Ventricular Function Research Articles

Clinical profile of patients undergoing percutaneous stellate ganglion block for electrical storm and association with antiarrhythmic efficacy

Abstract Background Percutaneous stellate ganglion block (PSGB) usage for patients with refractory ventricular arrhythmias (VAs) in form of electrical storm (ES) is in quickly expanding. The clinical profile of patients and the potential association with the antiarrhythmic efficacy of the procedure are mostly unexplored. Purpose To better characterize clinical profile and potential association with antiarrhythmic efficacy of patients undergoing PSGB for ES. Methods Patients undergoing PSGB for ES in our Center from 2/2021 to 2/2024 were enrolled; all the dynamic variables were evaluated in a per procedure analysis. Results 45 patients (93% male, 64 ± 10 years) received a total of 80 PSGB performed with the lateral, ultrasound (US) guided technique; most PSGB consisted of a single bolus anesthetic injection (lidocaine + ropivacaine), 26% in an additional continuous infusion, mostly with ropivacaine. All procedures except for 3 in a single patient who had previously received left cardiac sympathetic denervation, were performed on the left side. Most of the patients (60%) suffered ischemic cardiomyopathy (CMP), including 10 with an acute coronary syndrome; the rest had non-ischemic CMP; 60% had an ICD. The type of VAs was ventricular tachycardia (VTs) only in 86% of the procedures (cycle length 404 ± 143 msec), VT and VF in 10% and VF only in 3 (4%). Most PSGB (81%) were performed in the setting of impending or manifest cardiogenic shock (SCAI classification B or more), including 20% with sepsis. Cardiac US performed before (within 12 hours) each PSGB showed a severely depressed left ventricular (LV) function (mean LVEF 22 ± 10%, mean LV outflow tract velocity time integral 12 ± 4 cm), calculated at a mean heart rate of 81 ± 16 bpm. Mean LVEDV was 252 ± 104 ml, 79% had mitral regurgitation (MR) ≥2+/4+ (including 39% severe MR), 50% had ≥ moderate diastolic dysfunction, 29% had right ventricular dysfunction (mean fractional areal change 33± 7%). Most cases (75%) experienced a complete VAs suppression (sustained or treated) in the 12 hours after PSGB; only 3/80 cases required additional urgent antiarrhythmic strategies (intra-aortic ballon pump in one case, urgent pacing in another one, urgent revascularization in the last one). None of the assessed clinical or echocardiographic characteristics was significantly associated with VT cycle length or the response to PSGB. Only 1 (1%) major complication occurred (respiratory arrest), that was quickly and effectively treated with lipid emulsion. Conclusions PSGB in our Center was mostly performed in the setting of primary impending or manifest cardiogenic shock with severely impaired cardiac function, with an excellent safety profile. None of the assessed clinical or echocardiographic variables were associated with response to PSGB. Our data, despite preliminary and requiring confirmation, suggests always considering PSGB in the urgent/emergent setting independently from patients’ characteristics.

Clinical value of anti-DSG2 antibodies in arrhythmogenic right ventricular cardiomyopathy: a real-life experience

Abstract Background/Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease leading to ventricular arrhythmias and heart failure. The diagnosis is challenging and currently based on a set of clinical criteria with limited sensitivity and specificity. Anti-desmoglein-2 (DSG2) antibodies were previously found in patients diagnosed with ARVC, while they were absent in both healthy controls and athletes. Purpose The study aimed to evaluate the diagnostic value of anti-DSG2 antibodies by comparing their concentration in patients with ARVC and other right ventricular diseases. Additionally, the prognostic value of the biomarker was assessed. Methods A cohort of 101 patients with a definite diagnosis of ARVC according to the 2010 Task Force criteria was enrolled (64 males, mean age 47 ± 16 years). The control group included patients with Ebstein anomaly and Eisenmenger syndrome (16 and 21 subjects, respectively). Anti-DSG2 antibody concentration was assessed using enzyme-linked immunosorbent assay (ELISA). After that, an ARVC cohort was followed for 3.9 ± 1.6 years for the occurrence of the primary endpoint of cardiac death or heart transplantation (HTx) and major arrhythmic events (MAEs) defined as ventricular fibrillation, sustained ventricular tachycardia (sVT) or appropriate implantable cardioverter-defibrillator intervention. Results The median anti-DSG2 antibody concentration presented as ELISA optical density (OD) reached 1.36 [0.54-2.15] in the ARVC cohort, while it was 0.4 [0.34-0.54] in Ebstein anomaly group and 0.36 [0.28-0.58] in the Eisenmenger syndrome group. There was a significant difference in antibody levels between ARVC and both control groups (p < 0.001, Figure 1). The cutoff value for the diagnosis of ARVC was 0.774, with 72.3% sensitivity and 100% specificity (AUC = 0.823). After dividing the ARVC cohort according to the designated cutoff point, the anti-DSG2-positive subgroup was significantly younger (44.5 ± 15.4 vs. 52.8 ± 15.5 years, p = 0.017) and more likely to have a history of sVT (68.5% vs. 46.4%, p = 0.041). There was no difference regarding sex, presence of PKP2 or DSG2 mutations, previous sports activities, history of sudden cardiac arrest or syncope, right ventricular dimensions and systolic function, left ventricular ejection fraction and heart failure symptoms. This threshold was not predictive for the primary endpoint and MAEs. However, a more stringent cutoff value for anti-DSG2 level (1.021) was found to predict death or HTx (HR [95% CI] 4.56 [1.05-19.76], p = 0.026, Figure 2). Conclusions The concentration of anti-DSG2 antibodies is significantly higher in ARVC compared to other right ventricular diseases. A high antibody level is prognostic for death or HTx in ARVC.Figure 1Figure 2

