Allison, Thomas G.

Background: Cardiac amyloidosis is a rapidly progressing and severe condition leading to heart failure and reduced quality of life. Amyloid deposits impair both chronotropic and pumping functions of the heart. The Cardiopulmonary Exercise Test (CPET) is a vital tool in assessing the severity and progression of this disease. Aims: This study aims to investigate the differences in chronotropic function associated with the stages of heart failure in patients with cardiac amyloidosis and outcomes. Methods: A retrospective cohort study was conducted involving 194 patients diagnosed with cardiac amyloidosis who underwent at least one CPET from February 2010 to February 2024. Medical records were reviewed for data on the type of amyloidosis, comorbidities, and CPET results. The cohort was divided into two groups according to the Weber Classification: Weber Class A/B and Weber Class C/D. Patients who had CPET studies post-heart transplant were excluded. Statistical analyses, including Fisher’s exact test and chi-square test, were used. Cox regression model analysis, proportional hazards model for time to event. Adjustment for beta-blocker use was made to assess chronotropic incompetence. A p-value <0.05 was considered significant. Results: Among the 194 patients, 94 were classified as Weber A/B and 100 as Weber C/D. The average age at the time of the stress test was similar between the groups: 62.9 ± 11.7 years for Weber A/B and 62.3 ± 10.7 years for Weber C/D (p=0.087) Table 1 . Chronotropic function, evaluated through CPET, showed significant differences. Heart rate reserve was significantly lower in the Weber C-D group compared to the A-B group (p<0.001). The chronotropic index was also significantly lower in the Weber C-D group Figure 2. Chronotropic incompetence was observed in 43.9% of the Weber A and increased progressively, being significantly more prevalent in the Weber D group (100%) (p<0.001). Additionally, Chronotropic incompetence was strongly associated with the composite outcome of (hospitalization for heart failure and death) HR 1.932 (1.126 -3.313) p =0.0167 (Table 2). Conclusion: CPET assessment of chronotropic function correlates with VO2 parameter evaluated in Weber classification. Patients with higher Weber stages of heart failure in amyloidosis exhibited a higher prevalence of chronotropic incompetence, indicating it could serve as a marker of cardiac function.

Background: Although exercise stress testing (EST) has shown to unmask latent electrical substrates in PKP2 -mediated arrhythmogenic cardiomyopathy (ACM), the prognostic role of EST-induced ventricular arrhythmia (VA) patterns in PKP2-ACM patients is unclear. Objective: To examine the exercise-induced VA patterns observed during EST in PKP2-ACM patients and explore their correlation with major VA outcomes. Methods: We retrospectively analyzed 621 patients with either genotype-positive ACM or genotype-positive dilated cardiomyopathy evaluated between 01/2015 and 04/2024 to identify those with a disease-causative variant in PKP2 (N = 108). After exclusion of 38 PKP2-ACM patients without EST data, demographic and electrocardiographic data was extracted from the electronic medical record. The arrhythmic burden [premature ventricular contractions (PVCs), PVCs in bigeminy, PVC couplets, non-sustained VT (NSVT), sustained VT, ventricular fibrillation (VF), and PVCs/minute] during each EST phase (baseline, peak, active and passive recovery) were reviewed and correlated with major VA outcomes [sudden cardiac arrest (SCA), sustained VT, and appropriate implantable cardioverter-defibrillator (ICD) shocks]. Results: A total of 186 exercise tests from 70/108 (65%) PKP2-ACM patients (mean age 36 ± 20 years, 40 % male) were analyzed. The presence and burden of PVCs occurring singly, bigeminy, couplets. and NSVT were more prevalent during the recovery phase, specifically the passive recovery phase ( Table ). PKP2-ACM patients with structural disease (64%) were more likely to have an increased VA burden during recovery than those without structural disease [28/45 (62%) vs 4/25 (16%); p<0.001]. Interestingly, the presence of an increased arrhythmic burden (worsening PVCs/min or complex PVCs) during the recovery was associated with major VA over a median follow-up of 47 months (HR 8.576 [1.015-72.449]; p= 0.019). Conclusion: Increased arrhythmic burden during the recovery phase (late > early) is associated with an increased risk of major VAs in PKP2-ACM. Further studies are needed to understand if this observation extends to other ACM genotypes and whether EST-induced VA patterns can be used to assess therapeutic efficacy in PKP2-ACM.

