Catheter Ablation for Ventricular Tachycardia in Patients With Desmoplakin Cardiomyopathy.

BACKGROUND: Desmoplakin (DSP) pathogenic/likely pathogenic (P/LP) variants are associated with malignant phenotypes of arrhythmogenic cardiomyopathy (DSP-ACM). Reports of outcomes after ventricular tachycardia (VT) ablation in DSP-ACM are scarce. OBJECTIVES: In this study, the authors sought to report on long-term outcomes of VT ablation in DSP-ACM. METHODS: Patients with P/LP DSP variants at 9 institutions undergoing VT ablation were included. Demographic, clinical, and instrumental data as well as all ventricular arrhythmia (VA) events were collected. Sustained VAs after the index procedure were the primary outcome. A per-patient before and after ablation comparison of rates of VA episodes per year was performed as well. RESULTS: Twenty-four DSP-ACM patients (39.3 ± 12.1 years of age, 62.5% male, median 6,116 [Q1-Q3: 3,362-7,760] premature ventricular complexes [PVCs] per 24 hours, median 4 [Q1-Q3: 2-11] previous VA episodes per patient at ablation) were included. Index procedure was most commonly endocardial/epicardial (19/24) The endocardium of the right ventricle (RV), the left ventricle (LV), or both ventricles were mapped in 8 (33.3%), 9 (37.5%), and 7 (29.2%) cases, respectively. Low voltage potentials were found in 10 of 15 patients in the RV and 11 of 16 in the LV. Endocardial ablation was performed in 18 patients (75.0%). Epicardial mapping in 19 patients (79.2%) identified low voltage potentials in 17, and 16 received epicardial ablation. Over the following 2.9 years (Q1-Q3: 1.8-5.5 years), 13 patients (54.2%) experienced VA recurrences. A significant reduction in per-patient event/year before and after ablation was observed (1.4 [Q1-Q3: 0.5-2.4] to 0.1 [Q1-Q3: 0.0-0.4]; P = 0.009). Two patients needed heart transplantation, and 4 died (3 of heart failure and 1 noncardiac death). CONCLUSIONS: VT ablation in DSP-ACM is effective in reducing the VA burden of the disease, but recurrences are common. Most VT circuits are epicardial, with both LV and RV low voltage abnormalities. Heart failure complicates clinical course and is an important cause of mortality.

The added value of abnormal regional myocardial function for risk prediction in arrhythmogenic right ventricular cardiomyopathy.

AIMS: A risk calculator for individualized prediction of first-time sustained ventricular arrhythmia (VA) in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients has recently been developed and validated (www.ARVCrisk.com). This study aimed to investigate whether regional functional abnormalities, measured by echocardiographic deformation imaging, can provide additional prognostic value. METHODS AND RESULTS: From two referral centres, 150 consecutive patients with a definite ARVC diagnosis, no prior sustained VA, and an echocardiogram suitable for deformation analysis were included (aged 41 ± 17 years, 50% female). During a median follow-up of 6.3 (interquartile range 3.1-9.8) years, 37 (25%) experienced a first-time sustained VA. All tested left and right ventricular (LV and RV) deformation parameters were univariate predictors for first-time VA. While LV function did not add predictive value in multivariate analysis, two RV deformation parameters did; RV free wall longitudinal strain and regional RV deformation patterns remained independent predictors after adjusting for the calculator-predicted risk [hazard ratio 1.07 (95% CI 1.02-1.11); P = 0.004 and 4.45 (95% CI 1.07-18.57); P = 0.040, respectively] and improved its discriminative value (from C-statistic 0.78 to 0.82 in both; Akaike information criterion change > 2). Importantly, all patients who experienced VA within 5 years from the echocardiographic assessment had abnormal regional RV deformation patterns at baseline. CONCLUSIONS: This study showed that regional functional abnormalities measured by echocardiographic deformation imaging can further refine personalized arrhythmic risk prediction when added to the ARVC risk calculator. The excellent negative predictive value of normal RV deformation could support clinicians considering the timing of implantable cardioverter defibrillator implantation in patients with intermediate arrhythmic risk.

