Diagnostic yield and financial implications of a nationwide electrocardiographic screening programme to detect cardiac disease in the young.

AIMS: There is limited information on the role of screening with electrocardiography (ECG) for identifying cardiovascular diseases associated with sudden cardiac death (SCD) in a non-select group of adolescents and young adults in the general population. METHODS AND RESULTS: Between 2012 and 2014, 26 900 young individuals (aged 14-35 years) were prospectively evaluated with a health questionnaire and ECG. Individuals with abnormal results underwent secondary investigations, the costs of which were being based on the UK National Health Service tariffs. Six hundred and seventy-five (2.5%) individuals required further investigation for an abnormal health questionnaire, 2175 (8.1%) for an abnormal ECG, and 114 (0.5%) for both. Diseases associated with young SCD were identified in 88 (0.3%) individuals of which 15 (17%) were detected with the health questionnaire, 72 (81%) with ECG and 2 (2%) with both. Forty-nine (56%) of these individuals received medical intervention beyond lifestyle modification advice in the follow-up period of 24 months. The overall cost of the evaluation process was €97 per person screened, €17 834 per cardiovascular disease detected, and €29 588 per cardiovascular disease associated with SCD detected. Inclusion of ECG was associated with a 36% cost reduction per diagnosis of diseases associated with SCD compared with the health questionnaire alone. CONCLUSION: The inclusion of an ECG to a health questionnaire is associated with a five-fold increase in the ability to detect disease associated with SCD in young individuals and is more cost effective for detecting serious disease compared with screening with a health questionnaire alone.

Prevalence of abnormal findings in 230 knees of asymptomatic adults using 3.0 T MRI.

OBJECTIVE: To identify abnormalities in asymptomatic sedentary individuals using 3.0 Tesla high-resolution MRI. MATERIALS AND METHODS: The cohort comprised of 230 knees of 115 uninjured sedentary adults (51 males, 64 females; median age: 44 years). All participants had bilateral knee 3.0 T MRIs. Two senior musculoskeletal radiologists graded all intraarticular knee structures using validated scoring systems. Participants completed Knee Injury and Osteoarthritis Outcome Score questionnaires at the time of the MRI scan. RESULTS: MRI showed abnormalities in the majority (97%) of knees. Thirty percent knees had meniscal tears: horizontal (23%), complex (3%), vertical (2%), radial (2%) and bucket handle (1%). Cartilage and bone marrow abnormalities were prevalent at the patellofemoral joint (57% knees and 48% knees, respectively). Moderate and severe cartilage lesions were common, in 19% and 31% knees, respectively, while moderate and severe bone marrow oedema in 19% and 31% knees, respectively. Moderate-intensity lesion in tendons was found in 21% knees and high-grade tendonitis in 6% knees-the patellar (11% and 2%, respectively) and quadriceps (7% and 2%, respectively) tendons being most affected. Three percent partial ligamentous ruptures were found, especially of the anterior cruciate ligament (2%). CONCLUSION: Nearly all knees of asymptomatic adults showed abnormalities in at least one knee structure on MRI. Meniscal tears, cartilage and bone marrow lesions of the patellofemoral joint were the most common pathological findings. Bucket handle and complex meniscal tears were reported for the first time in asymptomatic knees.

Is the immediate effect of marathon running on novice runners' knee joints sustained within 6 months after the run? A follow-up 3.0 T MRI study.

OBJECTIVE: To evaluate changes in the knee joints of asymptomatic first-time marathon runners, using 3.0 T MRI, 6 months after finishing marathon training and run. MATERIALS AND METHODS: Six months after their participation in a baseline study regarding their knee joints, 44 asymptomatic novice marathoners (17 males, 27 females, mean age 46 years old) agreed to participate in a repeat MRI investigation: 37 completed both a standardized 4-month-long training programme and the marathon (marathon runners); and 7 dropped out during training (pre-race dropouts). The participants already underwent bilateral 3.0 T MRIs: 6 months before and 2 weeks after their first marathon, the London Marathon 2017. This study was a follow-up assessment of their knee joints. Each knee structure was assessed using validated scoring/grading systems at all time points. RESULTS: Two weeks after the marathon, 3 pre-marathon bone marrow lesions and 2 cartilage lesions showed decrease in radiological score on MRI, and the improvement was sustained at the 6-month follow-up. New improvements were observed on MRI at follow-up: 5 pre-existing bone marrow lesions and 3 cartilage lesions that remained unchanged immediately after the marathon reduced in their extent 6 months later. No further lesions appeared at follow-up, and the 2-week post-marathon lesions showed signs of reversibility: 10 of 18 bone marrow oedema-like signals and 3 of 21 cartilage lesions decreased on MRI. CONCLUSION: The knees of novice runners achieved sustained improvement, for at least 6 months post-marathon, in the condition of their bone marrow and articular cartilage.

