to other groups (16 %-16 %, p < 0.0001). An association was observed between the number of segments with late gadolinium enhancement (LGE) at baseline CMR and the occurrence of adverse events (p < 0.0037). The sum of segments with LGE was statistically correlated with lower left ventricular GLS (p < 0.009). The number of segments with LGE that most accurately identified the occurrence of adverse events was 2.5 [AUC 0.5; p = 0.24]. Conclusions: Our study confirms the higher incidence of AE in the high group; the prognosis of patients at intermediate risk is not very different from those at low risk. It can be hypothesized that the extent of LGE at baseline is the main predictor of adverse events in patients at intermediate risk.

Background: This study aims to evaluate the cardiopulmonary effects of sacubitril/valsartan therapy in patients with heart failure with reduced ejection fraction (HFrEF), investigating a possible correlation with the degree of myocardial fibrosis, as assessed by cardiac magnetic resonance. Methods: A total of 134 outpatients with HFrEF were enrolled. Results: After a mean follow-up of 13.3 ± 6.6 months, an improvement in ejection fraction and a reduction in E/A ratio, inferior vena cava size and N-terminal pro-B-type natriuretic peptide levels were observed. At follow-up, we observed an increase in VO2 peak of 16% (p<0.0001) and in O2 pulse of 13% (p=0.0002) as well as an improvement in ventilatory response associated with a 7% reduction in the VE/VCO2 slope (p=0.0001). An 8% increase in the ΔVO2/Δ work ratio and an 18% increase in exercise tolerance were also observed. Multivariate logistic regression analysis showed that the main predictors of events during follow-up were VE/VCO2 slope >34 (OR 3.98; 95% CI [1.59–10.54]; p=0.0028); ventilatory oscillatory pattern (OR 4.65; 95% CI [1.55–16.13]; p=0.0052); and haemoglobin level (OR 0.35; 95% CI [0.21–0.55]; p<0.0001). In patients who had cardiac magnetic resonance, when delayed enhancement >4.6% was detected, a lower response after sacubitril/valsartan therapy was observed as expressed by improvement in ΔVO2 peak, O2 pulse, LVEF and N-terminal pro-B-type natriuretic peptide. No significant differences were observed in ΔVO2/Δ work and VE/VCO2 slope. Conclusion: Sacubitril/valsartan improves cardiopulmonary functional capacity in HFrEF patients. The presence of myocardial fibrosis on cardiac magnetic resonance is a predictor of response to therapy.

Introduction: The metabolic syndrome is frequently associated with liver disease; the presence of obesity and diabetes boost progression to liver cirrhosis. These conditions make lifestyle changes aiming weight loss, crucial for prevention and treatment. The Mediterranean Diet (MD) has proved to be the most useful tool for losing and maintaining weight, protecting from cardiovascular mortality.

Differential diagnosis between Anderson-Fabry (AF) and sarcomeric hypertrophic cardiomyopathy (HCM) is often very challenging particularly in AF patients with late onset cardiac involvement. To gain new insights from standard electrocardiogram (ECG) in AF disease for differential diagnosis from sarcomeric HCM. Additionally, to better understand ECG features in AF patients, a correlation substudy ECG-cardiac magnetic resonance (CMR) has been performed. From 162 patients with definite diagnosis of AF disease, 111 [65 males, median age 57 (51–67) years] with pathologic left ventricular hypertrophy (LVH) (Group A) were compared with 111 sarcomeric HCM patients (Group B) sex, age and maximal wall thickness matched by 1:1 propensity score. AF patients showed shorter PR interval [155 (140–180) vs 163 (149–184) msec; p=0.005) and wider QRS interval [110 (100–134) vs 100 (90–106) msec; p<0.0001). Additionally AF patients had a higher prevalence of complete (22% vs 3%; p<0.0001) and incomplete (13% vs 1%; p<0.0001) right bundle branch block (RBBB) and a higher percentage of ST segment depression (12% vs 1%; p=0.001) and inferior negative T waves (34% vs 19%; p=0.01). No differences in terms of Sokolow-Lyon and Cornell scores were found whereas total QRS score was higher in Group A [20 (16–27) vs 18 [14–22] mV; p=0.0004). Low QRS voltages and inferior Q waves were not present in AF patients. Among the 69 AF patients who underwent MRI, the 44 with late gadolinium enhancement (LGE) were older [59 (52–66) vs 53 (40–59) years; p=0.017] and had more frequently negative T waves on ECG, particularly in the inferior leads (64% vs 8%; p<0.0001), compared to the 25 without LGE. At multivariate analysis, age and negative T waves were independently associated to the presence of LGE on CMR. Compared to matched sarcomeric HCM, AF patients had a shorter PR, wider QRS and a higher percentage of RBBB in relation to to the different aetiology (storage vs “pure” hypertrophy). The higher total QRS score and the absence of inferior Q waves could reflect the more frequent concentric distribution of LVH. Additionally negative T waves, especially in inferior leads, are related to the presence of LGE on CMR (often in the postero-lateral wall). Type of funding source: None