Assessment of circulating biomarkers and hemodynamic response during stress to detect early cardiopulmonary complications in systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is characterised by persistent immune-inflammatory system activation and excessive extracellular matrix (ECM) accumulation leading to fibrosis. Exercise Doppler Echocardiography (EDE) is a promising method to detect the early changes of fibrosis-related pulmonary and myocardial complications, like elevated left ventricular filling pressure or stress-induced pulmonary hypertension (PH). Aims The study aims to assess the linkage between the activity of fibrosis markers and abnormal exercise haemodynamics during stress in patients with SSc. Methods A total of 18 patients with SSc were enrolled in the single-centre prospective study (age 54±15,5years, 94,4 % women). SSc patients with resting PH and moderate to severe pulmonary fibrosis were excluded. According to a standardised protocol, all subjects underwent resting and exercise echocardiography on a semi-recumbent cycle ergometer with an incremental (25 watts) workload up to the maximally tolerated workload. Measurements focused on the left ventricular diastolic function (E/e’) and right ventricular haemodynamics (estimated systolic pulmonary pressure: PASP, right ventricular coupling: TAPSE/PASP, pulmonary vascular resistance: PVR). Blood samples were taken immediately before the stress test, and the Matrix Metalloproteinase-9 and 2 (MMP-9, MMP-2) levels were assessed with gelatin zymography method. Results During the EDE, PASP from baseline increased significantly (24,6mmHg±11 vs 38±16mmHg, p <0,0001), also PVR (1,2±0,49 vs 1,5±0,15 Wood unit, p<0,001) RV coupling was decreased significantly (1,2±0,68 vs 0,93±0,5, p<0,001). Left ventricular E/e’ was also increased during the stress (8,2±2 vs 10,5±5,1, p<0,05). Enzymatically active MMP-9 level was significantly correlated with RV coupling at rest and stress (p<0,05, r 0,63 at rest and r 0,52 at stress) and negatively correlated with PASP (p<0,05, r:-0,62 at rest and r -0,5 at stress). MMP-2 level only negatively correlated with resting PASP (p<0,05, r:-0,527). The left ventricular parameters did not show any relationship with MMP levels. Conclusions The level of circulating MMP-9 predicts haemodynamic behaviour during stress in SSc. MMPs could be a promising marker for detecting early changes in the right ventricle-pulmonary circulation unit.

The implementation of speckle tracking echocardiography for cardiac resynchronization therapy optimization. A rotational myocardial mechanics interpretation

Abstract Background Cardiac resynchronization therapy (CRT) has an additive therapeutic influence on left ventricular (LV) function in heart failure (HF) patients, but the underlying mechanisms through which it works are not completely explained. Our aim was to further elucidate the role of this intervention via rotational mechanics using 2D speckle tracking echocardiography (2D-STE). Methods We investigated 46 patients (65 ± 9 years) who received CRT. All enrolled patients were assessed on admission by 2D-STE and 6 min walk test (6m WT) and followed in the outpatient device clinic by 2D-STE (at one week and 6 months post-implantation) and 6m WT (at 6 months post-implantation). On their first appointment all biventricular systems were optimized by atrioventricular delay optimization and by changing the temporal activation of ventricular electrodes aiming to reach the highest effective LV stroke volume (eff SV) across all activation options. A new 2D-STE based index (twist integral – TI) targeting to assess the rotational mechanics of the whole cardiac cycle was also measured to further explain the CRT response. For the calculation of LV TI of the full cardiac cycle, serial isochronal apical and basal rotation measurements (in degrees) were exported to a worksheet Excel file and the final algebraic summation was calculated by the formula: Twist Integral = (systolic twist integral – diastolic twist integral) Σ twisti= twist1+twist2+...+twistn (table 1). Results Twenty-two (48%) patients with dilated cardiomyopathy as the predominant aetiology of HF were responders at 6-month follow-up. The commonest selected mode that was related with the greatest LV performance response was the simultaneous activation of the 2 ventricular leads (39%). The strongest predictor of CRT response was the improvement of eff SV between admission and first appointment at clinic, followed by the improvement of TI, the non-existence of CAD, and the improvement of peak systolic twist (table 2). Conclusions Additional CRT optimization via changing the temporal activation of ventricular electrodes is beneficial for LV performance in HF patients. Rotational mechanics essentially explain the beneficial CRT contribution to these patients.

Efficacy and safety of reduced-dose and slow-infusion intravenous alteplase regimen in patients with acute pulmonary embolism at intermediate-high-risk