Individualized Family Screening for Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Clinical guidelines recommend regular screening for arrhythmogenic right ventricular cardiomyopathy (ARVC) to monitor at-risk relatives, resulting in a significant burden on clinical resources. Prioritizing relatives on their probability of developing definite ARVC may provide more efficient patient care. OBJECTIVES: The aim of this study was to determine the predictors and probability of ARVC development over time among at-risk relatives. METHODS: A total of 136 relatives (46% men, median age 25.5 years [IQR: 15.8-44.4 years]) from the Netherlands Arrhythmogenic Cardiomyopathy Registry without definite ARVC by 2010 task force criteria were included. Phenotype was ascertained using electrocardiography, Holter monitoring, and cardiac imaging. Subjects were divided into groups with "possible ARVC" (only genetic or familial predisposition) and "borderline ARVC" (1 minor task force criterion plus genetic or familial predisposition). Cox regression was performed to determine predictors and multistate modeling to assess the probability of ARVC development. Results were replicated in an unrelated Italian cohort (57% men, median age 37.0 years [IQR: 25.4-50.4 years]). RESULTS: At baseline, 93 subjects (68%) had possible ARVC, and 43 (32%) had borderline ARVC. Follow-up was available for 123 relatives (90%). After 8.1 years (IQR: 4.2-11.4 years), 41 (33%) had developed definite ARVC. Independent of baseline phenotype, symptomatic subjects (P = 0.014) and those 20 to 30 years of age (P = 0.002) had a higher hazard of developing definite ARVC. Furthermore, patients with borderline ARVC had a higher probability of developing definite ARVC compared with those with possible ARVC (1-year probability 13% vs 0.6%, 3-year probability 35% vs 5%; P < 0.01). External replication showed comparable results (P > 0.05). CONCLUSIONS: Symptomatic relatives, those 20 to 30 years of age, and those with borderline ARVC have a higher probability of developing definite ARVC. These patients may benefit from more frequent follow-up, while others may be monitored less often.

Circulating Biomarkers of Fibrosis Formation in Patients with Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a progressive inheritable disease which is characterized by a gradual fibro-(fatty) replacement of the myocardium. Visualization of diffuse and patchy fibrosis patterns is challenging using clinically applied cardiac imaging modalities (e.g., late gadolinium enhancement, LGE). During collagen synthesis and breakdown, carboxy-peptides are released into the bloodstream, specifically procollagen type-I carboxy-terminal propeptides (PICP) and collagen type-I carboxy-terminal telopeptides (ICTP). We collected the serum and EDTA blood samples and clinical data of 45 ACM patients (age 50.11 ± 15.53 years, 44% female), divided into 35 diagnosed ACM patients with a 2010 ARVC Task Force Criteria score (TFC) ≥ 4, and 10 preclinical variant carriers with a TFC < 4. PICP levels were measured using an enzyme-linked immune sorbent assay and ICTP levels with a radio immunoassay. Increased PICP/ICTP ratios suggest a higher collagen deposition. We found significantly higher PICP and PICP/ICTP levels in diagnosed patients compared to preclinical variant carriers (p < 0.036 and p < 0.027). A moderate negative correlation existed between right ventricular ejection fractions (RVEF) and the PICP/ICTP ratio (r = -0.46, p = 0.06). In addition, significant correlations with left ventricular function (LVEF r = -0.53, p = 0.03 and end-systolic volume r = 0.63, p = 0.02) were found. These findings indicate impaired contractile performance due to pro-fibrotic remodeling. Follow-up studies including a larger number of patients should be performed to substantiate our findings and the validity of those levels as potential promising biomarkers in ACM.

Longitudinal Prediction of Ventricular Arrhythmic Risk in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: The arrhythmogenic right ventricular cardiomyopathy (ARVC) risk calculator stratifies risk for incident sustained ventricular arrhythmias (VA) at the time of ARVC diagnosis. However, included risk factors change over time, and how well the ARVC risk calculator performs at follow-up is unknown. METHODS: This was a retrospective analysis of patients with definite ARVC and without prior sustained VA. Risk factors for VA including age, nonsustained ventricular tachycardia, premature ventricular complex burden, T-wave inversions on electrocardiogram, cardiac syncope, right ventricular function, therapeutic medication use, and exercise intensity were assessed at the time of 2010 Task Force Criteria based ARVC diagnosis and upon repeat evaluations. Changes in these risk factors were analyzed over 5-year follow-up. The 5-year risk of VA was predicted longitudinally using (1) the baseline ARVC risk calculator prediction, (2) the ARVC risk prediction calculated using updated risk factors, and (3) time-varying Cox regression. Discrimination and calibration were assessed in comparison to observed VA event rates. RESULTS: Four hundred eight patients with ARVC experiencing 132 primary VA events were included. Matched comparison of risk factors at baseline versus at 5 years of follow-up revealed decreased burdens of premature ventricular complexes (-1200/day) and nonsustained ventricular tachycardia (-14%). Presence of significant right ventricular dysfunction and number of T-wave inversions on electrocardiogram were unchanged. Observed risk for VA decreased by 13% by 5 years follow-up. The baseline ARVC risk calculator's ability to predict 5-year VA risk worsened during follow-up (C statistics, 0.83 at diagnosis versus 0.68 at 5 years). Both the updated ARVC risk calculator (C statistics of 0.77) and time-varying Cox regression model (C statistics, 0.77) had strong discrimination. The updated ARVC risk calculator overestimated 5-year VA risk by an average of +6%. CONCLUSIONS: Risk factors for VA in ARVC are dynamic, and overall risk for incident sustained VA decreases during follow-up. Up-to-date risk factor assessment improves VA risk stratification.

