Search

ObjectivesReduced cardiac output (CO) has been considered crucial in symptoms’ genesis in hypertrophic cardiomyopathy (HCM). Absolute value and temporal behaviour of O2-pulse (oxygen uptake/heart rate (VO2/HR)), and the VO2/work relationship during exercise reflect closely stroke volume (SV) and CO changes, respectively. We hypothesise that adding O2-pulse absolute value and kinetics, and VO2/work relationship to standard cardiopulmonary exercise testing (CPET) could help identify more exercise-limited patients with HCM.MethodsCPETs were performed in 3 HCM dedicated clinical units. We retrospectively enrolled non-end-stage consecutive patients with HCM, grouped according to left ventricle outflow tract obstruction (LVOTO) at rest or during Valsalva manoeuvre (72% of patients with LVOTO 2-pulse and VO2, respectively, considering their absolute values and temporal behaviour during exercise.ResultsWe included 312 patients (70% males, age 49±18 years). Peak VO2(percentage of predicted), O2-pulse and ventilation to carbon dioxide production (VE/VCO2) slope did not change across LVOTO groups. Ninety-six (31%) patients with HCM presented an abnormal O2-pulse temporal behaviour, irrespective of LVOTO values. These patients showed lower peak systolic pressure, workload (106±45 vs 130±49 W), VO2(21.3±6.6 vs 24.1±7.7 mL/min/kg; 74%±17% vs 80%±20%) and O2-pulse (12 (9–14) vs 14 (11–17) mL/beat), with higher VE/VCO2slope (28 (25–31) vs 27 (24–31)) (p2/work slope.ConclusionNone of the frequently used CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal temporal behaviour of O2-pulse during exercise, which is strongly related to inadequate SV increase, correlates with reduced functional capacity (peak and anaerobic threshold VO2and workload) and increased VE/VCO2slope, identifying more advanced disease irrespectively of LVOTO.

Background: The prognostic role of moderate hyperkalemia in reduced ejection fraction (HFrEF) patients is still controversial. Despite this, it affects the use of renin–angiotensin–aldosterone system inhibitors (RAASi) with therapy down-titration or discontinuation. Objectives: Aim of the study was to assess the prognostic impact of moderate hyperkalemia in chronic HFrEF optimally treated patients. Methods and results: We retrospectively analyzed MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes) database, with median follow-up of 4.2 [IQR 1.9–7.5] years. Data on K+ levels were available in 7087 cases. Patients with K+ plasma level ≥ 5.6 mEq/L and < 4 mEq/L were excluded. Remaining patients were categorized into normal >4 and < 5 mEq/L (n = 4826, 68%) and moderately high ≥5.0 and ≤ 5.5 mEq/L (n = 496, 7%) K+. Then patients were matched by propensity score in 484 couplets of patients. MECKI score value was 7% [IQR 3.1–14.1%] and 7.3% [IQR 3.4–15%] (p = 0.678) in patients with normal and moderately high K+ values while cardiovascular mortality events at two years follow-up were 41 (4.2%) and 33 (3.4%) (p = 0.333) in each group respectively. Conclusions: Moderate hyperkalemia does not influence patients' outcome in a large cohort of ambulatory HFrEF patients.

Background: The role of risk scores in heart failure (HF) management has been highlighted by international guidelines. In contrast with HF, which is intrinsically a dynamic and unstable syndrome, all its prognostic studies have been based on a single evaluation. We investigated whether time-related changes of a well-recognized risk score, the MECKI score, added prognostic value. MECKI score is based on peak VO2, VE/VCO2 slope, Na+, LVEF, MDRD and Hb. Methods: A multi-centre retrospective study was conducted involving 660 patients who performed MECKI re-evaluation at least 6 months apart. Based on the difference between II and I evaluation of MECKI values (MECKI II - MECKI I = ∆ MECKI) the study population was divided in 2 groups: those presenting a score reduction (∆ MECKI 0, clinical deterioration). Results: The prognostic value of MECKI score is confirmed also when re-assessed during follow-up. The group with improved MECKI (366 patients) showed a better prognosis compared to patients with worsened MECKI (294 patients) (p < 0.0001). At 1st evaluation, the two groups differentiated by LVEF, VE/VCO2 slope and blood Na+ concentration, while at 2nd evaluation they differentiated in all 6 parameters considered in the score. The patients who improved MECKI score, improved in all components of the score but hemoglobin, while patients who worsened the score, worsened all parameters. Conclusions: This study shows that re-assessment of MECKI score identifies HF subjects at higher risk and that score improvement or deterioration regards several MECKI score generating parameters confirming the holistic background of HF.