Abstract Background In patients with intermediate-high-risk (IHR) pulmonary embolism (PE), full-dose systemic thrombolytic treatment (STT) has been documented to lower the risk of hemodynamic decompensation and mortality, at the expense of an elevated risk of life-threatening bleeding. In this study, we aimed to evaluate the safety of reduced-dose STT regimen while maintaining effective reperfusion. Methods This single-center study comprised 124 retrospectively evaluated patients (female 58.9 % and mean age 55.4+15.8 years) diagnosed with acute PE at IHR status in accordance with European Society of Cardiology (ESC) 2019 acute PE guidelines in whom intravenous (i.v.) alteplase treatments were utilized. Patients fulfilling at least one of the following criteria have been included in the study: systolic blood pressure ≤ 110 mm Hg, heart rate > 100 bpm, SaO2 < 90 % on room air, respiratory rate > 20 breaths per minute, or serum lactate > 2 mmol/L. Exclusion criteria were any contraindication for STT and symptom onset > 14 days. Standard protocol for initial STT was i.v. infusion of alteplase of 25 mg over 4-6 hours. After completion of the infusion, a second STT in the same manner if one of the following criteria were present; heart rate > 100 bpm, SaO2 < 90 % or signs of organ hypoperfusion. Results Syncope and concomitant deep vein thrombosis were documented in 27.4 % and 49.2 % of patients, respectively. Baseline vital measures were as follows; heart rate: 112 +16.6 bpm, systolic blood pressure: 123+14.9 mm Hg, SaO2: 89 % (85-93), serum lactate 2.35 (1.6-2.9) mmol/L. Median alteplase dose and infusion duration were 50 (25-50) mg and 6 (4-10) hours, respectively. There were significant improvements in clinical parameters, pulmonary thrombus burden, pressure strain and right ventricular size and function as assessed by computed tomography and echocardiography (p< 0.001 for all). Minor and major bleeding events occurred in 3.2 % and 4.8 % of patients, respectively. One major bleed was due to cerebellar hemorrhage, but did not require surgery and patient was discharged without sequela. There were 6 (4.8 %) in-hospital deaths in which 2 were attributed to major hemorrhages and 4 due to hemodynamic decompensation. Conclusion In patients with acute IHR PE, reduced-dose and slow-infusion i.v. alteplase regimen seems to be a clinically relevant and safe reperfusion alternative to full-dose STT protocols associated with well-known major bleeding risks.

Evolution and prognostic relevance of right ventricular morphofunctional parameters in patients undergoing isolated tricuspid valve surgery

Abstract Background Right ventricular (RV) function is key in evolution after isolated tricuspid valve surgery (ITVS). Right ventricular-pulmonary artery coupling (RV-PA coupling), determined with echocardiography as the ratio TAPSE/sPAP, has merged as a relevant functional parameter in many clinical scenarios. Purpose Our aim is to evaluate the prognostic relevance of RV-PA coupling in patients undergoing ITVS. Methods We carried out a retrospective study involving all the patients undergoing ITVS at our tertiary centre. Several RV function measurements were assessed from the baseline echocardiogram (TAPSE, fractional area change (FAC), systolic pulmonary artery pressure (sPAP), tricuspid annulus tissue Doppler velocity (RVS´) and free-wall global longitudinal strain (FW-GLS)) and RV-PA coupling was calculated. Association between RV morphofunctional variables and mortality during one year follow-up was determined. Results 45 patients were included (68 years-old, 51,1% female). The most common TR etiology was functional (51.1%) and 42.2% had previous left-sided valvular surgery. The median Tri-Score was 2 (1-4) points and the most frequent procedure was biological valve replacement (65%). Baseline echocardiographic parameters were as follows: basal 52 (48 – 53.5) mm, mid 40 (36-45.5) mm and longitudinal 73 (68-80) RV diameters, TAPSE 18.1 (15.5-20.7) mm, RVS´ 10.1 (9-12.5) cm/s, FAC 0.5 (0.43-0.57), sPAP 35 (31.5-37.5) mmHg, and FW-GLS - 21.1 (17.2-25) %. During the follow-up 8 (18%) patients died. Solely TAPSE (16 vs 19, p= 0.047) and RV-PA coupling (0.35 vs 0.5; p= 0.035) showed significant differences in mortality among RV echocardiographic parameters. An RV-PA coupling <0.375 mm/mmHg appeared to be the best mortality predictor (RR 1.45; p= 0.04) one year after the intervention (Figure). Conclusions In our series RV-PA coupling has proved to be the best echocardiographic prognostic factor in ITVS, so it could be considered a relevant parameter in risk stratification previous to this surgery. Figure. Kaplan Meier curves of mortality after ITVS by RV-PA coupling.Figure

Reverse RV remodeling after isolated tricuspid valve surgery

Abstract Background Impact of tricuspid regurgitation (TR) on right ventricular (RV) and atrial (RA) size and function is one of the main determinants of prognosis. However, there is scarce data about the recovery of right chambers after isolated tricuspid valve surgery (ITVS). Purpose Our aim is to evaluate postsurgical changes in right chamber morphofunctional parameters by echocardiography after ITVS. Methods We selected all the patients that underwent ITVS in our tertiary centre between 2009 and 2022 excluding those with congenital anomalies. Echocardiographic right ventricular classical parameters (RV diameters, RA area, TAPSE and fractional area change (CAF)) as well as myocardial deformation (free wall (FW)- and 4 chambers (4C)- global longitudinal strain (GLS)) were compared in baseline studies, early and late postsurgical periods. Results Among the 45 patients included (65 ± 2 years-old, 51% female, TRI-SCORE 2 [1-4]) surgical indication was functional TR in 51%, 29% underwent tricuspid valve repair and 71% replacement. The treatment was considered ineffective (postoperative TR ≥ moderate) in 9%. In the early postsurgical phase (1.9 [1.2 – 3] months) a significant reduction in basal (-17%, p<0.01), mid (-15%, p<0.01) and longitudinal (- 7%, p<0,01) RV diameters as well as RA area (-26%, p<0.01) was noted. These changes persist in the late postoperative period for basal (-16%, p<0.01) and mid (-20%, p<0.01) RV diameters and RA area (-19%, p=0.03). RV function parameters suffer significant reduction in the early phases: TAPSE (-39%, p<0.01), FAC (-24%, p<0.01), FW-GLS (-17.1%, p<0.01) and 4C-GLS (-16.3%, p<0.01). In later stages the major worsening in classical parameters persist: TAPSE (-28%, p=0.01) y FAC (-20%. P=0.01). However, strain variables recover to the baseline values. Postoperative RV reverse remodeling is reflected in Table and Figure. Conclusions Postoperative changes in echocardiographic right chambers features after ITVS suggest that myocardial deformation parameters should be the method of choice for follow-up of this surgical procedure. Table. Comparison of baseline and postsurgical echocardiographic parameters. Figure. Echocardiographic parameters evolution.TableFigure

