Congenital Long QT Syndrome in Children and Adolescents: A General Overview.

Congenital long QT syndrome (LQTS) represents a disorder of myocardial repolarization characterized by a prolongation of QTc interval on ECG, which can degenerate into fast polymorphic ventricular arrhythmias. The typical symptoms of LQTS are syncope and palpitations, mainly triggered by adrenergic stimuli, but it can also manifest with cardiac arrest. At least 17 genotypes have been associated with LQTS, with a specific genotype-phenotype relationship described for the three most common subtypes (LQTS1, -2, and -3). ß-Blockers are the first-line therapy for LQTS, even if the choice of the appropriate patients needing to be treated may be challenging. In specific cases, interventional measures, such as an implantable cardioverter-defibrillator (ICD) or left cardiac sympathetic denervation (LCSD), are useful. The aim of this review is to highlight the current state-of-the-art knowledge on LQTS, providing an updated picture of possible diagnostic algorithms and therapeutic management.

Cardiac Magnetic Resonance Feature-Tracking Identifies Preclinical Abnormalities in Hypertrophic Cardiomyopathy Sarcomere Gene Mutation Carriers.

BACKGROUND: Assessing myocardial strain by cardiac magnetic resonance feature tracking (FT) has been found to be useful in patients with overt hypertrophic cardiomyopathy (HCM). Little is known, however, of its role in sarcomere gene mutation carriers without overt left ventricular hypertrophy (subclinical HCM). METHODS: Thirty-eight subclinical HCM subjects and 42 healthy volunteers were enrolled in this multicenter case-control study. They underwent a comprehensive cardiac magnetic resonance study. Two-dimensional global radial, circumferential, and longitudinal strain of the left ventricle (LV) were evaluated by FT analysis. RESULTS: The subclinical HCM sample was 41 (22-51) years old and 32% were men. FT analysis revealed a reduction in global radial strain (29±7.2 versus 47.9±7.4; P<0.0001), global circumferential strain (-17.3±2.6 -versus -20.8±7.4; P<0.0001) and global longitudinal strain (-16.9±2.4 versus -20.5±2.6; P<0.0001) in subclinical HCM compared with control subjects. The significant differences persisted when considering the 23 individuals free of all the structural and functional ECG and cardiac magnetic resonance abnormalities previously described. Receiver operating characteristic curve analyses showed that the differential diagnostic performances of FT in discriminating subclinical HCM from normal subjects were good to excellent (global radial strain with optimal cut-off value of 40.43%: AUC, 0.946 [95% CI, 0.93-1.00]; sensitivity 90.48%, specificity 94.44%; global circumferential strain with cut-off, -18.54%: AUC, 0.849 [95% CI, 0.76-0.94]; sensitivity, 88.10%; specificity, 72.22%; global longitudinal strain with cut-off, -19.06%: AUC, 0.843 [95% CI, 0.76-0.93]; sensitivity, 78.57%; specificity, 78.95%). Similar values were found for discriminating those subclinical HCM subjects without other phenotypic abnormalities from healthy volunteers (global radial strain with optimal cut-off 40.43%: AUC, 0.966 [95% CI, 0.92-1.00]; sensitivity, 90.48%; specificity, 95.45%; global circumferential strain with cut-off, -18.44%: AUC, 0.866 [95% CI, 0.76-0.96]; sensitivity, 92.86%; specificity, 77.27%; global longitudinal strain with cut-off, -17.32%: AUC, 0.838 [95% CI, 0.73-0.94]; sensitivity, 90.48%; specificity, 65.22%). CONCLUSIONS: Cardiac magnetic resonance FT-derived parameters are consistently lower in subclinical patients with HCM, and they could emerge as a good tool for discovering the disease during a preclinical phase.

Implantable-cardioverter-defibrillator after ST-elevation myocardial infarction: when and how frequently is it implanted and what is the rate of appropriate interventions? Insight from Trieste registry.