Background Myocardial infarction with non-obstructed coronary arteries (MINOCA) is an increasingly recognized condition with challenging management. Prognosis of this patients could be of concern, in particular for those who experienced recurrent acute myocardial infarction (re-AMI). Moreover, there are limited data on characteristics of re-AMI among MINOCA patients. Methods In this retrospective multicentre cohort study involving seven Hub Hospitals across Italy we enrolled consecutive patients 18 years and older discharged with diagnosis of MINOCA according to the IV universal definition of myocardial infarction who experienced hospitalization for re-AMI during follow-up. Results A total of 54 patients were included (mean age 66±13). Compared to MINOCA patients without re-AMI (n=695), on first angiography MINOCA patients with re-AMI showed less frequently angiographically normal coronaries (37 versus 53%, p=0,032) and had higher prevalence of atherosclerosis involving 3 vessels or left main stem (17% versus 8%, p=0,049). Twenty four patients (44%) with re-AMI underwent a new coronary angiography and 25% had normal coronary arteries, 12% had mild luminal irregularities ( Among patients undergoing new angiography, only 4% had LDL cholesterol under 55 mg/dL, atherosclerosis progression was observed in 11 (46%), 38% received revascularization and 33% experienced a new cardiovascular event (death, AMI, heart failure, stroke) at subsequent follow-up. Conclusions In the present study near one out of two patients with re-AMI after MINOCA showed angiographic atherosclerosis progression requiring revascularization in the majority of cases. These patients rarely presented with recommended LDL cholesterol levels and are at risk for further cardiovascular events, indicating a possible underestimation of cardiovascular risk in this population.

Background although cardiopulmonary exercise testing (CPET) is a recognized tool for prognostic stratification in patients with dilated cardiomyopathy (DCM), there are no data about the prognostic value of its repetition during follow-up in this setting. The aim of this study was to test the prognostic value of repeating CPET during follow-up, among a large cohort of DCM patients. Methods in this multicenter, retrospective study, we analyzed DCM patients who consecutively performed at least two CPET during a clinical stable phase of disease. All patients performed CPET and echocardiogram within 10 days. The study end-point was a composite of death from all causes, heart transplantation, implantation of durable left ventricular assist device, life-threatening ventricular arrhythmias or hospitalization for HF. Results 216 DCM patients were enrolled (52±12 years, 78% male, NYHA I-II 82%, LVEF 32±9%, 94% on ACE inhibitors, 95% on beta-blockers); the duration of the disease at the time of first CPET was 68 months. The interval between the two CPETs was 15 (11;23) months. During a median follow-up of 38 months from the second CPET, 108 (47%) patients went through the end-point. Time-dependent ROC curves revealed that to repeat during a follow-up of 12 months both CPET and echocardiogram gives a more accurate prognostic stratification than basal echocardiography + basal CPET. Despite an higher AUC (0.91 vs 0.85) there were no significant different accuracies (95% CI: 83.6 - 98 vs 75.5–96.5; p-value: 0.2) between the repetition of CPET plus echocardiogram vs. the repetition of the echocardiogram alone. Among patients who experienced the study outcome, there was a substantial stability of echocardiographic values (relative variation of LVEF +2.7%, LVEDV +1.3%) but a significant worsening of functional capacity (relative variation of percentage predicted VO2 peak +6%, p-value: 0.002). Conversely, there were a significant improvement in echocardiographic values and CPET values in events-free patients (LVEF relative variation -8.6% p-value: 0.002; ppVO2 peak relative variation -6.8%, p-value: 0.002). Conclusion in a large population of clinically stable DCM patients, the systematic repetition of echocardiography or both CPET and echocardiography showed no significant prognostic impact, in presence of stable or worsened echocardiogram. Nevertheless, when there is a clinical variation of symptoms or a failing in the reverse remodeling process, 1-year repetition of CPET can identify higher risk patients.