Iron deficiency (ID) is recognized as an important comorbidity in patients undergoing cardiac surgery; however, it still remains under-diagnosed and under-treated in clinical practice. This study aims at comparing efficacy and the effects on exercise capacity of intravenous ferric carboxymaltose (FCM) versus ferric gluconate (FG) in patients with ID anemia (IDA) resulting from cardiac surgery. We retrospectively analyzed data from our records of in-hospital patients with IDA after cardiac surgery undergoing cardiac rehabilitation. Group I was treated with FG, group II with FCM. Efficacy measures included changes (baseline vs discharge) in hemoglobin (Hb) and in distance traveled at six-minutes walking test (6MWT). Data from 74 in-patients (mean age 67.5±10.4 years, 43% women) were analyzed. At discharge, patients treated with FCM showed higher levels of Hb (11.1±1.2g/dl vs 10.2±1.1 g/dl; p=0.001), greater distance traveled at 6MWT (279.2±108.8 meters vs 236.3±72.7 meters; p=0.048), and lower in-hospital rehabilitation length of stay (20.3±7 vs 25.3±11.7 days; p=0.043) as compared to FG group. At multivariate analysis, the most powerful predictors of Hb increase >1 g/dl at discharge were transferrin levels (p=0.019) and treatment with FCM (p<0.001). FCM replacement therapy and iron serum levels were the most powerful predictors of 6MWT distance improvement (>100 meters) at discharge (p=0.13 and p=0.003, respectively). In patients with IDA following cardiac surgery, intravenous FCM is effective in restoring Hb levels and in improving exercise capacity after cardiac surgery.

Abstract Background Anderson Fabry (AF) disease is a X-linked lysosomal storage disorder with multiorgan involvement. Cardiac disease, mainly represented by left ventricular hypertrophy (LVH) and arrhythmias, is the most frequent cause of premature death. It is well know that specific therapy is less effective after the development of LVH and myocardial fibrosis, therefore early cardiac detection (before LVH) is important. New cardiac magnetic resonance (CMR) parametric imaging techniques (T1 and T2 maps) enable myocardial tissue changes associated with AF disease. Purpose To evaluate the relationship between CMR tissue characterization and clinical and instrumental manifestations of AF disease to find early markers of cardiac involvement. Methods 31 AF patients (9 males, mean age 49±16 years) underwent ECG, echocardiogram and contrast CMR. TnI, BNP, pro-BNP and serum lyso-Gb3 were dosed. T1 mapping was performed in a pre-contrast acquisition with the modified Look-Locker inversion recovery (MOLLI) sequences. CMR results were compared with those of 43 healthy age and gender-matched controls. Results In AF patients native septal T1 values were significantly lower compared to healthy controls (median 949 vs 991 msec, p=0.0137) and were inversely related to Lyso-Gb3 serum levels (p=0.003). Patients with LVH had lower T1 septal values in comparison with patients without LVH (892 vs 981 msec; p=0.0012). Patients with classic form had abnormal low T1 values more frequently than pts with late onset variant (78 vs 23%; p=0.038). In AF patients native septal T2 values were significantly higher compared to the control group (53 vs 49 msec; p=0.0004) and correlated with troponin I (p=0.008) and NT-pro BNP (p=0.006) serum levels. No difference was found between pts with and without LVH (53.5 vs 52.5 ms; p=0.797) and the prevalence of abnormal high T2 values was similar between patients with late onset AF and pts with classical form (53% vs 50%; p=1.000). All patients with late onset AF and high T2 values were females. Conclusions CMR T1 (low values) and T2 (high values) mapping are useful tools to detect early cardiac involvement before LVH and to better understand the pathophysiology of cardiac disease in AF patients. Subclinical tissue inflammation, detectable through T2 maps, seems to be an additional pathogenetic mechanism related to the Gb3 storage that contributes to organ damage and precedes LVH, particularly in females patients with late onset phenotype. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Sant'Orsola-Malpighi Hospital