BACKGROUND: There are limited data on implantable-cardioverter-defibrillator (ICD) implantation after ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). Therefore, we evaluated when and how frequently an ICD is implanted after pPCI, the rate of appropriate ICD interventions, and predictors of ICD implantation. METHODS: We analyzed STEMI patients treated with pPCI at the University Hospital of Trieste, Italy, between January 2010 and December 2019. We cross-matched patients' data with those present in the Trieste ICD registry. RESULTS: Among 1805 consecutive patients treated with pPCI, 3.6% underwent ICD implantation during a median follow-up of 6.7 [interquartile range (IQR) 4.3-9.2] years. At 12 months, the mean number of ICD implantations was 2.3/100 patients [95% confidence interval (95% CI) 1.7-3.1] and remained stable over time (at 24 months: 2.5/100 patients, 95% CI 2.0-3.5 and at 36 months: 2.6/100 patients, 95% CI 2.3-3.8); 83.1% of ICDs were implanted for primary prevention, and more than half (55%) were implanted in patients with ejection fraction more than 35% at the moment of STEMI discharge. The rate of appropriate ICD interventions was 16.9% at a median follow-up of 5.7 years (IQR 3.3-8.3 years) after ICD implantation. At 12 months, the mean number of appropriate ICD interventions was 5/100 patients and 7/100 patients after 24 months. In patients with ejection fraction more than 35% at STEMI discharge (median ejection fraction 43%; IQR 40-48), independent predictors of ICD implantation were male sex, anterior STEMI and troponin peak more than 100 000 ng/dl. CONCLUSION: The rate of ICD implantations after pPCI is low; however, the rate of appropriate ICD interventions is high. A relevant subgroup of patients received ICD implantations at follow-up despite a nonsevere ejection fraction at discharge after STEMI. Among these patients, those with high troponin release deserve strict follow-up and full optimal medical treatment.

Determinants of exercise performance in heart failure patients with extremely reduced cardiac output and left ventricular assist device.

The evaluation of exercise capacity and cardiac output (QC) is fundamental in the management of patients with advanced heart failure (AdHF). QC and peak oxygen uptake (VO2) have a pivotal role in the prognostic stratification and in the definition of therapeutic interventions, including medical therapies and devices, but also specific treatments such as heart transplantation and left ventricular assist device (LVAD) implantation. Due to the intertwined relationship between exercise capacity and daily activities, exercise intolerance dramatically has impact on the quality of life of patients. It is a multifactorial process that includes alterations in central and peripheral haemodynamic regulation, anaemia and iron deficiency, pulmonary congestion, pulmonary hypertension, and peripheral O2 extraction. This paper aims to review the pathophysiological background of exercise limitations in HF patients and to examine the complex physiology of exercise in LVAD recipients, analysing the interactions between the cardiopulmonary system, the musculoskeletal system, the autonomic nervous system, and the pump. We performed a literature review to highlight the current knowledge on this topic and possible interventions that can be implemented to increase exercise capacity in AdHF patients-including administration of levosimendan, rehabilitation, and the intriguing field of LVAD speed changes. The present paper confirms the role of CPET in the follow-up of this peculiar population and the impact of exercise capacity on the quality of life of AdHF patients.

Heart failure patients with improved ejection fraction: Insights from the MECKI score database.