Background: Optimum timing of surgery for severe primary mitral regurgitation (MR) particularly in the absence of significant symptoms or echo evidence of LV impairment remains unclear. Other modalities of assessment include cardiopulmonary exercise testing (CPET) and novel echo measurements, such as LV global longitudinal strain (LVGLS). We sought to evaluate whether pre-op CPET or LVGLS are associated with survival after surgery. Methods: We identified consecutive patients who had surgery for severe primary MR between 2007 and 2017 and had pre-op CPET. Clinical and mortality data were collected from chart review and our institutional database. LVGLS was retrospectively collected by a single person blinded to patient outcomes. Primary outcome was post surgery all cause death, and we used univariable analysis to identify variables associated with all cause death. Results: We included 176 patients with median age 63 (IQR 51, 71) years, 63 patients (35.8%) were female and 31 patients (14.8%) had a history of atrial fibrillation. 165 patients (93.8%) had mitral repair, 18 (10.2%) had concomitant CABG, 22 (12.5%) had concomitant ablation procedure and 14 (8.0%) had concomitant tricuspid procedure. 114 patients (64.8%) were in NYHA Class I and 56 (31.8%) were in NYHA Class II. There was no operative mortality. Median % predicted peak VO2 (ppVO2) was 89 (74, 101), median ventilatory equivalent of carbon dioxide (VE/VCO2) was 28.0 (25.7, 31.0) l/min/l/min and median respiratory exchange ratio was 1.2 (1.1, 1.2). 73 patients (41.5%) had abnormal CPET (defined as ppVO2<85%). Median LVEF was 65 (60, 68) %, median LVESD was 35 (32, 38) mm and median LVGLS was 18.5 (16.6, 20.3) %. 45 patients (25.9%) had abnormal LVEF (defined as ≤ 60%), 11 patients (6.7%) had abnormal LVESD (defined as ≥45mm) and 35 patients (20.8%) had abnormal LVGLS (defined as <16%). At a median follow up of 10.2 (6.8, 13.2) years, there were 19 (10.8%) deaths. In the univariate analysis, age at surgery (HR 1.12, p<0.001), LVESD (HR 1.11, p=0.009), LVGLS (HR 1.11, p=0.013) and VE/VCO2 (HR 1.08, p=0.044) were associated with all cause mortality. Conclusion: A significant proportion of patients with no or mild symptoms exhibit echocardiographic evidence of LV impairment when having surgery for severe primary MR. CPET parameters such as VE/VCO2 and novel echocardiographic measurements such as LVGLS may predict risk of long term mortality and potentially inform timing of surgery in these patients.

