Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia: a landmark study.

AIMS: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. METHODS AND RESULTS: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. CONCLUSION: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.

ECG-only explainable deep learning algorithm predicts the risk for malignant ventricular arrhythmia in phospholamban cardiomyopathy.

BACKGROUND: Phospholamban (PLN) p.(Arg14del) variant carriers are at risk for development of malignant ventricular arrhythmia (MVA). Accurate risk stratification allows timely implantation of intracardiac defibrillators and is currently performed with a multimodality prediction model. OBJECTIVE: This study aimed to investigate whether an explainable deep learning-based approach allows risk prediction with only electrocardiogram (ECG) data. METHODS: A total of 679 PLN p.(Arg14del) carriers without MVA at baseline were identified. A deep learning-based variational auto-encoder, trained on 1.1 million ECGs, was used to convert the 12-lead baseline ECG into its FactorECG, a compressed version of the ECG that summarizes it into 32 explainable factors. Prediction models were developed by Cox regression. RESULTS: The deep learning-based ECG-only approach was able to predict MVA with a C statistic of 0.79 (95% CI, 0.76-0.83), comparable to the current prediction model (C statistic, 0.83 [95% CI, 0.79-0.88]; P = .054) and outperforming a model based on conventional ECG parameters (low-voltage ECG and negative T waves; C statistic, 0.65 [95% CI, 0.58-0.73]; P < .001). Clinical simulations showed that a 2-step approach, with ECG-only screening followed by a full workup, resulted in 60% less additional diagnostics while outperforming the multimodal prediction model in all patients. A visualization tool was created to provide interactive visualizations (https://pln.ecgx.ai). CONCLUSION: Our deep learning-based algorithm based on ECG data only accurately predicts the occurrence of MVA in PLN p.(Arg14del) carriers, enabling more efficient stratification of patients who need additional diagnostic testing and follow-up.

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction.

AIMS: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model. METHODS AND RESULTS: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75). CONCLUSION: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.

New risk factors for atrial fibrillation: causes of 'not-so-lone atrial fibrillation'.

Atrial fibrillation (AF) is a prevalent arrhythmia in patients with cardiovascular disease. The classical risk factors for developing AF include hypertension, valvular disease, (ischaemic) cardiomyopathy, diabetes mellitus, and thyroid disease. In some patients with AF, no underlying (cardiovascular) pathology is present and the aetiology remains unknown. This condition is known as lone AF. However, in recent years, other factors playing a role in the genesis of AF have gained attention, including obesity, sleep apnoea, alcohol abuse and other intoxications, excessive sports practice, latent hypertension, genetic factors, and inflammation. In this review, we address these 'new risk factors' (i.e. as opposed to the classical risk factors) and the mechanisms by which they lead to AF.

Long-term outcome of the atrioventricular node ablation and pacemaker implantation for symptomatic refractory atrial fibrillation.

AIMS: To investigate long-term outcome and to determine predictors of development of heart failure (HF) in patients with atrioventricular (AV) node ablation and permanent right ventricular pacing because of symptomatic refractory atrial fibrillation (AF). BACKGROUND: Atrioventricular node ablation and subsequent permanent pacing is a well-established therapy for patients with AF. Long-term right ventricular pacing may induce HF. METHODS AND RESULTS: In 121 (45 with previous HF) patients with drug refractory AF, AV node ablation and implantation of a pacemaker was performed. At baseline and after a mean follow-up of 4.3 +/- 3.3 years, New York Heart Association (NYHA) functional class for HF and left ventricular (LV) and atrial diameters were assessed. During and at the end of follow-up, hospitalizations for HF, mortality, and quality of life were assessed using the SF-36 and an AVN-specific questionnaire. No significant changes in NYHA functional class (87 vs. 77% in NYHA I/II at baseline vs. end of follow-up) and LV end diastolic diameter (51 +/- 7 vs. 52 +/- 8 mm) were observed. Left ventricular end systolic diameter decreased (from 37 +/- 9 to 34 +/- 7 mm, P = 0.03) and fractional shortening improved (from 28 +/- 10 to 34 +/- 9, P = 0.02) in all patients and in patients with previous HF, but not in patients without previous HF. Hospitalizations for HF occurred in 24 patients (20%), predominantly those with previous HF. All-cause mortality occurred in 31 (26%) patients. At the end of follow-up, quality of life was comparable with the control group. CONCLUSION: Long-term outcome of AV node ablation and permanent pacing is good. Atrioventricular node ablation remains a treatment option for AF.

Electrical and structural remodeling: role in the genesis and maintenance of atrial fibrillation.

Atrial fibrillation (AF) and congestive heart failure (CHF) are 2 frequently encountered conditions in clinical practice. Both lead to changes in atrial function and structure, an array of processes known as atrial remodeling. This review provides an overview of ionic, electrical, contractile, neurohumoral, and structural atrial changes responsible for initiation and maintenance of AF. In the last decade, many studies have evaluated atrial remodeling due to AF or CHF. Both conditions often coexist, which makes it difficult to distinguish the contribution of each. Because of atrial stretch in the setting of hypertension or CHF, atrial remodeling frequently occurs long before AF arises. Alternatively, AF may lead to electrical remodeling, that is, shortening of refractoriness due to the high atrial rate itself. In many experimental AF or rapid atrial pacing studies, the ventricular rate was uncontrolled. In those studies, atrial stretch due to CHF may have interfered with the high atrial rate to produce a mixed type of electrical and structural remodeling. Other studies have dissected the individual role of AF or atrial tachycardia from the role CHF plays in atrial remodeling. Atrial fibrillation itself does not lead to structural remodeling, whereas this is frequently produced by hypertension or CHF, even in the absence of AF. Primary and secondary prevention programs should tailor treatment to the various types of remodeling.