Abstract BACKGROUND Cardiac Masses (CM) represent an heterogeneous group with a prevalence of 0.3% at autopsy, divided in benign masses (primary tumors and pseudotumors) and malignant ones (primitive tumors and metastasis). 2-D Echocardiography is nowadays the first line approach to define nature and management of CM, but is it enough to guide a therapeutic strategy? PURPOSE To evaluate echocardiographic diagnosis accuracy for CM in patients admitted to our Centre between 1997 and 2017. MATERIALS AND METHODS We retrospectively evaluated a population of 180 consecutive patients (45% males; mean age 60 ± 16 years; BMI 25 ± 5 Kg/m2), referred to our echocardiographic lab with suspicion CM. All patients were examined in both left lateral and supine position, and heart was visualized from all available echocardiographic windows. Definite diagnosis was obtained by histologic examination of biopsy, surgical samples or, in cases of cardiac thrombi, by radiological evidence of thrombus resolution after adequate anticoagulant treatment. We excluded normal anatomical variants in the group of pseudotumors due to the impossibility of obtaining histological examination. Sensitivity, specificity, predictive accuracy for a positive test, and predictive accuracy for a negative test were calculated by standard formulas (corrected for prevalence by Bayes theorem). RESULTS We detected 129 benign CM and 51 malignant cardiac tumors. In 7 cases a poor acoustic window did not allow an optimal examination; in remaining 173 patients, the classical 2-D echocardiogram identified 157 masses with a diagnostic accuracy of 91%. Of 173 CM diagnosed, 146 were classified by echocardiographer as benign masses (125 true benign on histological examination) and 27 as malignant ones (all malignant after histological confirmation); the results showed 56% sensitivity, 100% specificity, 100% positive predictive value, 98% negative predictive value, with 88% overall diagnostic accuracy in identifying the nature of masses. 23 cases were undetermined and needed second level instrumental investigations to be characterized. Diagnostic accuracy for distinguishing primary benign tumors and pseudotumors decreased to 80%, with a significant increase in both "false" benign tumors (9 out of 91) and "false" pseudotumors (15 out of 34) with 85% sensitivity, 68% specificity, 10% positive predictive value, 99% negative predictive value. CONCLUSION 2D Echocardiography is an excellent, non invasive technique for first line evaluation of patients with suspicion CM. It is safe, reliable with a high predictive value and diagnostic accuracy in identifying CM and their benign or malignant nature. In contrast, these results were insufficient to start an anticoagulant in suspicion thrombus or cardiac surgery for primary tumor, since second level instrumental examinations needed. 2D Echocardiography alone seems unuseful for classifying malignant masses in primitive or metastasis.