Evaluation of the cardiac amyloidosis clinical pathway implementation: a real-world experience.

Aims: The aim of this study is to evaluate the implementation of the cardiac amyloidosis (CA) clinical pathway on awareness among referring cardiologists, diagnostic delay, and severity of CA at diagnosis. Methods and results: Patients with CA were retrospectively included in this study and divided into two periods: pre-implementation of the CA clinical pathway (2007-18; T1) and post-implementation (2019-20; T2). Patients' and disease characteristics were extracted from electronic health records and compared. In total, 113 patients (mean age 67.8 ± 8.5 years, 26% female) were diagnosed with CA [T1 (2007-18): 56; T2 (2019-20): 57]. The number of CA diagnoses per year has increased over time. Reasons for referral changed over time, with increased awareness of right ventricular hypertrophy (9% in T1 vs. 36% in T2) and unexplained heart failure with preserved ejection fraction (22% in T1 vs. 38% in T2). Comparing T1 with T2, the diagnostic delay also improved (14 vs. 8 months, P < 0.01), New York Heart Association Class III (45% vs. 23%, P = 0.03), and advanced CA stage (MAYO/Gillmore Stage III/IV; 61% vs. 33%, P ≤ 0.01) at time of diagnosis decreased. Conclusion: After implementation of the CA clinical pathway, the awareness among referring cardiologists improved, diagnostic delay was decreased, and patients had less severe CA at diagnosis. Further studies are warranted to assess the prognostic impact of CA clinical pathway implementation.

Hypertensive response to exercise in adult patients with repaired aortic coarctation.

OBJECTIVE: The clinical and prognostic implications of a hypertensive response to exercise after repair of coarctation of the aorta (CoA) remain controversial. We aimed to determine the prevalence of a hypertensive response to exercise, identify factors associated with peak exercise systolic blood pressure (SBP) and explore the association of peak exercise SBP with resting blood pressure and cardiovascular events during follow-up. METHODS: From the Dutch national CONgenital CORvitia (CONCOR) registry, adults with repaired CoA who underwent exercise stress testing were included. A hypertensive response to exercise was defined as a peak exercise SBP ≥210 mm Hg in men and ≥190 mm Hg in women. Cardiovascular events consisted of coronary artery disease, stroke, aortic complications and cardiovascular death. RESULTS: Of the original cohort of 920 adults with repaired CoA, 675 patients (median age 24 years (range 16-72 years)) underwent exercise stress testing. Of these, 299 patients (44%) had a hypertensive response to exercise. Mean follow-up duration was 10.1 years. Male sex, absence of a bicuspid aortic valve and elevated resting SBP were independently associated with increased peak exercise SBP. Peak exercise SBP was positively predictive of office SBP (ß=0.11, p<0.001) and 24-hour SBP (ß=0.05, p=0.03) at follow-up, despite correction for baseline SBP. During follow-up, 100 patients (15%) developed at least 1 cardiovascular event. Peak exercise SBP was not significantly associated with the occurrence of cardiovascular events (HR 0.994 (95% CI 0.987 to 1.001), p=0.11). CONCLUSIONS: A hypertensive response to exercise was present in nearly half of the patients in this large, prospective cohort of adults with repaired CoA. Risk factors for increased peak exercise SBP were male sex, absence of a bicuspid aortic valve and elevated resting SBP. Increased peak exercise SBP independently predicted hypertension at follow-up. These results support close follow-up of patients with a hypertensive response to exercise to ensure timely diagnosis and treatment of future hypertension.

Cardiovascular Morbidity and Mortality in Adult Patients With Repaired Aortic Coarctation.

Background The long-term burden of cardiovascular disease after repair of coarctation of the aorta (CoA) has not been elucidated. We aimed to determine the incidence of and risk factors for cardiovascular events in adult patients with repaired CoA. Additionally, mortality rates were compared between adults with repaired CoA and the general population. Methods and Results Using the Dutch Congenital Corvitia (CONCOR) registry, patients aged ≥16 years with previous surgical or transcatheter CoA repair from 5 tertiary referral centers were included. Cardiovascular events were recorded, comprising coronary artery disease, stroke/transient ischemic attack, aortic complications, arrhythmias, heart failure hospitalizations, endocarditis, and cardiovascular death. In total, 920 patients (median age, 24 years [range 16-74 years]) were included. After a mean follow-up of 9.3±5.1 years, 191 patients (21%) experienced at least 1 cardiovascular event. A total of 270 cardiovascular events occurred, of which aortic complications and arrhythmias were most frequent. Older age at initial CoA repair (hazard ratio [HR], 1.017; 95% CI, 1.000-1.033 [P=0.048]) and elevated left ventricular mass index (HR, 1.009; 95% CI, 1.005-1.013 [P<0.001]) were independently associated with an increased risk of cardiovascular events. The mortality rate was 3.3 times higher than expected based on an age- and sex-matched cohort from the Dutch general population (standardized mortality ratio, 3.3; 95% CI, 2.3-4.4 [P<0.001]). Conclusions This large, prospective cohort of adults with repaired CoA showed a high burden of cardiovascular events, particularly aortic complications and arrhythmias, during long-term follow-up. Older age at initial CoA repair and elevated left ventricular mass index were independent risk factors for the occurrence of cardiovascular events. Mortality was 3.3-fold higher compared with the general population. These results advocate stringent follow-up after CoA repair and emphasize the need for improved preventive strategies.