Beyond 2D echocardiography: A novel multiparametric assessment of right ventricular dysfunction in transcatheter tricuspid valve repair

Abstract Background Patients with severe tricuspid regurgitation (TR) are heterogenous and complex in terms of etiology, comorbidities and state of disease. Right ventricular (RV) function measured by RV to pulmonary artery coupling (RVPAc) is prognostic in transcatheter tricuspid valve repair (T-TEER). However, traditional 2D echocardiographic measures have critical limitations and RVPAc fails to respect the degree of volume overload/dilation of the RV, which is a key clinical tracer for right ventricular dysfunction (RVD). Purpose We aimed to refine RVPAc by incorporating RV dilation, assessed by 3D echocardiography, to improve the assessment of RV dysfunction for an enhanced outcomeprediction in T-TEER patients. Methods We analyzed 262 patients undergoing T-TEER with complete 3D echocardiography. Results Despite similar RV function across groups, RV dilation (HR 1.85; 1.10, 3.12; p=0.020) and impaired RV free wall longitudinal strain (RVFWLS, HR 1.73, 1.02, 2.92, p=0.042) predicted increased 1-year mortality. A novel RVPAc parameter [RVFWLS/(3D-RVEDV*sPAPinvasive)] was developed, associating RVPA-Uncoupling with a tripled risk of death (HR 3.19, 1.7-6.0, p<0.001). NYHA Class IV and the new RVPAc were independent mortality predictors after T-TEER, with the modified RVPAc showing superior predictive value over traditional RVPAc (c-index 0.68 vs. 0.57, p=0.027). Conclusion The novel RVPAc parameter, integrating RV dilation and function, is a powerful predictor of survival post-T-TEER, underscoring the importance of timely intervention in severe TR and RVD. 3D echocardiography plays a critical role in assessing RV dimension and function, with implications for the management and prognosis of TR patients.Central Figure

Prevalence of cardiomyopathies and myocardial scar in patients with non-complicated premature ventricular beats: a CMR study

Abstract Introduction Frequent or symptomatic premature ventricular beats (PVBs) in subjects with no personal or family history of cardiac disease or sudden death is a recurrent motive for cardiac magnetic resonance (CMR) prescriptions. This represents a significant burden on healthcare services, given the low availability of CMR technique. If CMR is a recommended imaging modality in patients with history of cardiac arrest due to ventricular arrhythmia, sustained ventricular arrhythmias or when first-line tests are abnormal, its diagnostic value in this specific setting has not been evaluated. Purpose To determine the prevalence of significant CMR abnormalities (myocardial fibrosis, arrhythmogenic cardiomyopathies) in patients with no personal nor family history of cardiac disease and non-complicated PVBs. Methods Between September 2010 and July 2021, 416 healthy adults with no personal nor family cardiac disease history underwent CMR at our institution to explore non complicated PVBs, and were retrospectively included (Figure 1). Right and left ventricular (RV/LV) function and dimensions were systematically evaluated on CMR, as the presence of myocardial late gadolinium enhancement (LGE). Criteria for cardiomyopathies (hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), ARVD), the presence and location of myocardial fibrosis were looked after. Results A total of 605 patients were referred for CMR to explore frequent PVBs, representing 14% of all tests performed during this period. Among them, 12 patients (3%) presented significant myocardial abnormalities possibly related to PVBs: 2 patients had sequelae of myocardial infarction and 3 of myocarditis, 1 patient had criteria of HCM and 1 of ARVD, finally 5 presented non-specific myocardial fibrosis (septal mid-wall LGE). In addition, after a mean follow-up of 5 years, there was no death in patients with abnormal CMR, and only 2 patients underwent transcatheter ablation for focal non complicated but symptomatic PVBs. There was no hospitalization for heart failure. Conclusion In patients with non-complicated PVBs and no history of cardiac disease, the rate of cardiomyopathy pattern or myocardial scar on CMR is very low (3%). In this specific population, events were very rare: frequent isolated PVBs, even when associated with myocardial abnormalities, were a benign condition in our study. Given the high volume of patients referred for this indication in daily practice (14% of total CMRs in our center), the limited availability and high costs of CMR, and the difficulties of CMR sequences acquisition in the context of frequent PVBs (possibly leading to misdiagnosis), these data suggest that we should refine the selection of patients undergoing CMR for PVBs exploration.

Trimethylamine N-oxide as a Novel Biomarker for Left Ventricular Diastolic Dysfunction and Functional Remodeling in ST-Elevation Myocardial Infarction Patients