Abstract Aims Ventilation vs. carbon dioxide production (VE/VCO2) is among the strongest cardiopulmonary exercise testing prognostic parameters in heart failure (HF). It is usually reported as an absolute value. The current definition of normal VE/VCO2 slope values is inadequate, since it was built from small groups of subjects with a particularly limited number of women and elderly. We aimed to define VE/VCO2 slope prediction formulas in a sizable population and to test whether the prognostic power of VE/VCO2 slope in HF was different if expressed as a percentage of the predicted value or as an absolute value. Methods and results We calculated the linear regressions between age and VE/VCO2 slope in 1136 healthy subjects (68% male, age 44.9 ± 14.5, range 13–83 years). We then applied age‐adjusted and sex‐adjusted formulas to predict VE/VCO2 slope to HF patients included in the metabolic exercise test data combined with cardiac and kidney indexes score database, which counts 6112 patients (82% male, age 61.4 ± 12.8, left ventricular ejection fraction 33.2 ± 10.5%, peakVO2 14.8 ± 4.9, mL/min/kg, VE/VCO2 slope 32.7 ± 7.7) from 24 HF centres. Finally, we evaluated whether the use of absolute values vs. percentages of predicted VE/VCO2 affected HF prognosis prediction (composite of cardiovascular mortality + urgent transplant or left ventricular assist device). We did so in the entire cardiac and kidney indexes score population and separately in HF patients with severe (peakVO2 < 14 mL/min/kg, n = 2919, 61.1 events/1000 pts/year) or moderate (peakVO2 ≥ 14 mL/min/kg, n = 3183, 19.9 events/1000 pts/year) HF. In the healthy population, we obtained the following equations: female, VE/VCO2 = 0.052 × Age + 23.808 (r = 0.192); male, VE/VCO2 = 0.095 × Age + 20.227 (r = 0.371) (P = 0.007). We applied these formulas to calculate the percentages of predicted VE/VCO2 values. The 2‐year survival prognostic power of VE/VCO2 slope was strong, and it was similar if expressed as absolute value or as a percentage of predicted value (AUCs 0.686 and 0.690, respectively). In contrast, in severe HF patients, AUCs significantly differed between absolute values (0.637) and percentages of predicted values (0.650, P = 0.0026). Moreover, VE/VCO2 slope expressed as a percentage of predicted value allowed to reclassify 6.6% of peakVO2 < 14 mL/min/kg patients (net reclassification improvement = 0.066, P = 0.0015). Conclusions The percentage of predicted VE/VCO2 slope value strengthens the prognostic power of VE/VCO2 in severe HF patients, and it should be preferred over the absolute value for HF prognostication. Furthermore, the widespread use of VE/VCO2 slope expressed as percentage of predicted value can improve our ability to identify HF patients at high risk, which is a goal of utmost clinical relevance.

Cancer and cardiovascular diseases are globally the leading causes of mortality and morbidity. These conditions are closely related, beyond that of sharing many risk factors. The term bidirectional relationship indicates that cardiovascular diseases increase the likelihood of getting cancer and vice versa. The biological and biochemical pathways underlying this close relationship will be analyzed. In this new overlapping scenario, physical activity and exercise are proven protective behaviors against both cardiovascular diseases and cancer. Many observational studies link an increase in physical activity to a reduction in either the development or progression of cancer, as well as to a reduction in risk in cardiovascular diseases, a non-negligible cause of death for long-term cancer survivors. Exercise is an effective tool for improving cardio-respiratory fitness, quality of life, psychological wellbeing, reducing fatigue, anxiety and depression. Finally, it can counteract the toxic effects of cancer therapy. The protection obtained from physical activity and exercise will be discussed in the various stages of the cancer continuum, from diagnosis, to adjuvant therapy, and from the metastatic phase to long-term effects. Particular attention will be paid to the shelter against chemotherapy, radiotherapy, cardiovascular risk factors or new onset cardiovascular diseases. Cardio-Oncology Rehabilitation is an exercise-based multi-component intervention, starting from the model of Cardiac Rehabilitation, with few modifications, to improve care and the prognosis of a patient’s cancer. The network of professionals dedicated to Cardiac Rehabilitation is a ready-to-use resource, for implementing Cardio-Oncology Rehabilitation.