Accuracy of the 2017 international recommendations for clinicians who interpret adolescent athletes' ECGs: a cohort study of 11 168 British white and black soccer players.

AIM: To investigate the accuracy of the recently published international recommendations for ECG interpretation in young athletes in a large cohort of white and black adolescent soccer players. METHODS: 11 168 soccer players (mean age 16.4±1.2 years) were evaluated with a health questionnaire, ECG and echocardiogram; 10 581 (95%) of the players were male and 10 163 (91%) were white. ECGs were retrospectively analysed according to (1) the 2010 European Society of Cardiology (ESC) recommendations, (2) Seattle criteria, (3) refined criteria and (4) the international recommendations for ECG interpretation in young athletes. RESULTS: The ESC recommendations resulted in a higher number of abnormal ECGs compared with the Seattle, refined and international criteria (13.2%, 4.3%, 2.9% and 1.8%, respectively). All four criteria were associated with a higher prevalence of abnormal ECGs in black athletes compared with white athletes (ESC: 16.2% vs 12.9%; Seattle: 5.9% vs 4.2%; refined: 3.8% vs 2.8%; international 3.6% vs 1.6%; p<0.001 each). Compared with ESC recommendations, the Seattle, refined and international criteria identified a lower number of abnormal ECGs-by 67%, 78% and 86%, respectively. All four criteria identified 36 (86%) of 42 athletes with serious cardiac pathology. Compared with ESC recommendations, the Seattle criteria improved specificity from 87% to 96% in white athletes and 84% to 94% in black athletes. The international recommendations demonstrated the highest specificity for white (99%) and black (97%) athletes and a sensitivity of 86%. CONCLUSIONS: The 2017 international recommendations for ECG interpretation in young athletes can be applied to adolescent athletes to detect serious cardiac disease. These recommendations perform more effectively than previous ECG criteria in both white and black adolescent soccer players.

Exercise, the athlete's heart, and sudden cardiac death.

Physical activity is a potent therapy for both the prevention and treatment of cardiovascular disease. Exercise appears to most benefit people who are the least active. There is some evidence to suggest that a curvilinear relationship exists between exercise and survival, whereby beyond an optimal level of fitness, the principle of diminishing returns applies. Indeed, some go further in suggesting that there is evidence that extreme athletic training may be harmful in some individuals. The incidence of sudden cardiac death in athletes is greater than in matched, nonathletic counterparts, and this finding is driven by the provocation of an underlying cardiac abnormality by strenuous exertion. The task of detecting pathological myocardial substrate in athletes is made difficult by physiological adaptations to exercise that can mimic the appearance of cardiomyopathies and ion channelopathies in some individuals. This article details the clinical evaluation of the athlete with reference limits for cardiac physiological remodeling and discusses the diagnostic dilemmas that arise.

Evaluating initiation and real-world tolerability of dapagliflozin for the management of HFrEF.

Untreated heart failure with reduced ejection fraction (HFrEF) has a one-year mortality rate of 40%. The DAPA-HF trial found that dapagliflozin reduces mortality and heart failure (HF) hospitalisation by 17% and 30%, respectively. We describe the initiation and real-world tolerability of dapagliflozin for the management of HFrEF at a large university teaching hospital in central London. We reviewed 118 HFrEF patients initiated on dapagliflozin from January to August 2021 in both inpatient and outpatient settings using the Trust's electronic records. A total of 69 (58.4%) patients were on optimised HF pharmacological therapy upon initiation of dapagliflozin. Dapagliflozin was discontinued in 12 (13.0%) patients. Twenty-three (42.6%) patients either discontinued or had a dose reduction in loop diuretics post-initiation of dapagliflozin. In clinical practice, early initiation of dapagliflozin is safe, well-tolerated and resulted in earlier discontinuation or dose reduction in loop diuretics, providing opportunities to further optimise other HF medicines. This retrospective observational study supports the safety of the updated European Society of Cardiology (ESC) guidelines to initiate all four key HF medicines to minimise delays in HF treatment optimisation, which could translate to reduced National Health Service healthcare costs through fewer HF hospitalisations.