Atrial ultrastructural changes during experimental atrial tachycardia depend on high ventricular rate.

INTRODUCTION: Atrial structural and electrophysiologic changes occur during atrial tachycardia. The role of high ventricular rate in these processes remains to be established. METHODS AND RESULTS: Six goats were subjected to 4 weeks of rapid atrioventricular (AV) pacing at an atrial and ventricular rate of 240 beats/min, resulting in development of congestive heart failure. In another five goats, AV block was created. These goats then were subjected to 4 weeks of atrial pacing, also at 240 beats/min while the ventricular rate was kept low and regular at 80 beats/min (A-paced). Pacing was interrupted only for measurement of atrial effective refractory period and right atrial diameter. The ultrastructure of both atria was examined by light and electron microscopy, including quantification of the percentage of atrial extracellular matrix (%ECM). A group of six goats served as controls. In the AV-paced group, severe structural remodeling occurred in the atria, including severe loss of sarcomeres, glycogen accumulation, disruption of sarcoplasmic reticulum, and appearance of numerous small mitochondria and nuclei with homogeneously distributed chromatin. In contrast, structural changes were virtually absent in the atria of A-paced goats. Only a redistribution of nuclear chromatin and the appearance of numerous mitochondria were observed. The ultrastructure was normal in control animals. The%ECM was increased in AV-paced goats (29%) compared to A-paced animals (18%) and controls (17%) (P < 0.05). Finally, right atrial diameter increased by 51% in AV-paced goats but was unchanged in A-paced goats (P < 0.05). In both experimental groups, atrial effective refractory period shortened during pacing. CONCLUSION: Structural remodeling during chronic atrial tachycardia is related to the concomitant presence of a high ventricular rate and hence the occurrence of congestive heart failure rather than a high atrial rate. Electrical remodeling can occur in the absence of significant structural changes.

Atrial natriuretic peptides during experimental atrial tachycardia: role of developing tachycardiomyopathy.

INTRODUCTION: Atrial tachycardia and chronic heart failure (CHF) are associated with elevated levels of atrial natriuretic peptide (ANP) and its amino terminal part NT-ANP. Chronic high atrial rates may cause CHF due to a rapid ventricular response. The aim of this study was to establish the contribution of elevated atrial rate and of high ventricular rate, resulting in CHF, on ANP and NT-ANP levels during chronic atrial tachycardia. METHODS AND RESULTS: Thirteen goats (AV-paced group) were subjected to 4 weeks of rapid AV pacing with an atrial and ventricular rate of 240 beats/min. Another five goats (A-paced group) were subjected to 4 weeks of atrial pacing at 240 beats/min while the ventricular rate was kept low and regular at 80 beats/min. Pacing was interrupted only for measurement of right atrial (RA) and left ventricular (LV) diameter and sampling for ANP, NT-ANP, and renin. In the AV-paced group, RA and LV diameter reached 152% and 109% of baseline values, respectively. Both ANP and NT-ANP (8.3 +/- 9.2 pmol/L and 0.5 +/- 0.4 nmol/L at baseline, respectively) increased progressively (53.1 +/- 37.9 pmol/L and 2.0 +/- 0.9 nmol/L, respectively, after 4 weeks). There was a significant correlation between the magnitude of atrial dilation and natriuretic peptide levels after 3 days. In A-paced goats, however, RA and LV diameters did not change. Furthermore, ANP and NT-ANP levels (9.1 +/- 6.0 pmol/L and 0.8 +/- 0.2 nmol/L at baseline, respectively) were unchanged after 4 weeks (5.3 +/- 3.4 pmol/L and 0.6 +/- 0.2 nmol/L, respectively). CONCLUSION: Elevated levels of ANPs during chronic atrial tachycardia are related to a high ventricular rate rather than a high atrial rate alone. Rather than atrial tachycardia, the atrial hemodynamic burden is an important determinant of the sustained ANP response.

Rapid pacing results in changes in atrial but not in ventricular refractoriness.

It is well known that atrial tachycardia causes atrial electrical remodeling, characterized by shortening of atrial effective refractory periods (AERPs) and loss of physiological adaptation of AERP to rate. However, the nature and time course of changes in ventricular effective refractory periods (VERP) caused by rapid rates are to be established. After being instrumented with epicardial electrodes on both atria and both ventricles nine goats were subjected to 1 week of rapid AV pacing with a rate of 240 beats/min and an AV delay of 100 ms. Pacing was only interrupted for measurement of left and right AERPs and VERPs at three basic cycle lengths (BCL) of 400 ms, 300 ms, and 200 ms during sinus rhythm in the conscious animal. Left and right AERPs decreased at all BCLs, reaching minimum values after 3 days (right AERP at BCL of 400 ms, 96 +/- 16 ms after 3 days vs 144 +/- 16 ms at baseline, P < 0.05). In contrast, both left and right VERPs did not change at any BCL. This study demonstrates a difference between the atria and ventricles with respect to tachycardia induced changes in refractoriness.