BACKGROUND:atherosclerotic process inexorably advances in patients reaching low-density lipoprotein cholesterol (LDL-C) targets. An attractive hypothesis is that lipoprotein particles (very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL)), could contribute to residual risk. The present study aims to investigate the relationship between carotid intima-media thickness (IMT) and different lipoprotein subfractions in a cohort of healthy postmenopausal women.METHODS:75 postmenopausal women, at LDL-C target levels without overt cardiovascular disease, underwent biochemical analyses (including subfraction assay of plasma lipoproteins) and carotid ultrasound examination.RESULTS:a statistically significant correlation between VLDL and carotid IMT (p < 0.001) was found. No significant correlation was found between carotid IMT and LDL-C (p = 0.179), IDL-C (p = 0.815), high-density lipoprotein (HDL) (p = 0.855), and LDL score (p = 0.240). Moreover, IMT is significantly correlated to LDL particle diameter (p = 0.044). After adjusting for age, systolic blood pressure, body mass index, smoking habits, glucose plasma concentration, and Lipoprotein(a) (Lpa) levels, multivariate analysis showed that women in the third tertile of VLDL-C, compared with those in the first tertile, were significantly associated to the highest IMT (p = 0.04).CONCLUSIONS:in this cohort of postmenopausal women, VLDL-C was significantly associated to carotid IMT, independent of main cardiovascular risk factors. These findings pave the way for targeting circulating concentrations of VLDL-C to reduce cardiovascular events in patients with target LDL-C levels.

Owing to its ease of application, noninvasive nature, and safety, echocardiography is an essential imaging modality to assess cardiac function in patients affected by ischemic heart disease (IHD). Over the past few decades, we have witnessed a continuous series of evolutions in the ultrasound field that have led to the introduction of innovative echocardiographic modalities which allowed to better understand the morphofunctional abnormalities occurring in cardiovascular diseases. This article offers an overview of some of the newest echocardiographic modalities and their promising application in IHD diagnosis, risk stratification, management, and monitoring after cardiac rehabilitation.

Atrial fibrillation (AF) and Heart Failure (HF) are evolving epidemies, together responsible for substantial human suffering and health-care expenditure. The simultaneous co-existence of the two conditions is associated with higher mortality rates than those observed in individuals with only one or none of them. Patients with concomitant HF and AF suffer from even worse symptoms and poorer prognosis, yet evidence-based evaluation and management of this group of patients is lacking. In this review, we evaluate the common mechanisms for the development of AF in HF patients and vice versa, focusing on the evidence for potential treatment strategies. Recent data have suggested that these patients may respond differently if compared to those with HF or AF alone. These results highlight the clear clinical need to identify and treat these diseases according to best evidence, in order to prevent adverse outcomes and reduce the huge burden that HF and AF are expected to have on global healthcare systems in the future.

Oxidative stress and mitochondrial dysfunction are hallmarks of heart failure (HF). Coenzyme Q10 (CoQ10) is a vitamin-like organic compound widely expressed in humans as ubiquinol (reduced form) and ubiquinone (oxidized form). CoQ10 plays a key role in electron transport in oxidative phosphorylation of mitochondria. CoQ10 acts as a potent antioxidant, membrane stabilizer and cofactor in the production of adenosine triphosphate by oxidative phosphorylation, inhibiting the oxidation of proteins and DNA. Patients with HF showed CoQ10 deficiency; therefore, a number of clinical trials investigating the effects of CoQ10 supplementation in HF have been conducted. CoQ10 supplementation may confer potential prognostic advantages in HF patients with no adverse hemodynamic profile or safety issues. The latest evidence on the clinical effects of CoQ10 supplementation in HF was reviewed.

Atrial fibrillation (AF) and heart failure (HF) are evolving epidemies, together responsible for substantial human suffering and health-care expenditure. The simultaneous co-hexistence of the two conditions is associated with mortality rates higher than those observed in individuals with only one or none of them. Patients with concomitant HF and AF suffer from even worse symptoms and poorer prognosis, yet evidence-based evaluation and management of this group of patients is lacking. In this review, we evaluate the common mechanisms for the development of AF in HF patients and vice versa, focusing on the evidence for potential treatment strategies. Recent data have suggested that these patients may respond differently if compared to those with HF or AF alone. These results highlight the clear clinical need to identify and treat these diseases according to best evidence, in order to prevent adverse outcomes and reduce the huge burden that HF and AF are expected to have on global healthcare systems in the future.