Background: Physiological cardiac remodelling in highly trained athletes may overlap with dilated cardiomyopathy (DCM). Objectives: The aim of this study was to investigate the role of the electrocardiogram (ECG) in differentiating between physiological and pathological remodelling. Methods: The study population consisted of 30 patients with DCM who revealed a pathogenic variant at genetic testing and 30 elite athletes with significant cardiac remodelling defined by a left ventricular (LV) end-diastolic diameter >62 mm and/or LV ejection fraction between 45% and 50%. Results: The ECG was abnormal in 22 (73%) patients with DCM. The most common abnormalities were low voltages (n = 14, 47%), lateral T-wave inversion (TWI) (n = 6, 20%), ventricular ectopic beats (n = 5, 17%) and anterior TWI (n = 4, 13). Two athletes revealed an abnormal ECG: complete left bundle branch block (LBBB) in one case and atrial flutter in the other. The sensitivity, specificity and accuracy of the ECG in differentiating DCM from physiological adaptation to exercise in athletes was 73% (confidence interval [CI]: 54%-88%), 93% (CI: 78%-99%) and 0.83 (CI: 0.71-0.92) respectively. Conclusions: While the ECG is usually normal in athletes exhibiting significant LV dilatation and/or systolic dysfunction, this test is often abnormal in patients with DCM harbouring a pathogenic variant. Low voltages in the limb leads and lateral TWI are the most common abnormalities.

Background: Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood. Objectives: We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing. Methods: Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD). Results: Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD. Conclusions: Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing.

Prognostic stratification of cardiomyopathies represents a cornerstone for the appropriate management of patients and is focused mainly on arrhythmic events and heart failure. Cardiopulmonary exercise testing provides additional prognostic information, particularly in the setting of heart failure. Cardiopulmonary exercise testing data, integrated in scores such as the Metabolism Exercise Cardiac Kidney Index score have been shown to improve the risk stratification of these patients. Cardiopulmonary exercise testing has been analysed as a potential supplier of prognostic parameters in the context of hypertrophic cardiomyopathy, for which it has been shown that a reduced oxygen consumption peak, an increased ventilation/carbon dioxide production slope and chronotropic incompetence correlate with a worse prognosis. To a lesser extent, in dilated cardiomyopathy, it has been shown that the percentage of oxygen consumption peak, not the pure value, and the ventilation/carbon dioxide production slope are associated with a greater cardiovascular risk. Few data are available about other cardiomyopathies (arrhythmogenic and restrictive). Cardiomyopathy patients should be early and routinely referred to heart failure advanced centres in order to perform a comprehensive risk stratification which should include a cardiopulmonary exercise test, with variables and cut-offs shown to improve their risk stratification.

Nonischemic-dilated cardiomyopathy (NIDCM) is an entity that gathers extremely heterogeneous diseases. This awareness, although leading to continuous improvement in survival, has increased the complexity of NIDCM patients' management. Even though the endorsed 'red-flags' approach helps clinicians in pursuing an accurate etiological definition in clinical practice, it is not clear when and how peripheral centers should interact with referral centers with specific expertise in challenging scenarios (e.g. postmyocarditis and genetically determined dilated cardiomyopathy) and with easier access to second-line diagnostic tools and therapies. This position paper will summarize each step in NIDCM management, highlighting the multiple interactions between peripheral and referral centers, from first-line diagnostic workup and therapy to advanced heart failure management and long-term follow-up.

