What does this research mean for the field?

PKP2 mutation carriers exhibit impaired fat oxidation during exercise and have a lower VO2max compared to healthy controls. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to investigate the impact of exercise on oxidative metabolism and right ventricular function in ACM mutation carriers compared to healthy controls.

February 8, 2026

Metabolic and contractile dysfunction in arrhythmogenic cardiomyopathy: an echocardiography and CPET study

Key Result

PKP2 mutation carriers showed 44% lower fat oxidation (0.18 vs 0.32 g/min, p=0.002) and higher carbohydrate oxidation during low-intensity exercise, with 35% experiencing VAs linked to abnormal RV str

Key Points

This research aims to investigate the impact of exercise on oxidative metabolism and right ventricular function in ACM mutation carriers compared to healthy controls.
Cross-sectional study design
Involvement of 20 ACM mutation carriers and 10 matched healthy controls
Assessment through cardiopulmonary exercise test and echocardiography
Measurement of oxidative metabolism and right ventricular strain during exercise
Lower maximal oxygen uptake (VO2max) in PKP2 group compared to controls (29.1 vs 40.0 ml/kg/min)
Reduced heart rate at peak intensity in PKP2 group (159 vs 175 bpm)
Impaired fat oxidation at low-intensity exercise in PKP2 group (0.18 vs 0.32 g/min)
Increased carbohydrate oxidation in PKP2 group at the same exercise level (0.80 vs 0.30 g/min)
35% of PKP2 carriers experienced non-sustained ventricular arrhythmias during exercise

Structured PICO

Does a standardized exercise workload elicit different oxidative metabolism and right ventricular contraction patterns in ACM-associated mutation carriers compared to healthy controls?

Population

30 participants, including 20 ACM-associated pathogenic variant carriers (all Plakophilin-2 variant, PKP2; 10 with definite ACM diagnosis, 10 without ACM phenotype) and 10 healthy controls, matched for age (mean 35 vs 30) and sex (60% male).

Intervention

Cardiopulmonary exercise test (CPET) on a bicycle ergometer with incremental workload until volitional exhaustion, with simultaneous echocardiography and indirect calorimetry.

Comparator

Healthy controls matched for age and sex undergoing the same CPET and echocardiography protocol.

Outcome

Oxidative metabolism (fat and carbohydrate oxidation) measured using indirect calorimetry and right ventricular (RV) contraction patterns measured by speckle tracking echocardiography during CPET.surrogate

ACM-associated mutation carriers exhibit impaired fat oxidation and abnormal RV strain during aerobic exercise, suggesting metabolic dysfunction and unmasking of latent arrhythmic substrates.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy (CMP) associated with a risk of ventricular arrhythmias (VAs). The majority of VAs occur during exercise, and exercise increases penetrance among ACM-associated mutation carriers(1). However, evidence explaining the interaction between exercise and ACM is lacking. Simultaneously, while metabolic dysfunction has been demonstrated in other CMPs, there is no data for ACM(2,3). Purpose To determine if a standardized exercise workload elicits a different response between ACM-associated mutation carriers and healthy controls in: - oxidative metabolism measured using indirect calorimetry during cardiopulmonary exercise test (CPET); - right ventricular (RV) contraction patterns measured by speckle tracking echocardiography. Methods This is a cross-sectional single-center study involving 20 ACM-associated pathogenic variant carriers (all Plakophilin-2 variant, PKP2) and 10 healthy controls, matched for age (35±11 vs 30±3 years, respectively, p=0.20) and sex (60% males in each group). The PKP2 group included 10 patients with a definite ACM diagnosis as per 2010 Task Force Criteria and 10 patients without ACM phenotype. All participants underwent a CPET on a bicycle ergometer with incremental workload until volitional exhaustion. Fat and carbohydrate (CHO) oxidation were calculated using indirect calorimetry(4). Simultaneous echocardiography was performed. Data for both methods were collected at rest, low-intensity exercise (defined as reaching of heart rate of 100 bpm), moderate-intensity exercise (defined as reaching of the ventilatory anaerobic threshold, VAT) and peak-intensity exercise. Data regarding VAs during CPET were collected. Results Maximal oxygen uptake (VO2max) was significantly lower in the PKP2 group than in controls (29.1 ± 6.5 vs 40.0 ± 7.4 ml/kg/min, p=0.003), as well as heart rate at peak intensity (159±16 vs 175±9 bpm, p=0.009) despite no significant difference in peak respiratory exchange ratio (1.16±0.08 vs 1.16±0.06, p=0.98). PKP2 mutation carriers and controls did not show a difference in fat oxidation and CHO oxidation at rest, while at low intensity exercise (i.e. before VAT) fat oxidation was significantly lower (0.18±0.10 vs 0.32±0.14 g/min, p=0.002) and CHO oxidation higher (0.80±0.34 vs 0.30±0.26 g/min, p0.001) in the PKP2 group than in controls, even when correcting for VO2max and body mass index (BMI). Additionally, 7 PKP mutation carriers (35%) developed non-sustained VAs or premature ventricular contractions during exercise. These patients showed more abnormal free wall RV strain values than controls throughout all exercise stages (Figure 1). Conclusions Fat oxidation was impaired in ACM-associated mutation carriers during aerobic exercise, independently of VO2max and BMI. RV strain analysis may unmask a latent arrhythmic substrate at rest and during exercise in ACM-associated mutation carriers.

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