AIMS: Improvement of left ventricular ejection fraction is a major goal of heart failure (HF) treatment. However, data on clinical characteristics, exercise performance and prognosis in HF patients who improved ejection fraction (HFimpEF) are scarce. The study aimed to determine whether HFimpEF patients have a distinct clinical phenotype, biology and prognosis than HF patients with persistently reduced ejection fraction (pHFrEF). METHODS AND RESULTS: A total of 7948 patients enrolled in the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database were evaluated (median follow-up of 1490 days). We analysed clinical, laboratory, electrocardiographic, echocardiographic, exercise, and survival data from HFimpEF (n = 1504) and pHFrEF (n = 6017) patients. The primary endpoint of the study was the composite of cardiovascular death, left ventricular assist device implantation, and urgent heart transplantation. HFimpEF patients had lower HF severity: left ventricular ejection fraction 44.0 [41.0-47.0] versus 29.7 [24.1-34.5]%, B-type natriuretic peptide 122 [65-296] versus 373 [152-888] pg/ml, haemoglobin 13.5 [12.2-14.6] versus 13.7 [12.5-14.7] g/dl, renal function by the Modification of Diet in Renal Disease equation 72.0 [56.7-89.3] versus 70.4 [54.5-85.3] ml/min, peak oxygen uptake 62.2 [50.7-74.1] versus 52.6 [41.8-64.3]% predicted, minute ventilation-to-carbon dioxide output slope 30.0 [26.9-34.4] versus 32.1 [28.0-38.0] in HFimpEF and pHFrEF, respectively (p < 0.001 for all). Cardiovascular mortality rates were 26.6 and 46.9 per 1000 person-years for HFimpEF and pHFrEF, respectively (p < 0.001). Kaplan-Meier analysis showed that HFimpEF had better a long-term prognosis compared with pHFrEF patients. After adjustment for variables differentiating HFimpEF from pHFrEF, except echocardiographic parameters, the Kaplan-Meier curves showed the same prognosis. CONCLUSIONS: Heart failure with improved ejection fraction represents a peculiar group of HF patients whose clinical, laboratory, electrocardiographic, echocardiographic, and exercise characteristics parallel the recovery of systolic function. Nonetheless, these patients remain at risk for adverse outcome.

Cardiology of the future: xenotransplantation with porcine heart.

The reduced availability of human donor hearts compared with the needs of patients with advanced heart failure refractory to medical therapy has promoted the search for therapeutic alternatives to cardiac allografts. Porcine heart xenotransplantation represents one of the most promising frontiers in this field today. From the first researches in the 1960s to today, the numerous advances achieved in the field of surgical techniques, genetic engineering and immunosuppression have made it possible at the beginning of 2022 to carry out the first swine-to-human heart transplant, attaining a survival of 2 months after surgery. The main intellectual and experimental stages that have marked the history of xenotransplantation, the latest acquisitions in terms of genetic editing, as well as the improvement of immunosuppressive therapy are discussed analytically in this article in order to illustrate the underlying complexity of this therapeutic model.

Global longitudinal strain by CMR improves prognostic stratification in acute myocarditis presenting with normal LVEF.

BACKGROUND: Prognostic stratification of acute myocarditis (AM) presenting with normal left ventricular ejection fraction (LVEF) relies mostly on late gadolinium enhancement (LGE) characterization. Left ventricular peak global longitudinal strain (LV-GLS) measured by feature tracking analysis might improve prognostication of AM presenting with normal LVEF. METHODS: Data of patients undergoing cardiac magnetic resonance (CMR) for clinically suspected AM in seven European Centres (2013-2020) were retrospectively analysed. Patients with AM confirmed by CMR and LVEF ≥50% were included. LGE was visually characterized: localized versus. non-localized, subepicardial versus midwall. LV-GLS was measured by dedicated software. The primary outcome was the first occurrence of an adverse cardiovascular event (ACE) including cardiac death, life-threatening arrhythmias, development of heart failure or of LVEF <50%. RESULTS: Of 389 screened patients, 256 (66%) fulfilled inclusion criteria: median age 36 years, 71% males, median LVEF 60%, median LV-GLS -17.3%. CMR was performed at 4 days from hospitalization. At 27 months, 24 (9%) patients experienced ≥1 ACE (71% developed LVEF <50%). Compared to the others, they had lower median LV-GLS values (-13.9% vs. -17.5%, p = .001). At Kaplan-Meier analysis, impaired LV-GLS (both considered as > -20% or quartiles), non-localized and midwall LGE were associated with ACEs. Patients with LV-GLS ≤-20% did not experience ACEs. LV-GLS remained associated with ACEs after adjustment for non-localized and midwall LGE. CONCLUSION: In AM presenting with LVEF ≥50%, LV-GLS provides independent prognostic value over LGE characterization, improving risk stratification and representing a rationale for further studies of therapy in this cohort.

The double anaerobic threshold in heart failure: MECKI score database overview.