Abstract Background Over the last three decades, the mortality from ST-elevation myocardial infarction (STEMI) has halved. However, the incidence of heart failure or persistent angina remains high after STEMI, and the post-STEMI left ventricular (LV) systolic and diastolic function remains unpredictable. Thus, there is an unmet need to identify patients at risk of LV diastolic dysfunction or adverse remodeling. Purpose This study aims to investigate the potential of Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite associated with heart failure, and atherosclerosis, as a biomarker for adverse LV remodeling and diastolic dysfunction following STEMI. Methods In this prospective, observational cohort study, 210 STEMI patients with multivessel coronary artery disease (CAD) were enrolled after primary PCI. At 3 months follow-up, all patients underwent complete revascularization with FFR-guided PCI. Plasma TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP) levels at 3 months follow-up and peak troponin level at primary PCI were collected. Echocardiographies were performed within 24 hours of STEMI and at 12-month follow-ups. Diastolic dysfunction was defined according to the ASE 2016 guidelines.(1) Functional LV remodeling (FLVR) was categorized into 4 categories according to Chimed et al.(2) Receiver operating characteristic (ROC) curve analysis, including the Delong test and Youden index, was performed to compare the biomarkers' diagnostic value and determine the optimal cutoffs for predicting diastolic dysfunction and FLVR, respectively. Results Of the 210 patients enrolled, 85 (40.48%) were female, with a median age of 65 years [interquartile range (IQR): 58.00, 76.00] and a median body mass index (BMI) of 27.39 kg/m² (IQR: [24.56, 30.69]). The area under the ROC curve for predicting post-PCI LV diastolic dysfunction ≥ grade II was 0.72 (95% CI 0.63–0.81; p<0.001) for TMAO (Figure 1). The optimal TMAO cutoff value of 3.80 yielded a sensitivity of 0.75 (95% CI 0.63–0.86) and a specificity of 0.82 (95% CI 0.76–0.88). For FLVR grade 3 or 4, the area under the ROC curve was 0.62 (95% CI 0.50–0.74) and 0.72 (95% CI 0.62 -0.83) for TMAO and BNP, respectively (Figure 2), but the AUC was not significantly different (p= 0.191). In multivariable logistic regression analysis, TMAO was independently associated with FLVR grade 3 or 4 (OR 1.18, 95% CI 1.00-1.38, p = 0.046) and diastolic dysfunction ≥grade 2 (OR 1.30, 95% CI 1.12-1.50, p < 0.001). Conclusion The novel parameter of TMAO is a useful predictor for LV diastolic dysfunction after STEMI. TMAO is independently associated with an increased risk of LV diastolic dysfunction and worse FLVR. These results suggest that monitoring plasma TMAO levels could be an effective and cost-efficient strategy for monitoring patients with an elevated risk of LV diastolic dysfunction or adverse LV remodeling.Figure 1Figure 2

Hypoperfused myocardium and systolic function in patients with AMI undergoing complete revascularization

Abstract Background and Aim Coronary revascularization is the standard treatment for acute myocardial infarction (AMI), while the restoration of epicardial flow is non-parallel to myocardial reperfusion. This study sought to investigate the dynamic of myocardial perfusion and its association with left ventricular (LV) systolic function in AMI patients undergoing complete revascularization. Methods AMI patients who underwent complete revascularization were prospectively enrolled, and hybrid positron emission tomography/magnetic resonance (PET/MR) was performed at 2 months and 1 year. Hypoperfused myocardium was defined as myocardium with reduced perfusion and normal metabolism. Results Forty-five patients (59.80 ± 10.68 years, 80.0% male) were enrolled, and hypoperfused myocardium (median: 12% of LV) was detected in 21 (46.7%) patients 2 months post-AMI. Patients with hypoperfused myocardium (Group A) had significantly higher hypersensitive C-reactive protein (hs-CRP) (p = 0.016) and lower T2 value (p = 0.010) than those without (Group B). In the follow-up PET/MR at 1 year, significant LV ejection fraction improvement was observed in Group A (56.39 ± 9.76% vs. 54.58 ± 10.39%, p = 0.016) but not in Group B (51.63 ± 13.09% vs. 50.79 ± 16.95%, p = 0.615). Six (31.6%) patients in Group A showed recovery of perfusion, of which there were more females (p = 0.025), fewer diabetics (p = 0.044), or overweight (p = 0.035), with better global longitudinal strain (GLS) (p = 0.005). Conclusions Myocardial hypoperfusion is not rare and evolves over time in AMI patients undergoing complete revascularization, of which the reversal is probably associated with improved LV systolic function.Structured Graphical AbstractRepresentative PET/MR image of 2 separat

Spermidine attenuates left ventricular dysfunction in estrogen deprived aging rats through mitigating lipid peroxidation and mitochondrial dysfunction

Abstract Background Aging women with postmenopause are particularly susceptible to cardiovascular diseases (CVDs), which are associated with the elevation of oxidative stress and mitochondrial dysfunction. Although hormone replacement therapy (HRT) has been reported to provide cardiometabolic protection, long-term HRT could be linked to CVD consequences. A novel organic therapy with spermidine has shown promise as cardioprotection in several CVDs. However, the effects of spermidine on left ventricular (LV) function, mitochondrial function and oxidative stress in estrogen-deprived aging rats have not been investigated. Purpose To evaluate the effects of spermidine on LV function, mitochondrial function and oxidative stress in estrogen-deprived and D-galactose-induced aging rats Methods Twenty female Wistar rats were randomly assigned to the sham and the ovariectomy (OVX) along with D-galactose (150 mg/kg/day, s.c.) administration throughout the experiment for 12 weeks. OVX with D-galactose-treated rats were divided into three interventional groups: vehicle (ODV), spermidine (20 mg/kg/day, p.o., ODS), and estradiol (50 ug/kg/day, s.c., ODE) (n=5/group) for 8 weeks. The sham group received a vehicle (SVV, n=5). At the end, all rats underwent echocardiography, followed by euthanasia. The hearts were removed for measuring mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes (ΔΨm), and malondialdehyde (MDA) levels. Results Rats with OVX-induced estrogen deprivation with D-galactose-induced aging had LV impairments indicated by decreased LV ejection fraction, reduced ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E) to peak velocity flow by atrial contraction (A), and increased sympathovagal imbalance (elevated low/high frequency (LF/HF) ratio) (Fig. 1A-C). These estrogen-deprived aging rats also had an increase in cardiac tissue MDA levels, mitochondrial ROS production, and MMP depolarization (Fig. 1D-F). Both spermidine and estrogen similarly demonstrated a significant reduction in all of those detrimental effects, leading to improved LV function (Fig. 1A-F). Conclusion Spermidine exerted cardioprotection comparable to estrogen supplement through mitigating oxidative stress and mitochondrial impairments in cardiac tissue, resulting in improved LV dysfunction and cardiac autonomic balance due to estrogen deprived aging conditions in rats. These findings suggest that spermidine administration could be a promising strategy for cardioprotection in postmenopausal women with aging.