BACKGROUND:Heart rate recovery (HRR) is a marker of vagal tone, which is a powerful predictor of mortality in patients with cardiovascular disease. Sacubitril/valsartan (S/V) is a treatment for heart failure with reduced ejection fraction (HFrEF), which impressively impacts cardiovascular outcome. This study aims at evaluating the effects of S/V on HRR and its correlation with cardiopulmonary indexes in HFrEF patients.METHODS:Patients with HFrEF admitted to outpatients' services were screened out for study inclusion. S/V was administered according to guidelines. Up-titration was performed every 4 weeks when tolerated. All patients underwent laboratory measurements, Doppler-echocardiography, and cardiopulmonary exercise stress testing (CPET) at baseline and at 12-month follow-up.RESULTS:Study population consisted of 134 HFrEF patients (87% male, mean age 57.9 ± 9.6 years). At 12-month follow-up, significant improvement in left ventricular ejection fraction (from 28% ± 5.8% to 31.8% ± 7.3%, p < 0.0001), peak exercise oxygen consumption (VO2peak) (from 15.3 ± 3.7 to 17.8 ± 4.2 mL/kg/min, p < 0.0001), the slope of increase in ventilation over carbon dioxide output (VE/VCO2 slope )(from 33.4 ± 6.2 to 30.3 ± 6.5, p < 0.0001), and HRR (from 11.4 ± 9.5 to 17.4 ± 15.1 bpm, p = 0.004) was observed. Changes in HRR were significantly correlated to changes in VE/VCO2slope (r = -0.330; p = 0.003). After adjusting for potential confounding factors, multivariate analysis showed that changes in HRR were significantly associated to changes in VE/VCO2slope (Beta (B) = -0.975, standard error (SE) = 0.364, standardized Beta coefficient (Bstd) = -0.304, p = 0.009). S/V showed significant reduction in exercise oscillatory ventilation (EOV) detection at CPET (28 EOV detected at baseline CPET vs. 9 EOV detected at 12-month follow-up, p < 0.001). HRR at baseline CPET was a significant predictor of EOV at 12-month follow-up (B = -2.065, SE = 0.354, p < 0.001).CONCLUSIONS:In HFrEF patients, S/V therapy improves autonomic function, functional capacity, and ventilation. Whether these findings might translate into beneficial effects on prognosis and outcome remains to be elucidated.

Raw data of the manuscript "Gender and age normalization and ventilation efficiency during exercise in heart failure with reduced ejection fraction." Aims: Ventilation vs. carbon dioxide production (VE/VCO2 ) is among the strongest cardiopulmonary exercise testing prognostic parameters in heart failure (HF). It is usually reported as an absolute value. The current definition of normal VE/VCO2 slope values is inadequate, since it was built from small groups of subjects with a particularly limited number of women and elderly. We aimed to define VE/VCO2 slope prediction formulas in a sizable population and to test whether the prognostic power of VE/VCO2 slope in HF was different if expressed as a percentage of the predicted value or as an absolute value. Methods and results: We calculated the linear regressions between age and VE/VCO2 slope in 1136 healthy subjects (68% male, age 44.9 ± 14.5, range 13-83 years). We then applied age-adjusted and sex-adjusted formulas to predict VE/VCO2 slope to HF patients included in the metabolic exercise test data combined with cardiac and kidney indexes score database, which counts 6112 patients (82% male, age 61.4 ± 12.8, left ventricular ejection fraction 33.2 ± 10.5%, peakVO2 14.8 ± 4.9, mL/min/kg, VE/VCO2 slope 32.7 ± 7.7) from 24 HF centres. Finally, we evaluated whether the use of absolute values vs. percentages of predicted VE/VCO2 affected HF prognosis prediction (composite of cardiovascular mortality + urgent transplant or left ventricular assist device). We did so in the entire cardiac and kidney indexes score population and separately in HF patients with severe (peakVO2 < 14 mL/min/kg, n = 2919, 61.1 events/1000 pts/year) or moderate (peakVO2 ≥ 14 mL/min/kg, n = 3183, 19.9 events/1000 pts/year) HF. In the healthy population, we obtained the following equations: female, VE/VCO2 = 0.052 × Age + 23.808 (r = 0.192); male, VE/VCO2 = 0.095 × Age + 20.227 (r = 0.371) (P = 0.007). We applied these formulas to calculate the percentages of predicted VE/VCO2 values. The 2-year survival prognostic power of VE/VCO2 slope was strong, and it was similar if expressed as absolute value or as a percentage of predicted value (AUCs 0.686 and 0.690, respectively). In contrast, in severe HF patients, AUCs significantly differed between absolute values (0.637) and percentages of predicted values (0.650, P = 0.0026). Moreover, VE/VCO2 slope expressed as a percentage of predicted value allowed to reclassify 6.6% of peakVO2 < 14 mL/min/kg patients (net reclassification improvement = 0.066, P = 0.0015). Conclusions: The percentage of predicted VE/VCO2 slope value strengthens the prognostic power of VE/VCO2 in severe HF patients, and it should be preferred over the absolute value for HF prognostication. Furthermore, the widespread use of VE/VCO2 slope expressed as percentage of predicted value can improve our ability to identify HF patients at high risk, which is a goal of utmost clinical relevance.