Energy drink-induced cardiomyopathy.

We report a case of severe biventricular heart failure potentially related to excessive energy drink consumption in a 21-year-old man. The patient presented with a 4-month history of shortness of breath on exertion, orthopnoea and weight loss. Transthoracic echocardiography demonstrated severely impaired biventricular systolic function and bilateral ventricular thrombi, subsequently confirmed on cardiac magnetic resonance imaging, which found in addition no oedema, inflammation or focal fibrosis. Blood tests, renal ultrasound and subsequent abdominal MRI demonstrated severe renal failure caused by a chronic obstructive uropathy, long-standing and previously undiagnosed. There was no significant past medical, family or social history other than excessive intake of an energy drink. This case report adds to the growing concern in the literature about the potential cardiotoxic effects of energy drinks, which should be considered when assessing young patients presenting with a non-ischaemic dilated cardiomyopathy.

Lack of morphometric evidence for ventricular compaction in humans.

The remodeling of the compact wall by incorporation of trabecular myocardium, referred to as compaction, receives much attention because it is thought that its failure causes left ventricular non-compaction cardiomyopathy (LVNC). Although the notion of compaction is broadly accepted, the nature and strength of the evidence supporting this process is underexposed. Here, we review the literature that quantitatively investigated the development of the ventricular wall to understand the extent of compaction in humans, mice, and chickens. We queried PubMed using several search terms, screened 1127 records, and selected 56 publications containing quantitative data on ventricular growth. For humans, only 34 studies quantified wall development. The key premise of compaction, namely a reduction of the trabecular layer, was never documented. Instead, the trabecular layer grows slower than the compact wall in later development and this changes wall architecture. There were no reports of a sudden enlargement of the compact layer (from incorporated trabeculae), be it in thickness, area, or volume. Therefore, no evidence for compaction was found. Only in chickens, a sudden increase in compact myocardial thickness layer was reported coinciding with a decrease in trabecular thickness. In mice, morphometric and lineage tracing investigations have yielded conflicting results that allow for limited compaction to occur. In conclusion, compaction in human development is not supported while rapid intrinsic growth of the compact wall is supported in all species. If compaction takes place, it likely plays a much smaller role in determining wall architecture than intrinsic growth of the compact wall.

Age matters: differences in exercise-induced cardiovascular remodelling in young and middle aged healthy sedentary individuals.

AIMS: Remodelling of the cardiovascular system (including heart and vasculature) is a dynamic process influenced by multiple physiological and pathological factors. We sought to understand whether remodelling in response to a stimulus, exercise training, altered with healthy ageing. METHODS: A total of 237 untrained healthy male and female subjects volunteering for their first time marathon were recruited. At baseline and after 6 months of unsupervised training, race completers underwent tests including 1.5T cardiac magnetic resonance, brachial and non-invasive central blood pressure assessment. For analysis, runners were divided by age into under or over 35 years (U35, O35). RESULTS: Injury and completion rates were similar among the groups; 138 runners (U35: n = 71, women 49%; O35: n = 67, women 51%) completed the race. On average, U35 were faster by 37 minutes (12%). Training induced a small increase in left ventricular mass in both groups (3 g/m2, P < 0.001), but U35 also increased ventricular cavity sizes (left ventricular end-diastolic volume (EDV)i +3%; left ventricular end-systolic volume (ESV)i +8%; right ventricular end-diastolic volume (EDV)i +4%; right ventricular end-systolic volume (ESV)i +5%; P < 0.01 for all). Systemic aortic compliance fell in the whole sample by 7% (P = 0.020) and, especially in O35, also systemic vascular resistance (-4% in the whole sample, P = 0.04) and blood pressure (systolic/diastolic, whole sample: brachial -4/-3 mmHg, central -4/-2 mmHg, all P < 0.001; O35: brachial -6/-3 mmHg, central -6/-4 mmHg, all P < 0.001). CONCLUSION: Medium-term, unsupervised physical training in healthy sedentary individuals induces measurable remodelling of both heart and vasculature. This amount is age dependent, with predominant cardiac remodelling when younger and predominantly vascular remodelling when older.

Training for a First-Time Marathon Reverses Age-Related Aortic Stiffening.