Phase I gene therapy clinical trial design of RP-A601 in adult patients with PKP2-arrhythmogenic cardiomyopathy (PKP2-ACM)

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is a rare, progressive, autosomal dominant disorder characterized by increased risk of ventricular arrhythmias and sudden cardiac death. Up to 45% of all ACM cases are caused by pathogenic variants in the PKP2 gene, which encodes for the desmosomal protein Plakophilin-2. This genetic cardiomyopathy is referred to as PKP2-ACM. AAVrh.74-PKP2a is a recombinant adeno-associated viral (AAV) vector containing the coding sequence of human PKP2 isoform A (PKP2a) and delivers the functional PKP2 gene to cardiomyocytes. Preclinical testing conducted in a clinically relevant mouse model of PKP2-ACM (with survival ≤50 days post disease onset) demonstrated that administration of a single AAVrh.74-PKP2a dose after disease onset extended survival through 5 months with improved right ventricular (RV) function, and decreased cardiac dilation, myocardial fibrosis, and arrhythmias. Additional studies in rodents and nonhuman primates demonstrated AAVrh.74-PKP2a safety. These preclinical findings support clinical initiation. Purpose We describe the design of a phase I trial to assess safety and preliminary efficacy of AAVrh.74-PKP2a (RP-A601) in high-risk adult patients with PKP2-ACM. Methods This study (NCT05885412) is a multi-center, open-label, dose escalation trial evaluating the safety and preliminary efficacy of a single intravenous infusion of RP-A601 in adult patients (age ≥18 yrs) with clinical and genetic PKP2-ACM diagnosis and an implanted ICD. Patients with severe right ventricular dysfunction, LV ejection fraction ≤50% (echocardiogram or cardiac MRI) and/or NYHA Class IV heart failure are excluded. Preliminary efficacy will be assessed at 12 months after RP-A601 infusion and includes evaluation of change in PKP2 myocardial tissue expression and clinical markers of arrhythmia burden. Conclusions PKP2-ACM is a devastating disease associated with high morbidity and mortality. This Phase I trial will evaluate the safety and preliminary efficacy of RP-A601 and was initiated based on robust preclinical efficacy and safety data.

Comprehensive remote myocardium characterisation using T1 mapping in patients with ST-segment elevation myocardial infarction

Abstract Background Myocardial tissue injury due to acute myocardial infarction (AMI) does not only occur in the myocardium that is supplied by the culprit lesion, but can also extend to the remote, non-infarcted myocardium. The prognostic implications of remote myocardium changes assessed by cardiac magnetic resonance (CMR) are not fully understood. The aim was to investigate the prognostic relevance of remote myocardium alterations assessed by CMR T1 mapping (native T1 and extracellular volume (ECV)) in patients after ST-segment elevation myocardial infarction (STEMI). Methods This study analyzed 491 STEMI patients treated with primary percutaneous coronary intervention (PCI) that were included in the prospective MARINA-STEMI study (NCT04113356). CMR imaging was performed 4 (Interquartile range [IQR]: 3-5) days after PCI. CMR images were analyzed for left ventricular (LV) function, standard infarct characteristics as well as native remote T1 and remote ECV. The primary clinical endpoint was the composite of all-cause mortality, re-infarction and new congestive heart failure (Major adverse cardiovascular events, MACE). Results Remote native T1 (median: 1009 [IQR: 979-1044] ms) was associated with female sex, peak NT-pro-BNP levels, peak hs-cTnT elevations, TIMI-risk score, admission Killip class, anterior infarct location, post-interventional TIMI-flow, LV ejection fraction and microvascular injury. Remote ECV (median: 26.37 [IQR: 24.28-29.27] %) was associated with age, female sex, peak NT-pro-BNP levels, diabetes, TIMI-risk score, admission Killip class, anterior infarct location, LV ejection fraction and microvascular injury. Over a median follow-up of 12 months (IQR: 12-13) after STEMI, 42 MACE outcomes occurred. Higher native remote T1-times (1018.5 [IQR: 997.0-1064.0] ms vs. 1007.0 [IQR: 977.0-1041.5] ms, p=0.033) as well as a higher remote ECV-values (28.07 vs. 26.27 %, p=0.009) were observed in patients with MACE. Multivariable Cox regression analysis demonstrated that remote ECV (hazard ratio (HR): 1.53 [confidence interval (CI): 1.07-2.19], p=0.020) but not native remote T1 associated with MACE. Conclusions A comprehensive assessment of the remote myocardium with native T1 and ECV provides prognostic information in a contemporary cohort of low risk STEMI patients. Remote ECV, but not remote native T1, was found to be an independent predictor of MACE.