Background: In clinical practice, anaerobic threshold (AT) is used to guide training and rehabilitation programs, to define risk of major thoracic or abdominal surgery, and to assess prognosis in heart failure (HF). AT of oxygen uptake (V.O2; V.O2AT) has been reported as an absolute value (V.O2ATabs), as a percentage of predicted peak V.O2 (V.O2AT%peak_pred), or as a percentage of observed peak V.O2 (V.O2AT%peak_obs). A direct comparison of the prognostic power among these different ways to report AT is missing. Research question: What is the prognostic power of these different ways to report AT? Study design and methods: In this observational cohort study, we screened data of 7,746 patients with HF with a history of reduced ejection fraction (< 40%) recruited between 1998 and 2020 and enrolled in the Metabolic Exercise Combined With Cardiac and Kidney Indexes register. All patients underwent a maximum cardiopulmonary exercise test, executed using a ramp protocol on an electronically braked cycle ergometer. Results: This study considered 6,157 patients with HF with identified AT. Follow-up was median, 4.2 years (25th-75th percentiles, 1.9-5.0 years). Both V.O2ATabs (mean ± SD, 823 ± 305 mL/min) and V.O2AT%peak_pred (mean ± SD, 39.6 ± 13.9%), but not V.O2AT%peak_obs (mean ± SD, 69.2 ± 17.7%), well stratified the population regarding prognosis (composite end point: cardiovascular death, urgent heart transplant, or left ventricular assist device). Comparing area under the receiver operating characteristic curve (AUC) values, V.O2ATabs (0.680) and V.O2AT%peak_pred (0.688) performed similarly, whereas V.O2AT%peak_obs (0.538) was significantly weaker (P < .001). Moreover, the V.O2AT%peak_pred AUC value was the only one performing as well as the AUC based on peak V.O2 (0.710), with an even a higher AUC (0.637 vs 0.618, respectively) in the group with severe HF (peak V.O2 < 12 mL/min/kg). Finally, the combination of V.O2AT%peak_pred with peak V.O2 and V. per CO2 production shows the highest prognostic power. Interpretation: In HF, V.O2AT%peak_pred is the best way to report V.O2 at AT in relationship to prognosis, with a prognostic power comparable to that of peak V.O2 and, remarkably, in patients with severe HF.

Aims Physiological cardiac remodelling in highly trained athletes may overlap with dilated cardiomyopathy (DCM). The aim of this study was to investigate the role of the ECG in differentiating between physiological and pathological remodelling. Methods and results The study population consisted of 30 patients with DCM who revealed a pathogenic variant at genetic testing and 30 elite athletes with significant cardiac remodelling defined by a left ventricular (LV) end-diastolic diameter > 62 mm and/or LV ejection fraction between 45% and 50%. The ECG was abnormal in 22 (73%) patients with DCM. The most common abnormalities were low voltages (n = 14, 47%), lateral TWI (n = 6, 20%), ventricular ectopic beats (n = 5, 17%) and anterior TWI (n = 4, 13). Two athletes revealed an abnormal ECG: complete left bundle branch block (LBBB) in one case and atrial flutter in the other. The sensitivity, specificity and accuracy of the ECG in differentiating DCM from physiological adaptation to exercise in athletes was 73% [confidence interval (CI: 54–88%), 93% (CI: 78–99%), and 0.83 (CI: 0.71–0.92), respectively. Conclusions While the ECG is usually normal in athletes exhibiting significant LV dilatation and/or systolic dysfunction, this test is often abnormal in patients with DCM harbouring a pathogenic variant. Low voltages in the limb leads and lateral TWI are the most common abnormalities.