Repetitive Immune-Mediated Noninfectious Endocarditis Necessitating 5 Mitral Valve Replacements.

We present a young patient who had to undergo 5 mitral valve replacements (MVR) because of a repetitive immune-mediated noninfectious endocarditis. The patient was treated with multiple anti-inflammatory drugs and high-dose prednisone. After the fifth MVR, the patient remained in stable condition using Anakinra after 22 months of follow-up. (Level of Difficulty: Advanced.).

One year improvement of exercise capacity in patients with mechanical circulatory support as bridge to transplantation.

AIMS: Mechanical circulatory support (MCS) results in substantial improvement of prognosis and functional capacity. Currently, duration of MCS as a bridge to transplantation (BTT) is often prolonged due to shortage of donor hearts. Because long-term results of exercise capacity after MCS are largely unknown, we studied serial cardiopulmonary exercise tests (CPETs) during the first year after MCS implantation. METHODS AND RESULTS: Cardiopulmonary exercise tests at 6 and 12 months after MCS implantation in BTT patients were retrospectively analysed, including clinical factors related to exercise capacity. A total of 105 MCS patients (67% male, 50 ± 12 years) underwent serial CPET at 6 and 12 months after implantation. Power (105 ± 35 to 114 ± 40 W; P ≤ 0.001) and peak VO2 per kilogram (pVO2/kg) improved significantly (16.5 ± 5.0 to 17.2 ± 5.5 mL/kg/min (P = 0.008)). Improvement in pVO2 between 6 and 12 months after LVAD implantation was not related to heart failure aetiology or haemodynamic severity prior to MCS. We identified maximal heart rate at exercise as an important factor for pVO2. Younger age and lower BMI were related to further improvement. At 12 months, 25 (24%) patients had a normal exercise capacity (Weber classification A, pVO2 > 20 mL/kg/min). CONCLUSIONS: Exercise capacity (power and pVO2) increased significantly between 6 and 12 months after MCS independent of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile or heart failure aetiology. Heart rate at exercise importantly relates to exercise capacity. This long-term improvement in exercise capacity is important information for the growing group of long-term MCS patients as this is critical for the quality of life of patients.

Routinely measured hematological parameters and prediction of recurrent vascular events in patients with clinically manifest vascular disease.

BACKGROUND AND AIMS: The predictive value of traditional risk factors for vascular events in patients with manifest vascular disease is limited, underscoring the need for novel biomarkers to improve risk stratification. Since hematological parameters are routinely assessed in clinical practice, they are readily available candidates. METHODS: We used data from 3,922 vascular patients, who participated in the Second Manifestations of ARTerial Disease (SMART) study. We first investigated associations between recurrent vascular events and 22 hematological parameters, obtained from the Utrecht Patient Oriented Database (UPOD), and then assessed whether parameters associated with outcome improved risk prediction. RESULTS: After adjustment for all SMART risk score (SRS) variables, lymphocyte %, neutrophil count, neutrophil % and red cell distribution width (RDW) were significantly associated with vascular events. When individually added to the SRS, lymphocyte % improved prediction of recurrent vascular events with a continuous net reclassification improvement (cNRI) of 17.4% [95% CI: 2.1, 32.1%] and an increase in c-statistic of 0.011 [0.000, 0.022]. The combination of lymphocyte % and neutrophil count resulted in a cNRI of 22.2% [3.2, 33.4%] and improved c-statistic by 0.011 [95% CI: 0.000, 0.022]. Lymphocyte % and RDW yielded a cNRI of 18.7% [3.3, 31.9%] and improved c-statistic by 0.016 [0.004, 0.028]. However, the addition of hematological parameters only modestly increased risk estimates for patients with an event during follow-up. CONCLUSIONS: Several hematological parameters were independently associated with recurrent vascular events. Lymphocyte % alone and in combination with other parameters enhanced discrimination and reclassification. However, the incremental value for patients with a recurrent event was limited.