AIMS: In heart failure (HF), anaerobic threshold (AT) may be indeterminable but its value held a relevant prognostic role. AT is evaluated joining three methods: V-slope, ventilatory equivalent, and end-tidal methods. The possible non-concordance between the V-slope (met AT) and the other two methods (vent AT) has been highlighted in healthy individuals and named double threshold (DT). METHODS AND RESULTS: We reanalysed 1075 cardiopulmonary exercise tests of HF patients recruited in the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score database. We identified DT in 43% of cases. Met AT precedes vent AT being met-ventΔVO2 221 (interquartile range: 129-319) mL/min. Peak VO2 , 1307 ± 485 vs. 1343 ± 446 mL/min (63 ± 17 vs. 63 ± 17 percentage of predicted), was similar between DT+ and DT- patients. Differently, DT+ showed a lower ventilatory vs. carbon dioxide production (VE/VCO2 ) slope (29.6 ± 6.1 vs. 31.0 ± 6.3), a lower peak exercise end-tidal oxygen tension (PetO2 ) 115.3 (111.5-118.9) vs. 116.4 (112.4-120.2) mmHg, and a higher carbon dioxide tension (PetCO2 ) 34.2 (30.9-37.1) vs. 32.4 (28.7-35.5) mmHg. Vent AT showed a significant higher VO2 , 957 ± 318 vs. 719 ± 252 mL/min, VCO2 , 939 ± 319 vs. 627 ± 226 mL/min, ventilation, 31.0 ± 8.3 vs. 22.5 ± 6.3 L/min, respiratory exchange ratio, 0.98 ± 0.08 vs. 0.87 ± 0.07, PetO2 , 108 (104-112) vs. 105 (101-109) mmHg, PetCO2 , 37 (34-40) vs. 36 (33-39) mmHg, and VE/VO2 ratio, 33.5 ± 6.7 vs. 32.6 ± 6.9, but lower VE/VCO2 ratio, 33 (30-37) vs. 36 (32-41), compared with met AT. At 2 year survival by Kaplan-Meier analysis, even adjusted for confounders, DT resulted not associated with survival. CONCLUSIONS: Double threshold is frequently observed in HF patients. DT+ is associated to a decreased ventilatory response during exercise.

Exercise oxygen pulse kinetics in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Reduced 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. METHODS: CPETs 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 <30; 10% between 30 and 49 and 18% ≥50 mm Hg). We evaluated the CPET response in HCM focusing on parameters strongly associated with SV and CO, such as O2-pulse and VO2, respectively, considering their absolute values and temporal behaviour during exercise. RESULTS: We 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/VCO2 slope (28 (25-31) vs 27 (24-31)) (p<0.005 for all). Only 2 patients had an abnormal VO2/work slope. CONCLUSION: None 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 VO2 and workload) and increased VE/VCO2 slope, identifying more advanced disease irrespectively of LVOTO.

Evidence of a double anaerobic threshold in healthy subjects.

AIMS: The anaerobic threshold (AT) is an important cardiopulmonary exercise test (CPET) parameter both in healthy and in patients. It is normally determined with three approaches: V-slope method, ventilatory equivalent method, and end-tidal method. The finding of different AT values with these methods is only anecdotic. We defined the presence of a double threshold (DT) when a ΔVO2 > 15 mL/min was observed between the V-slope method (met AT) and the other two methods (vent AT). The aim was to identify whether there is a DT in healthy subjects. METHODS AND RESULTS: We retrospectively analysed 476 healthy subjects who performed CPET in our laboratory between 2009 and 2018. We identified 51 subjects with a DT (11% of cases). Cardiopulmonary exercise test data at rest and during the exercise were not different in subjects with DT compared to those without. Met AT always preceded vent AT. Compared to subjects without DT, those with DT showed at met AT lower carbon dioxide output (VCO2), end-tidal carbon dioxide tension (PetCO2) and respiratory exchange ratio (RER), and higher ventilatory equivalent for carbon dioxide (VE/VCO2). Compared to met AT, vent AT showed a higher oxygen uptake (VO2), VCO2, ventilation, respiratory rate, RER, work rate, and PetCO2 but a lower VE/VCO2 and end-tidal oxygen tension. Finally, subjects with DT showed a higher VO2 increase during the isocapnic buffering period. CONCLUSION: Double threshold was present in healthy subjects. The presence of DT does not influence peak exercise performance, but it is associated with a delayed before acidosis-induced hyperventilation.