Aims Cardiomyopathies (CMP) are a heterogeneous group of heart disease characterized by structural and electrical abnormalities with no other secondary causative etiology and frequently related to mutations in disease related genes. Clinical evaluation and phenotype definition are the key factors for clinical classification of CMPs. Recent studies in this field have showed important phenotype overlaps between Dilated Cardiomyopathy (DCM) and Arrhythmogenic Cardiomyopathy (ACM), making the diagnosis a challenging task. The aim of this study is to assess whether a classification of CMP patients (not hypertrophic) based on genetic characterization outperforms in diagnostic and prognostic accuracy the classical, phenotype-driven, diagnostic approach. Methods and results We analysed a population of patients affected by genetically determined DCM and ACM, carriers of ‘pathogenic’ or ‘likely pathogenic’ (P/LP) variants, registered into the Heart Disease Centers of Trieste and Denver hospitals. First, we described the phenotype distribution in our population with a clinical and echocardiographic evaluation based on the different disease-related mutated genes. Then, we examined the prognostic impact of the single gene/genetic cluster in assessing these composite outcomes: (1) all-cause mortality and heart transplant; (2) heart failure-related death, heart transplant or destination left ventricular assist device implantation (DHF/HTx/VAD); and (3) sudden cardiac death, sustained ventricular tachycardia/ventricular fibrillation or appropriate defibrillator shock (SCD/VT/VF/shock). 281 patients carrying P/LP variants (82% DCM) were included in the study. Titin (TTN) and sarcomeric genes (SARC) variants were the most prevalent (TTN: 95 patients, 34% of total population; SARC: 63 patients, 22% of total population) and almost completely related to DCM phenotype (TTN: 100% DCM, SARC: 95% DCM), such as lamin (LMNA) patients (29 patients, 10% of total population, 96% DCM). A more heterogeneous phenotypic distribution between DCM and ACM were detected for desmoplakin (DSP), plakoglobin (PKP2), and filamin (FLNC) variants. Patients with not isolated DCM phenotype and patients’ carriers of DSP, PKP2, FLNC and LMNA variants (arrhythmic genes) experienced more frequent SCD/VT/VF/shock events (P-value = 0.002 and P = 0.023), compared respectively to patients with DCM phenotype and to patients’ carriers of TTNtv and SARC variants, during follow-up (median time 132 months). The multivariable analysis shown that only P/LP variants of arrhythmic genes, younger age of disease onset and male gender, were associated with an increased risk of SCD/VT/VF/shock events during follow-up. No difference in terms of HF events was significantly related to genotype. Conclusions Our study demonstrated that the classification based on the presence of a specific genotype outperforms phenotypic classification in terms of arrhythmic risk in a large DCM and ACM population with a positive genetic test for P/LP variants. These findings support the need of extensive genetic testing to support CMP diagnosis and prognosis.

Aims Reduced cardiac output (CO) has been considered crucial in symptoms’ genesis in hypertrophic cardiomyopathy (HCM). We evaluated the cardiopulmonary exercise testing (CPET) response in HCM focusing on parameters strongly associated with stroke volume (SV) and cardiac output (CO), such as oxygen uptake (VO2) and O2-pulse, considering both their absolute values and temporal behaviour during physical exercise. Methods and results We enrolled 312 non-end stage HCM patients, divided according to left ventricle outflow tract obstruction (LVOTO) at rest or during Valsalva manoeuver (72% with LVOTO Conclusions None of CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal O2-pulse exercise behaviour, which is strongly related to inadequate SV during exercise, correlates with reduced functional capacity (peak and anaerobic threshold VO2 and workload) and increased VE/VCO2 slope, helping identifying more advanced disease irrespectively of LVOTO. Adding O2-pulse kinetics evaluation to standard CPET could lead to a potential incremental benefit in terms of HCM prognostic stratification and, then, therapeutic management.