BACKGROUND: Aging increases aortic stiffness, contributing to cardiovascular risk even in healthy individuals. Aortic stiffness is reduced through supervised training programs, but these are not easily generalizable. OBJECTIVES: The purpose of this study was to determine whether real-world exercise training for a first-time marathon can reverse age-related aortic stiffening. METHODS: Untrained healthy individuals underwent 6 months of training for the London Marathon. Assessment pre-training and 2 weeks post-marathon included central (aortic) blood pressure and aortic stiffness using cardiovascular magnetic resonance distensibility. Biological "aortic age" was calculated from the baseline chronological age-stiffness relationship. Change in stiffness was assessed at the ascending (Ao-A) and descending aorta at the pulmonary artery bifurcation (Ao-P) and diaphragm (Ao-D). Data are mean changes (95% confidence intervals [CIs]). RESULTS: A total of 138 first-time marathon completers (age 21 to 69 years, 49% male) were assessed, with an estimated training schedule of 6 to 13 miles/week. At baseline, a decade of chronological aging correlated with a decrease in Ao-A, Ao-P, and Ao-D distensibility by 2.3, 1.9, and 3.1 × 10-3 mm Hg-1, respectively (p < 0.05 for all). Training decreased systolic and diastolic central (aortic) blood pressure by 4 mm Hg (95% CI: 2.8 to 5.5 mm Hg) and 3 mm Hg (95% CI: 1.6 to 3.5 mm Hg). Descending aortic distensibility increased (Ao-P: 9%; p = 0.009; Ao-D: 16%; p = 0.002), while remaining unchanged in the Ao-A. These translated to a reduction in "aortic age" by 3.9 years (95% CI: 1.1 to 7.6 years) and 4.0 years (95% CI: 1.7 to 8.0 years) (Ao-P and Ao-D, respectively). Benefit was greater in older, male participants with slower running times (p < 0.05 for all). CONCLUSIONS: Training for and completing a marathon even at relatively low exercise intensity reduces central blood pressure and aortic stiffness-equivalent to a ∼4-year reduction in vascular age. Greater rejuvenation was observed in older, slower individuals.

Recreational marathon running does not cause exercise-induced left ventricular hypertrabeculation.

BACKGROUND: Marathon running in novices represents a natural experiment of short-term cardiovascular remodeling in response to running training. We examine whether this stimulus can produce exercise-induced left ventricular (LV) trabeculation. METHODS: Sixty-eight novice marathon runners aged 29.5 ± 3.2 years had indices of LV trabeculation measured by echocardiography and cardiac magnetic resonance imaging 6 months before and 2 weeks after the 2016 London Marathon race, in a prospective longitudinal study. RESULTS: After 17 weeks unsupervised marathon training, indices of LV trabeculation were essentially unchanged. Despite satisfactory inter-observer agreement in most methods of trabeculation measurement, criteria defining abnormally hypertrabeculated cases were discordant with each other. LV hypertrabeculation was a frequent finding in young, healthy individuals with no subject demonstrating clear evidence of a cardiomyopathy. CONCLUSION: Training for a first marathon does not induce LV trabeculation. It remains unclear whether prolonged, high-dose exercise can create de novo trabeculation or expose concealed trabeculation. Applying cut off values from published LV noncompaction cardiomyopathy criteria to young, healthy individuals risks over-diagnosis.

Differentiation between athlete's heart and dilated cardiomyopathy in athletic individuals.

OBJECTIVE: Distinguishing early dilated cardiomyopathy (DCM) from physiological left ventricular (LV) dilatation with LV ejection fraction <55% in athletes (grey zone) is challenging. We evaluated the role of a cascade of investigations to differentiate these two entities. METHODS: Thirty-five asymptomatic active males with DCM, 25 male athletes in the 'grey zone' and 24 male athletes with normal LV ejection fraction underwent N-terminal pro-brain natriuretic peptide (NT-proBNP) measurement, ECG and exercise echocardiography. Grey-zone athletes and patients with DCM underwent cardiovascular magnetic resonance (CMR) and Holter monitoring. RESULTS: Larger LV cavity dimensions and lower LV ejection fraction were the only differences between grey-zone and control athletes. None of the grey-zone athletes had abnormal NT-proBNP, increased ectopic burden/complex arrhythmias or pathological late gadolinium enhancement on CMR. These features were also absent in 71%, 71% and 50% of patients with DCM, respectively. 95% of grey-zone athletes and 60% of patients with DCM had normal ECG. During exercise echocardiography, 96% grey-zone athletes increased LV ejection fraction by >11% from baseline to peak exercise compared with 23% of patients with DCM (p<0.0001). Peak LV ejection fraction was >63% in 92% grey-zone athletes compared with 17% patients with DCM (p<0.0001). Failure to increase LV ejection fraction >11% from baseline to peak exercise or achieve a peak LV ejection fraction >63% had sensitivity of 77% and 83%, respectively, and specificity of 96% and 92%, respectively, for predicting DCM. CONCLUSION: Comprehensive assessment using a cascade of routine investigations revealed that exercise stress echocardiography has the greatest discriminatory value in differentiating between grey-zone athletes and asymptomatic patients with DCM. Our findings require validation in larger studies.