Intact DNA repair in differentiated cardiomyocytes is essential for maintaining cardiac function in response to pressure overload in mice

Abstract Introduction DNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage-induced aging-related diseases. For example, deficient repair of endogenously generated DNA damage in mice with cardiomyocyte-restricted inactivation of Xpg, is associated with progressive heart failure. Purpose Here we tested the hypothesis that unrepaired DNA damage in differentiated cardiomyocytes increases cardiac vulnerability in response to hemodynamic overload. Methods To increase the burden of spontaneous DNA damage, we generated mice with cardiomyocyte-restricted inactivation of DNA repair endonuclease XPG. At 8 weeks of age, αMHC-Xpgc/- and control (Ctrl) mice were subjected to pressure overload by transverse aortic constriction (TAC). Eight weeks after TAC, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements, followed by molecular and histological analyses. Results Cardiomyocyte-restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction (Table). TAC-induced LV hypertrophy is similar in both groups (Ctrl 38%; αMHC-Xpgc/- 34%). In Ctrl mice, LV hypertrophy was accompanied by minimal LV dilation and modest changes in systolic and diastolic LV function. Conversely, TAC in αMHC-Xpgc/- produced severe LV dysfunction and resulted in overt congestive heart failure, demonstrated by aggravation of LV dilation, and marked increases in LV end-diastolic pressure, left atrial weight and lung fluid weight, which was accompanied by further increases in the expression levels of the hypertrophic marker genes atrial natriuretic peptide and beta-myosin heavy chain (Table). Moreover, lectin staining revealed a decrease in capillary density and TUNEL staining revealed further elevated levels of myocardial apoptosis. In addition, a significant increase of myocardial collagen content was observed. Conclusion Cardiomyocyte-restricted loss of DNA repair protein XPG increases cardiac vulnerability to develop heart failure in response to pressure overload. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only during basal conditions, but also in response to a pathological stimulus.

Prognostic evaluation with cardiac magnetic resonance in patients with systemic sclerosis

Abstract Systemic sclerosis (SSc) is an autoimmune disease with multiorgan involvement. Cardiac involvement is common and impact in prognosis. Cardiac magnetic resonance (CMR) allows an evaluation in ventricular and atrial function and hemodynamics forces. Our study aimed to assess RVD prevalence in SSc patients and analyze its impact on cardiovascular events. Methods In this retrospective study, we included patients diagnosed with SSc and followed-up in a specialized unit. We collected clinical, hemodynamic, and imaging data, including baseline CMR studies. Pulmonary function tests were also performed. RVD was defined as a right ventricular ejection fraction ≤52% in men and ≤51% in women. Patients were monitored for a composite endpoint consisting of cardiovascular death and/or admissions due to heart failure (HF). We assessed the predictors of this endpoint using Cox regression analysis. Results The study included 74 patients with SSc, most were female (81 %) with a mean age of 60±12 years. RVD prevalence was 32 %. Patients with RVD had greater ventricular volumes (160±44.9 vs 130±36.2; p=0.003), lower right ventricular global strain (-18 % vs. -26 %; p <0.001) and lower right atria strain (19% vs 29%; p=<0.001). We don’t found differences in presence of LGE of both ventricles. In the multivariate analysis RVEF (HR 2.9.; p = 0.022), pulmonary trunk dilatation (HR 1.15; p= 0.004, pulmonary hypertension at baseline (HR 2.98; 0.09); RV GLS (HR 1.08; p = 0.03) and RA GLS (HR 0.96; p = 0.024) were predictors of composite outcome of cardiovascular death and/or heart failure hospitalization. During a mean follow-up of 46 months, patients with RVD had higher rates of heart failure admissions (38% vs. 12%; p = 0.01) and cardiovascular mortality (29% vs. 6%; p 0.01). No ventricular arrhythmias occurred. Conclusion RVD is common among SSc patients. RVEF and pulmonary hypertension are the strongest variables linked to increased adverse cardiovascular clinical events and decreased survival in these patients.

Extremely rare coronary anomaly as cause of palpitations. A case report of single right coronary artery - multimodality imaging and its impact on treatment decisions

Abstract Background We report the case of a white caucasian 63-year-old patient admitted to the clinic because of atypical angina and palpitations. Other comorbidities included hypertension, hyperuricemia and hypercholesterolaemia. He was admitted to a tertiary cardiac centre for deepened diagnostics of his complaints. Case summary Echocardiography revealed no pathology, but due to high Calcium Score (Agatston > 400 units), signs of arrhythmia during exercise and atypical angina complaints further investigations were performed. Invasive coronary angiography revealed stenosis up to 53% in the middle part of the right coronary artery and computed tomography angiography showed no left coronary artery, only malignant-coursed vessel, running from the proximal part of the right coronary artery. Single photon emission tomography findings allowed to come to a decision to not perform invasive treatment (coronary artery bypass grafting), due to acceptable perfusion and viability of the heart muscle. Discussion Single coronary artery is an extremely rare anomaly. This requires highly individualised diagnostic approaches, which include multiple imaging modalities, as each adds different information. While the only coronary vessel was narrowed in 53%, no significant ischemia was detected. Left ventricular function remained preserved.

Comparative assessment of extracellular volume metrics in predicting adverse outcomes in patients with transthyretin amyloid cardiomyopathy

Abstract Introduction The indexed total extracellular volume of the myocardium (iECV) has recently been proposed to be superior in predicting adverse outcome in severe aortic stenosis as compared to conventional extracellular volume (ECV). So far, no study has assessed the comparative predictive performance of both measures in transthyretin amyloid cardiomyopathy (ATTR-CM). Aim We aimed to assess and compare the predictive performance of conventional ECV against iECV in determining adverse outcomes in patients with ATTR-CM. Methods From 2012 to 2023, patients with ATTR-CM undergoing contrast cardiac magnetic resonance (CMR) imaging prior to any specific treatment were enrolled. Both, conventional ECV and iECV were quantified on CMR alongside left ventricular volumetrics and late gadolinium enhancement. Adverse outcome was defined as a composite endpoint of hospitalization for heart failure and/or death. Results Analysis of 178 patients with ATTR-CM (82% males, mean age 77±8 years) revealed a mean conventional ECV of 47±13% and a mean iECV of 46±21 mL/m2, with a median follow-up of 2.5 years (IQR: 1.00-4.08 years). Conventional ECV was significantly associated with the composite endpoint (HR=1.03, 95%CI=1.01–1.05, p=0.006), outperforming iECV (HR=1.01, 95%CI=1.00–1.02, p=0.010). On multivariate analysis, adjusted for age, sex and left ventricular function, conventional ECV remained associated with the composite endpoint (p=0.002), while iECV demonstrated a slightly less significant association (p=0.003). Kaplan-Meier analysis, stratified by conventional ECV tertiles, revealed that patients in the highest tertile (ECV ≥53%) demonstrated the highest event rate (p = 0.043 by log rank test, see Figure 1A), in contrast to iECV (p=NS, Figure 1B). Conclusions High conventional ECV, among CMR fibrosis markers, is linked to heart failure hospitalizations and death in ATTR-CM, demonstrating superior prognostic value compared to iECV. Conventional ECV measurements may offer enhanced risk stratification for patients with ATTR-CM.