Abstract Background Cardiopulmonary exercise testing (CPET) has emerged as an important tool for risk stratification and prognosis assessment in patients with cardiac diseases. The Weber and Ventilatory Functional Classification have been correlated with outcomes in patients with Heart Failure (HF). Weber classification is based on VO2: Weber class A, peak VO2 &gt;20 mL/kg per minute; class B, peak VO2 16–20 mL/kg per minute; class C, peak VO2 10–16 mL/kg per minute; and class D, peak VO2 ≤10 mL/kg per minute and Ventilatory classification on VE/VCO2 slope I-IV (Figure A). Although VO2 and VE/VCO2 variables have found altered in the amyloidosis population, the applicability of this classification in a cohort of amyloidosis patients and its correlation with all-cause mortality have not been explored. Purpose To evaluate if the Weber and Ventilatory Classification of HF predicts mortality amyloidosis patients. Methods 194 with diagnosis of amyloidosis who underwent CPET from February 2010 to February 2024 were included in this retrospective cohort study. Patients with at least one CPET complete data were included in the analysis. Data on the type of amyloidosis, comorbidities, and echocardiogram were retrieved from medical records. Cohort was divided into two groups according to the Weber Classification: Weber Class A/B and Weber Class C/D. Individuals with CPET studies after heart transplant were excluded from the analysis. Statistical analyses including Fisher’s exact test, chi-square, Tukey-Kramer (TK), Cox regression model analysis, proportional hazards model for time to event, and Kaplan–Meier curves were performed. A p-value &lt;0.05 was considered significant. Results Out of the 194 patients, 94 were classified as Weber A-B and 100 as Weber B-C. The age at stress test was similar between the groups: Weber A/B 62.9 ± 11.7 years and Weber C/D 62.3 ± 10.7 years (p=0.087). Ejection Fraction was similar between groups, 32% and 28.9% in A-B and C-D respectively (p =0.207). Higher levels of NT-proBNP were found in the Weber C/D group. The prevalence of comorbidities was balanced among the groups except chronic kidney disease, which was higher in Weber Class C/D (40%) vs (20.2%) in Weber Class A/B (Table 1). Cox analysis revealed a strong association between higher Weber class and the outcome HR 2.36 (1.18 – 4.71) p=0.014. For Higher Ventilatory Class (Group III-IV) similar results were found HR 2.95 (1.60 – 5.45) p=0.005(Table 2). Mortality was significantly higher during the follow-up in the Weber C/D group (25%) vs (10%) in the Weber A-B group p=0.007(Figure D). Conclusion Weber and ventilatory Classification based on CPET, besides predicting outcomes in patients with cardiac disease, are strong predictors of mortality in patients with amyloidosis. These findings suggest that this patient group benefits from earlier stratification to assess prognosis and the potential requirement for transplant independently from other factors.

Abstract Background Cardiopulmonary exercise testing (CPET) is a widely used tool for risk stratification and prognosis in patients with chronic heart failure. In amyloid patients, cardiac amyloid deposits are associated with poor prognosis, increased risk for arrhythmias, sudden death, and subsequent exercise limitation due to restrictive cardiomyopathy. The type of amyloidosis and its affectation of the heart are different, and little is known about the CPET parameters according to the type of cardiac amyloidosis. Purpose In this study, we aim to compare CPET data in different types of amyloidosis to determine if CPET variables evaluated could have a significant difference that could impact the follow-up or prognosis of the patients based on the type of amyloidosis. Methods We conducted a retrospective cohort study of 194 patients with a diagnosis of cardiac amyloidosis referred for CPET from February 2010 to February 2024. Patients with at least one CPET data were included in our analysis. The type of amyloidosis, comorbidities, and echocardiogram data were retrieved from medical records. Patients were divided into 3 different groups according to the type of amyloidosis: AL Amyloidosis(AL), Variant TTR Amyloidosis (vTRR), and Wild Type TTR Amyloidosis (wtTTR). Individuals with CPET studies after heart transplant were excluded from the analysis. Fisher’s exact test or chi-square was used to compare categorical variables. ANOVA and Tukey-Kramer (TK) were used to compare continuous variables. Adjustment using General Linear Models (GLM) procedure was used to identify any confounder that could affect the results. A p-value &lt;0.05 was considered significant. Results Out of the 194 patients, 66 had AL Amyloidosis, 40 had vTTR Amyloidosis, and 88 had wtTTR Amyloidosis. Most of the patients were male, and the male predominance was higher in the wtTRR group. There were 41 (62.1%) males in the AL group, 35 (87.5%) in the vTRR group, and 83 (94.3%) in the wtTTR group (p&lt;0.0001). Comorbidities were balanced among the groups. Additional demographic and comorbidities data are shown in Table 1. From the evaluated CPET variables, VE/VCO2 nadir and slope were significantly higher in the wtTTR group when compared to the other groups, as well as Peak VE and Peak TV(Figure A). However, after adjusting for sex, BMI, and age, VE/VCO2 nadir was still significantly higher in the wtTRR group (p=0.003) compared to the other groups, as well as Peak VE, which was higher again in vTTR patients (p=0.001), and Peak TV (Table 2). Conclusion Ventilation variables evaluated in CPET showed alterations in the wtTTR group. These findings suggest that wtTRR amyloid patients could have a severe problem in ventilation that could be of significant relevance in future prognosis.