Cardiovascular Remodeling Experienced by Real-World, Unsupervised, Young Novice Marathon Runners.

AIMS: Marathon running is a popular ambition in modern societies inclusive of non-athletes. Previous studies have highlighted concerning transient myocardial dysfunction and biomarker release immediately after the race. Whether this method of increasing physical activity is beneficial or harmful remains a matter of debate. We examine in detail the real-world cardiovascular remodeling response following competition in a first marathon. METHODS: Sixty-eight novice marathon runners (36 men and 32 women) aged 30 ± 3 years were investigated 6 months before and 2 weeks after the 2016 London Marathon race in a prospective observational study. Evaluation included electrocardiography, cardiopulmonary exercise testing, echocardiography, and cardiovascular magnetic resonance imaging. RESULTS: After 17 weeks unsupervised marathon training, runners revealed a symmetrical, eccentric remodeling response with 3-5% increases in left and right ventricular cavity sizes, respectively. Blood pressure (BP) fell by 4/2 mmHg (P < 0.01) with reduction in arterial stiffness, despite only 11% demonstrating a clinically meaningful improvement in peak oxygen consumption with an overall non-significant 0.4 ml/min/kg increase in peak oxygen consumption (P = 0.14). CONCLUSION: In the absence of supervised training, exercise-induced cardiovascular remodeling in real-world novice marathon runners is more modest than previously described and occurs even without improvement in cardiorespiratory fitness. The responses are similar in men and women, who experience a beneficial BP reduction and no evidence of myocardial fibrosis or persistent edema, when achieving average finishing times.

Can marathon running improve knee damage of middle-aged adults? A prospective cohort study.

OBJECTIVES: To evaluate the short-term impact of long-distance running on knee joints using MRI. METHODS: 82 healthy adults participating in their first marathon underwent 3T (Tesla) MRI of both knees 6 months before and half a month after the marathon: 71 completed both the 4 month-long standardised training programme and the marathon; and 11 dropped-out during training and did not run the marathon. Two senior musculoskeletal radiologists graded the internal knee structures using validated scoring systems. Participants completed Knee Injury and Osteoarthritis Outcome Score questionnaires at each visit for self-reporting knee function. RESULTS: Premarathon and pretraining MRI showed signs of damage, without symptoms, to several knee structures in the majority of the 82 middle-aged volunteers. However, after the marathon, MRI showed a reduction in the radiological score of damage in: subchondral bone marrow oedema in the condyles of the tibia (p=0.011) and femur (p=0.082). MRI did also show an increase in radiological scores to the following structures: cartilage of the lateral patella (p=0.0005); semimembranosus tendon (p=0.016); iliotibial band (p<0.0001) and the prepatellar bursa (p=0.016). CONCLUSION: Improvement to damaged subchondral bone of the tibial and femoral condyles was found following the marathon in novice runners, as well as worsening of the patella cartilage although asymptomatic. This is the most robust evidence to link marathon running with knee joint health and provides important information for those seeking to understand the link between long distance running and osteoarthritis of the main weight-bearing areas of the knee.

Left Ventricular Trabeculations in Athletes: Epiphenomenon or Phenotype of Disease?