Prognostic Significance of Feature-Tracking Right Ventricular Global Longitudinal Strain in Non-ischemic Dilated Cardiomyopathy.

Aims: Left ventricular global longitudinal strain (GLS) by cardiac magnetic resonance feature tracking (CMR-FT) analysis has shown an incremental prognostic value compared to classical parameters in non-ischemic dilated cardiomyopathy (NICM). However, less is known about the role of right ventricular (RV) GLS. Our objective was to evaluate the prognostic impact of RV-GLS by CMR-FT analysis in a population of NICM patients. Methods: In this multicenter study, we examined NICM patients evaluated with a comprehensive CMR-FT study. Major cardiac events (MACEs) were considered as the study primary outcome measure and were defined as a composite of (a) cardiovascular death, (b) cardiac transplant or destination therapy ventricular assist device, (c) hospitalization for life-threatening ventricular arrhythmias or implantable cardiac defibrillator appropriate intervention. Heart failure (HF) related events, including hospitalizations and life-threatening arrhythmia-related events were considered as secondary end-points. Receiver operating time-dependent analysis were used to calculate the possible additional effect of RV-GLS to standard evaluation. Results: We consecutively enrolled 273 patients. During a median follow-up of 39 months, 41 patients (15%) experienced MACEs. RV-GLS and LV late gadolinium emerged as the strongest prognostic CMR-FT variables: their association provided an estimated 3-year MACEs rate of 29%. The addition of RV-GLS significantly improved the prognostic accuracy in predicting MACEs with respect to the standard evaluation including LGE (areas under the curve from 0.71 [0.66-0.82] to 0.76 [0.66-0.86], p = 0.03). On competing risk analysis, RV-GLS showed a significant ability to reclassify overall both HF-related and life-threatening arrhythmia-related events, regardless of LV and RV ejection fraction. Conclusions: In NICM patients, RV-GLS showed a significant prognostic role in reclassifying the risk of MACEs, incremental with respect to standard evaluation with standard prognostic parameters.

Prognostic role of global longitudinal strain by feature tracking in patients with hypertrophic cardiomyopathy: The STRAIN-HCM study.

BACKGROUND: The assessment of myocardial fiber deformation with cardiac magnetic resonance feature tracking (CMR-FT) has shown to be promising in terms of prognostic information in several structural heart diseases. However, little is known about its role in hypertrophic cardiomyopathy (HCM). Aims of the present study were: 1) to assess the prognostic role of CMR-FT derived strain parameters in patients with HCM. METHODS: CMR was performed in 130 consecutive HCM patients (93 males, mean age (54 ± 17 years) with an estimated 5-year risk of sudden cardiac death (SCD) <6% according to the HCM Risk-SCD calculator. 2D- and 3D-Global Radial (GRS), Longitudinal (GLS) and Circumferential (GCS) Strain was evaluated by FT analysis. The primary outcome of the study was a composite of major adverse cardiac events (MACE) including SCD, resuscitated cardiac arrest due to ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT), and hospitalization for heart failure. RESULTS: After a median follow-up of 51.7 (37.1-68.8) months, 4 (3%) patients died (all of them suffered from SCD) and 36 (28%) were hospitalized for heart failure. After multivariable adjustment for clinical and imaging covariates, among all strain parameters, only GLS remained a significant independent predictor of outcome events in both the model including 2D strain (HR 1.12, 95% CI 1.03-1.23, p = 0.01) and the model including 3D strain (HR 1.14, 95% CI 1.01-1.30, p = 0.04). The addition of 2D-GLS into the model with clinical and imaging predictors resulted in a significant increase in the C-statistic (from 0.48 to 0.65, p = 0.03). CONCLUSION: CMR-FT derived GLS is a powerful independent predictor of MACE in patients with HCM, incremental to common clinical and CMR risk factors including left ventricular ejection fraction and late gadolinium enhancement.