AbstractIntroductionLong QT syndrome (LQTS) is a cardiac channelopathy characterized by QT prolongation and a potential for arrhythmic syncope, sudden cardiac arrest or deaths (SCA/SCD). It has been speculated that patients with LQTS might have a primary sinoatrial node (SAN) phenotype of chronotropic insufficiency (CI). This has not been demonstrated convincingly before because of the potentially confounding effects of beta blocker (BB) therapy. Herein, we set out to determine whether untreated patients with LQTS demonstrate intrinsic CI.Methods and ResultsA retrospective review of all treadmill exercise stress tests (TEST) was performed on patients with one of the three most common LQTS genotypes: LQT1, LQT2, and LQT3. For each patient, the first TEST completed while off BB was analyzed. Patients with prior left cardiac sympathetic denervation (LCSD) therapy were excluded. CI was defined as having an age‐ and gender‐predicted peak heart rate (HR) < 85% and/or a predicted HR reserve (HRR) < 80%. Overall, 463 LQTS patients (245 LQT1, 125 LQT2, and 93 LQT3) were included (267 female [58%]; mean age at time of TEST [29 ± 17 years]). Mean % predicted peak HR for all LQTS patients was 87.6% (range 42.9% ‐ 119.1%) and mean % predicted HRR was 80% (range 19.1% ‐ 153%). Overall, half of all LQTS patients (n = 234; 51%) displayed CI; 64% of patients with LQT1 (n = 157), 37% with LQT2 (n = 46), and 33% with LQT3 (n = 31). Patients with LQT1 were most likely to exhibit CI compared to patients with LQT2 (p < .0001) and LQT3 (p < .0001). CI was significantly more common in LQT1 compared to controls (p < .0001), while there was no difference between LQT2 (p = .5) or LQT3 and controls (p > .9). Presence of CI was not a predictor of LQTS‐associated symptoms, BB side effects or likelihood of future breakthrough cardiac events (BCE).ConclusionsPatients with LQTS, particularly LQT1, demonstrate a SAN phenotype of CI. If assessing BB therapy effect by impact on peak HR, the patient's pretreatment peak HR, rather than an age‐ and gender‐predicted maximum HR, should be used.

Introduction: Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in the young and especially in young athletes. The treadmill exercise test (TEST) has an important role in the functional assessment of patients with HCM. Herein, TEST-derived peak oxygen uptake (VO2 max) is a proxy for cardiopulmonary fitness. However, the correlation between symptoms and VO2 - especially in active young patients with HCM - is unclear. Objective: To explore the relationship between TEST-derived VO2 and symptomology in athletes and non-athletes with HCM. Methods: Overall, 91 patients (40% female) with HCM and a TEST with VO 2 data were included in this case-control study. Data were abstracted from the electronic health record using the first TEST performed at Mayo Clinic. Patients were defined as an athlete if they participated in an organized, competitive sport. Results: Overall, 60 HCM patients (33% female) were categorized as an athlete. HCM athletes were younger (17 vs. 27 years; p<0.0001) and less likely to be symptomatic at the time of their TEST (OR=0.24; p=0.01). Additionally, athletes had a higher VO2 max (86% vs. 68% of predicted; p<0.0001) and reached higher exercise times (93% vs 76% of predicted; p<0.0001) compared to the non-athletes with HCM. When comparing symptomatic (n = 18) to asymptomatic patients (n = 73), symptomatic patients had i) a reduced exercise time (68% vs. 92% of predicted; p=0.002) and ii) lower VO2 max (62% vs 84% of predicted; p<0.001). Finally, among the 27 patients (30%) with a VO 2 max < 70% predicted (n=27), they i) more likely had a history of cardiac arrest (4 vs 0; p=0.006) and ii) were more likely to be symptomatic (OR=7.7; p< 0.0001) than those with VO2 ≥ 70% of predicted (n=64). Importantly, however, 15/27 (56%) patients (8 athletes/7 non-athletes) with a VO2 max < 70% were asymptomatic. Conclusions: Reduced exercise capacity is common in athletes with HCM and does not correlate with symptom status. However, if the TEST-derived VO2 max is < 70%, treatment intensification may be necessary as it may portend an adverse outcome both arrhythmically and mechanically.