Objective The objective was to provide an exhaustive characterization of ECG features in a large cohort of dilated cardiomyopathies (DCMs) and then investigate their possible prognostic role in the long term. Background ECG is an accessible, reproducible, low-cost diagnostic and prognostic tool. However, an extensive description of ECG features and their long-term prognostic role in a large cohort of DCM is lacking. Methods All available baseline ECGs of DCM patients enrolled from 1992 to 2013 were systematically analysed. Patients underwent to a complete clinical-laboratory evaluation. The study outcome measures were death or heart transplant (D/HT) and sudden death or malignant ventricular arrhythmias (SD/MVA). Results Four hundred and fourteen DCM patients were enrolled. During a median follow-up of 125 months, 55 and 57 patients experienced D/HT and SD/MVA, respectively. At multivariate analysis, left ventricular hypertrophy (P = 0.017), heart rate (HR, P = 0.005) and anterolateral T-wave inversion (P = 0.041) predicted D/HT. Regarding SD/MVA, S wave amplitude in V2 (P = 0.008), R wave amplitude in DIII (P = 0.007), anterolateral T-wave inversion (P = 0.017) emerged as predictors. At receiver-operating curve analyses, the addition of ECG models to the clinical-laboratory evaluation significantly increased the area under the curve both for D/HT (from 0.68 to 0.74, P = 0.042) and SD/MVA (from 0.70 to 0.77, P = 0.048). Conclusion The exhaustive systematic evaluation of ECG has an incremental impact in the prognostication of a large cohort of DCM patients, also regarding the arrhythmic stratification.

A feature of heart failure patients is exercise-induced hyperventilation, due to several causes including alteration of lung mechanics and gas diffusion, increased ventilation relative to CO2 production, elevated dead space ventilation, and overactive metaboreceptor and chemoreceptor reflexes.1 It is a well-established physiological concept that chemical ventilatory control depends and responds to afferent input, that is, arterial partial pressure of carbon dioxide (PaCO2) and of oxygen (PaO2), from the peripheral and central chemoreceptors to maintain PaCO2 and PaO2 within a specific and narrow range. However, this PaO2/PaCO2/pH-dependent regulation of ventilation seems too simplistic in several pathophysiological conditions including heart failure.

There is limited evidence on characterization and natural history of supraventricular tachycardia (SVT)-induced left ventricular (LV) dysfunction. The aim of this work was to characterize clinical features and long-term evolution of SVT-induced LV dysfunction. Patients consecutively admitted with sustained SVT and heart rate >100 bpm as the only known cause of a new onset LV systolic dysfunction (i.e., LV ejection fraction [EF]

Aims To assess the effect of pharmacological therapy on long-term prognosis of patients with MINOCA. Methods and results In this retrospective multicentre cohort study involving 9 Hub Hospitals across Italy we enrolled consecutive patients 18 years and older with diagnosis of MINOCA discharged from 1st March 2012 to 31st March 2018. Data on baseline characteristics and pharmacological therapy at discharge (ACEI/ARB, angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists; ASA, acetylsalicylic acid; beta-blockers; CCB, calcium-channel blockers; DAPT, dual anti-platelet therapy; statins), were collected systematically. The primary endpoint (PE) of the study was a composite of all cause death or acute myocardial infarction or acute coronary syndrome or heart failure leading to hospitalization or stroke. A total of 621 patients were included (mean [SD] age 65.1 [13.9] years; 344 [55.4%] female), of whom 106 (17.1%) experienced PE, including 27 patients (4.3%) who died. Multivariable analysis, after correction for all baseline differences, showed a significant association between pharmacological therapy at discharge and an increased risk of PE for aspirin (HR[95%CI] = 2.47[1.05–5.78], adjusted p = 0.04), whereas beta-blockers were associated with a significant benefit (HR[95%CI] = 0.49 [0.31–0.79], adjusted p = 0.02). Conclusion The use of beta-blockers was significantly associated to a less frequent occurrence of adverse outcomes at long-term follow-up among patients with MINOCA, whereas ASA displayed a potentially harmful impact on prognosis. The findings in the study may be relevant for the design of future studies which should take into account possible heterogeneity among MINOCA patients.