Long-term prognosis after ST-elevation myocardial infarction according to the Canadian Cardiovascular Society classification of tissue injury severity in acute myocardial infarction

Abstract Background The recently proposed Canadian Cardiovascular Society (CCS) classification of acute myocardial infarction (MI) describes 4 stages of tissue injury identified by cardiac magnetic resonance imaging (CMR); 1) oedema without late gadolinium enhancement (LGE); 2) LGE without microvascular obstruction (MVO); 3) MVO; and 4) intramyocardial haemorrhage (IMH). Prior studies examining the relationship between these characteristics and outcomes are limited by variations in imaging and measurement techniques, in particular the distinction between MVO and IMH. The relationship between the proposed CCS classification of MI and outcomes has not been described. Purpose To explore the prognostic significance of the CCS classification of MI tissue injury in patients with ST-elevation MI (STEMI). Methods The British Heart Foundation MR-MI study was a prospective single-centre CMR cohort study in patients with STEMI (July 2011-November 2012). CMR was performed on a single Siemens MAGNETOM Avanto 1.5-Tesla scanner at 2 days post-STEMI. The imaging protocol included LGE and T2* mapping, allowing for the identification of infarct, MVO, and IMH. Follow-up for the occurance of major adverse cardiovascular events (MACE) (recurrent MI, ischaemic stroke and cardiovascular death) and a composite outcome of heart failure hospitalization/ICD implantation (HFH) or all-cause death was performed via electronic case note review. Results 246 patients had complete data for this analysis. Of these, 6 (2%) were CCS Stage 1, 105 (43%) were Stage 2, 33 (13%) were Stage 3, and 102 (41%) were Stage 4. Due to the low number in CCS stage 1, these patients were pooled with Stage 2 for the purposes of this analysis (CCS Stage 1/2). Average age was 58 (SD 11) years and 188 (76%) were male. With higher CCS stage, more patients were Killip class III/IV at presentation, had the LAD as culprit artery and had TIMI flow 0/1 pre-PCI. Patients with higher CCS stage had higher peak troponin-I and NT-proBNP, lower left ventricular function, higher left ventricular volumes and larger infarct size (Table). Median follow-up was 11.8 years. HFH or all-cause death occurred in 80 (33%) patients (22 HFH and 58 all-cause deaths), and MACE occurred in 63 (26%) patients (41 recurrent MI, 11 ischaemic stroke events, and 11 cardiovascular deaths). There were no significant differences in outcomes between CCS Stage 3 and CCS Stage 1/2 (Figure). Patients with CCS Stage 4 had a higher risk of HFH or all-cause death (HR 1.73, 95%CI 1.08-2.77; p=0.022) and MACE (HR 1.88, 95%CI 1.10-3.20; p=0.021) as compared with those in CCS Stage 1/2 (Figure). Conclusion The novel CCS classification of MI tissue injury identifies patients at the highest risk of adverse outcomes following STEMI. The relationship between the presence of IMH (CCS Stage 4) and adverse outcomes highlights the importance of T2* imaging in post-MI CMR protocols in order to identify this prognostically important biomarker.

Decreased left atrial volume and preserved left atrial function in children with congenital Zika syndrome

Abstract Introduction The infection caused by Zika virus during pregnancy leads to congenital Zika syndrome (CZS). In a previous study of our group, we found that the heart is smaller in children with CZS, with few functional alterations. Left atrial strain imaging enables quantitative assessment of left atrial function, and recently its application has also shown promise in the pediatric population. Purpose To evaluate left atrial function in children affected by CZS, using echocardiogram and speckle tracking imaging technique. Methods This observational study was conducted with children with CZS using a two-dimensional speckle tracking technique to measure left atrial reservoir strain (LAS-r), conduit strain (LAS-cd), and contraction strain (LAS-ct). Also, to investigate the relationship between LAS-r and systolic excursion of the septum and lateral mitral annular plane (MAPSE), left atrial volume index and E/e’ ratio. Results A total of 52 patients were included, the median age of the studied population was 5 years (3 to 6), 59.6% male, and the body surface area was 0.66 [0.51, 0.90]. In the echocardiographic evaluation the left atrium volume index (ml/m²) was 13.15 [6.80, 18.00], considered smaller by the reference value. Also, the LAS-r (%) was 40.99 [24-70.5], LAS-cd (%) was 30,94 [32.5-52.5], LAS-cd (%) was 10,91 [5.2-24], values considered normal by the literature. Lateral MAPSE (cm) was 1.25 [0.81, 1.86] and septal MAPSE (cm) was 0.98 [0.78, 1.66] and E/e' ratio was 7.52 [4.57, 10.78]. A positive linear correlation was found between LAS-r and lateral MAPSE (r = 0.51, P = 0.019). Conclusion This original study with children with CZS shows that despite reduced atrial volume, the left atrial function remains normal, and correlates with left ventricular function evaluated by MAPSE. Further studies are needed to prospectively analyze the follow-up of left atrial morphology and function in this population.