Background: The Metabolically Obese Normal Weight (MONW) phenotype has been described as a unique subgroup of individuals with metabolic dysregulation similar to obese individuals, but not considered obese per se . In theory, these individuals have an adiposity-independent substrate predisposing them to metabolic dysregulation. We tested whether central obesity explains the metabolic abnormalities in persons with MONW in a prospective population-based cohort in the Czech Republic. Methods: We used data from Kardiovize Brno 2030 study, a prospective community-based cohort in Central Europe. We defined obesity using World Health Organization categories for body mass index (BMI) and central obesity by waist circumference (WC≥ 94 cm in men and ≥ 80 cm in women). Metabolically obese (MO) was defined using AHA criteria by having three or more of the following: Hypertriglyceridemia (≥ 1.7 mmol/l); HDL cholesterol level <1.0 mmol/l in men or <1.3 mmol/l in women; elevated blood pressure (systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg) or antihypertensive drug treatment or history of hypertension; elevated fasting plasma glucose ≥ 5.6 mmol/l; or drug treatment and central obesity. Results: Of the 2,056 participants (46% men; mean age= 47.2 years, SD=11.2) included in the current analysis, 975 (47.4%) had normal weight and 696 (33.8%) were overweight. Prevalence of MO in the overall sample was 20.6% (n=424), 3.7% (n=36) among those with normal BMI and 9.9% (n=204) among overweight individuals. From the 36 subjects with MONW, 33 (91.6%) had central obesity by WC, while 201/204 (98.5%) with metabolically obese overweight, had central obesity by WC. Remarkably, in a subgroup of people with no metabolic obesity factors nobody had central obesity, see Figure . Conclusions: Metabolic dysregulation in people labeled as MONW can be explained by excessive visceral adiposity and not by an inherent predisposition, independent of adiposity.These findings underscore the importance of identifying central obesity in clinical practice even if BMI is below the obese criteria.

Introduction: Exercise parameters such as peak heart rate (HR) are generally adjusted for age, whereas HR recovery is generally given as an absolute value: < 13 bpm at 1 minute post-peak exercise being abnormal. Hypothesis: We analyzed a large cohort of patients to determine the impact of age on HR recovery (HRRec) and if the prognostic performance of HRRec is improved by adjustment for age. Methods: Non-imaging exercise tests performed on patients aged 30-79 years from 1993 to 2010 were included. Patients with known cardiovascular diseases were excluded. Patients were assigned to 5 groups according to age: 30-39, 40-49, 50-59, 60-69, and 70-79. Mortality was reported according to HRRec during the first minute of active recovery using Cox regression analysis. Mortality was determined from Minnesota and National Death Indices. Results: 22,643 patients (64 % male) were included. The median HRRec in the age groups with IQR were as follows: 30-39: 20 [15-26]; 40-49: 19 [14-25]; 50-59: 18 [13-23]; 60-69: 15 [10-20]; and 70-79: 11 [6-16]. There were 1566 deaths (6.9%) over a mean follow-up of 11.8 ± 5.0 years. HRRec of 13 would fall at the 17 th percentile for patients 30-39 years old, but this increased to the 20 th , 27 th , 40 th , and 60 th percentiles with increasing age group. The mortality in age groups according to HRRec is shown in the Figure. For age groups 30-39 and 40-49, the hazard ratio for mortality at a HRRec of 11-12 bpm (i.e. just below the standard of 13) versus patients with a HRRec of ≥ 20 bpm was > 2.0. For age 50-59 and 60-69, however, a HRRec of < 11 bpm is necessary to obtain a doubling of risk, and for age 70-79 a HRRec of < 9 bpm is necessary. Conclusions: HRRec decreases significantly with age. The performance of abnormal HRRec defined as < 13 bpm is inconsistent across age groups. To standardize the ability of HRRec to identify at least a 2.0-fold increased risk, lowering the cup-point to < 11 bpm for ages 50-59 and 60-69 and < 9 bpm for age 70-79 is required.