PURPOSE OF REVIEW: Excessive trabeculation attracting a diagnosis of left ventricular noncompaction cardiomyopathy (LVNC) has been reported in ostensibly healthy athletes. This review aims to explain why this occurs and whether this represents a spectrum of athletic physiological remodelling or unmasking of occult cardiomyopathy. RECENT FINDINGS: Genetic studies have yet to identify a dominant mutation associated with the LVNC phenotype and reported gene mutations overlap with many distinct cardiomyopathies and ion channel disorders, implying that the phenotype is shared across different genetic conditions. Large contemporary cohort studies indicate that current LVNC imaging criteria are oversensitive and not predictive of adverse clinical outcomes. The majority of excessive LV trabeculation, as assessed by current quantification methods, is not due to cardiomyopathy but forms part of the normal continuum in health with potential contributions from cardiac remodelling processes. The study of rare, severe LVNC phenotypes may yield insights into an underlying molecular pathogenesis but in the absence of a universally accepted definition, contamination with aetiologically distinct conditions expressing a similar phenotype will remain an issue. Automated, objective quantification of trabeculation will help to define the normal distribution using big data without the constraint of wide interobserver variation.

Role of Doppler Diastolic Parameters in Differentiating Physiological Left Ventricular Hypertrophy from Hypertrophic Cardiomyopathy.

BACKGROUND: The association between athletic participation and alteration in diastolic function is not well established. The aims of this study were to determine the spectrum of Doppler parameters of left ventricular (LV) diastolic function in a large cohort of healthy athletes and to quantify the overlap between physiologic LV hypertrophy and hypertrophic cardiomyopathy (HCM). METHODS: A retrospective analysis of indices of LV diastolic function was performed in 1,510 healthy athletes (mean age, 22 ± 5 years; range, 13-33 years; 72% men). The results were compared with those from 58 young patients with HCM. RESULTS: Septal E' < 7 cm/sec and lateral E' < 10 cm/sec were found in five (0.3%) and eight (0.5%) athletes, respectively. Septal E' was >14.6 cm/sec in 170 (11%) and lateral E' was >19.9 cm/sec in 430 (28%) athletes. Athletes aged >25 years showed lower E' velocities compared with younger athletes (mean septal E', 11.8 ± 6.1 vs 12.9 ± 5.9 cm/sec [P < .001]; mean lateral E', 17.1 ± 3.6 vs 19.3 ± 4.1 cm/sec [P < .001]). Athletes with high indexed LV end-diastolic diameters (>32 mm/m2) exhibited lower septal E' compared with athletes with normal indexed LV end-diastolic diameters (mean septal E', 11.9 ± 6 vs 12.7 ± 6 cm/sec; P = .002). Septal E' < 10 cm/sec and lateral E' < 12 cm/sec showed the best accuracy in differentiating between HCM and athlete's heart. CONCLUSIONS: Reduced septal and lateral E' are rarely observed in young elite athletes. Tissue Doppler velocities tend to decrease with increasing age and LV size, and values representative of supernormal diastolic function are found in less than one-third of young athletes. Cutoff thresholds for Doppler parameters of diastolic function should be corrected for multiple demographic and clinical variables to differentiate cardiac adaptation to exercise from HCM in young individuals.

The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy.

BACKGROUND: Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome; SADS) may identify relatives at risk of fatal arrhythmias. OBJECTIVES: This study aimed to assess the impact of systematic ajmaline provocation testing using high right precordial leads (RPLs) on the diagnostic yield of Brugada syndrome (BrS) in a large cohort of SADS families. METHODS: Three hundred three SADS families (911 relatives) underwent evaluation with resting electrocardiogram using conventional and high RPLs, echocardiography, exercise, and 24-h electrocardiogram monitor. An ajmaline test with conventional and high RPLs was undertaken in 670 (74%) relatives without a familial diagnosis after initial evaluation. Further investigations were guided by clinical suspicion. RESULTS: An inherited cardiac disease was diagnosed in 128 (42%) families and 201 (22%) relatives. BrS was the most prevalent diagnosis (n = 85, 28% of families; n = 140, 15% of relatives). Ajmaline testing was required to unmask the BrS in 97% of diagnosed individuals. The use of high RPLs showed a 16% incremental diagnostic yield of ajmaline testing by diagnosing BrS in an additional 49 families. There were no differences of the characteristics between individuals and families with a diagnostic pattern in the conventional and the high RPLs. On follow-up, a spontaneous type 1 Brugada pattern and/or clinically significant arrhythmic events developed in 17% (n = 25) of the concealed BrS cohort. CONCLUSIONS: Systematic use of ajmaline testing with high RPLs increases substantially the yield of BrS in SADS families. Assessment should be performed in expert centers where patients are counseled appropriately for the potential implications of provocation testing.