Abstract Aim To look for differences in cardiac phenotype and natural history of patients affected by laminopathy, according to the presence or less of neuromuscular involvement at clinical presentation. Methods We prospectively analyzed 47 consecutive pts with a genetic diagnosis of laminopathy followed at a single centre between 1994 and 2017. Additionally, reports of clinical and instrumental evaluations before referral at our centre were retrospectively evaluated. Results Neuromuscular presentation, mainly as Emery-Dreifuss muscular dystrophy (EDMD), was present in 21 (46%) cases (14 LMNA and 7 EMD gene mutations). These pts had symptoms earlier (9 vs 39 years, p<0.001) in life compared to pts without neuromuscular onset (26 LMNA gene mutations), and clinical manifestations anticipated the first evidence of cardiac disease by a mean time of 15±8 years (maximum time gap of 38 years). Despite a similar prevalence of atrial fibrillation/flutter (AF) (71% vs 65%, p=0.758) and atrio-ventricular blocks (48% vs 65%, p=0.250), pts with neuromuscular onset experienced AF and pace-maker implantation at a significantly younger age (27 vs 41 yrs, p=0.015 and 23 vs 44 yrs, p=0.027 respectively). Differently a higher prevalence of sinus node dysfunction (33% vs 4%; p=0.015) and atrial paralysis (14% vs 4%; p=0.311) was reported in pts with neuromuscular onset. Prevalence of cardiomyopathy (CMP) (73% vs 33%, p=0.008) and sustained ventricular tachyarrhythmias were higher among pts with cardiac onset (23% vs 4%, p=0.111) whereas the prevalence of heart transplantations and median age of recipients were similar in the two groups (24% vs 20%, p=1.000 and 46 vs 43, p=0.592 years respectively). All pts with neuromuscular onset who received a diagnosis of CMP had a previous history of rhythm disturbance except 2 cases, where a concomitant diagnosis of the 2 disorders was formulated. On the contrary a strict temporal progression from rhythm disturbances to CMP (or viceversa) was not appreciable in the other group: AF and AVBs could precede the diagnosis of CMP be diagnosed at the same time or later. Conclusions In pts affected by laminopathy neuromuscular involvement, when present, was most often the first clinical manifestation and preceded cardiological involvement, with a long time frame in some cases. Except for sinus node dysfunction, much more frequent in patients with EDMD, a similar prevalence of rhythm disturbances was reported, although pts with neuromuscular clinical onset were younger at diagnosis of AF and at PM implantation. Pts without neuromuscular presentation had a higher prevalence of CMP and ventricular arrhythmias, albeit a similar rate of heart transplantation. In pts with neuromuscular onset, cardiac involvement was characterized by a stepwise progression from rhythm disturbances to CMP, where a strict temporal progression from rhythm disturbances to CMP was not observed in the group of pts without neuromuscular clinical onset.