Allometric scaling for left ventricular mass and geometry in male and female athletes of mixed and endurance sports.

BACKGROUND: The athlete's heart (AH) defines the phenotypical changes that occur in response to chronic exercise training. Echocardiographic assessment of the AH is used to calculate LV mass (LVM) and determine chamber geometry. This is, however, interpreted using standard linear (ratiometric) scaling to body surface area (BSA) whereas allometric scaling is now widely recommended. This study (1) determined whether ratiometric scaling of LVM to BSA (LVMiratio) provides a size-independent index in young and veteran athletes of mixed and endurance sports (MES), and (2) calculated size-independent beta exponents for allometrically derived (LVMiallo) to BSA and (3) describes the physiological range of LVMiallo and the classifications of LV geometry. METHODS: 1373 MES athletes consisting of young (< 35 years old) (males n = 699 and females n = 127) and veteran (> 35 years old) (males n = 327 and females n = 220) were included in the study. LVMiratio was calculated as per standard scaling and sex-specific LVMiallo were derived from the population. Cut-offs were defined and geometry was classified according to the new exponents and relative wall thickness. RESULTS: LVMiratio did not produce a size independent index. When tested across the age range the following indexes LVMi/BSA0.7663 and LVMi/BSA0.52, for males and females respectively, were size independent (r = 0.012; P = 0.7 and r = 0.003; P = 0.920). Physiological cut-offs for LVMiallo were 135 g/(m2)0.7663 in male athletes and 121 g/(m2)0.52 in female athletes. Concentric remodelling / hypertrophy was present in 3% and 0% of young male and female athletes and 24% and 17% of veteran male and female athletes, respectively. Eccentric hypertrophy was observed in 8% and 6% of young male and female athletes and 9% and 11% of veteran male and female athletes, respectively. CONCLUSION: In a large cohort of young and veteran male and female MES athletes, LVMiratio to BSA is not size independent. Sex-specific LVMiallo to BSA with LVMi/BSA0.77 and LVMi/BSA0.52 for male and female athletes respectively can be applied across the age-range. Population-based cut-offs of LVMiallo provided a physiological range demonstrating a predominance for normal geometry in all athlete groups with a greater percentage of concentric remodelling/hypertrophy occurring in veteran male and female athletes.

Transthyretin (Pro24Ser) variant amyloidosis: A case report of the first patient in Greece.

OBJECTIVE: Transthyretin cardiac amyloidosis (ATTR-CA) is a rare and potentially fatal disease caused by the accumulation of insoluble transthyretin (TTR) amyloid fibrils in the heart. The symptoms of ATTR-CA are often non-specific, often leading to underdiagnosis. Early diagnosis and treatment have a significant impact on disease progression and mortality. CASE PRESENTATION: In this case we report a 73-year-old male presented with dyspnea on exertion. The patient had a medical history of peripheral neuropathy, bilateral carpal tunnel syndrome, spinal fusion, and a family history of coronary artery disease. Upon his presentation at the Cardiology department, cardiac echo study revealed left and right ventricular hypertrophy with pulmonary hypertension, diastolic dysfunction and a restrictive pattern. Because of the high probability of amyloidosis, the patient underwent a technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphic study, which confirmed the diagnosis of ATTR-CA. Transthyretin gene sequencing analysis revealed the rare p. Pro24Ser pathogenic variant. Final diagnosis was ATTR-CA associated with the proline replaced by serine at position 24 (Pro24Ser) TTR variant, which is rare and only a few cases have been reported worldwide. The patient was treated with tafamidis and inotersen and followed up. CONCLUSION: This case highlights the importance of considering amyloidosis as a differential diagnosis for non-specific symptoms and the need for early diagnosis and management of ATTR-CA.

A truncating variant altering the extreme C-terminal region of desmoplakin (DSP) suggests the crucial functional role of the region: a case report study.

BACKGROUND: Homozygous truncating mutations located in the C-terminal region of the desmoplakin gene (DSP) are known to mainly cause Carvajal syndrome, an autosomal recessive syndromic form of arrhythmogenic cardiomyopathy with an extra-cardiac cutaneous phenotype. CASE PRESENTATION: Here we describe a female proband with a documented arrhythmogenic left ventricular cardiomyopathy and a syncopal episode at the age of 13, who was found homozygous for the novel DSP variant: NM_004415.4:c.8586delC, p.(Ser2863Hisfs*20) at the extreme C-terminal region of the protein, just 8 amino acids upstream the stop codon. She did not have any of the typical dermatological symptoms that characterize Carvajal syndrome. Her brother had died suddenly at the age of 18 during exercise and was found homozygous for the same variant at the post-mortem, while their parents were heterozygous. The region of origin of both parents was the same geographic area of Greece, but they were not aware of any common ancestor. Detailed clinical examination revealed that the mother displayed a mild arrhythmic phenotype, while the father was asymptomatic. CONCLUSION: These observations pinpoint to a significant functional role of the extreme C-terminal tail of the protein.

Hypertrophic cardiomyopathy or athlete's heart? A systematic review of novel cardiovascular magnetic resonance imaging parameters.

Hypertrophic cardiomyopathy (HCM) is a common cause of sudden cardiac death in athletes. Cardiac Magnetic Resonance (CMR) imaging is considered an excellent tool to differentiate between HCM and athlete's heart. The aim of this systematic review was to highlight the novel CMR-derived parameters with significant discriminative capacity between the two conditions. A systematic search in the MEDLINE, EMBASE and Cochrane Reviews databases was performed. Eligible studies were considered the ones comparing novel CMR-derived parameters on athletes and HCM patients. Therefore, studies that only examined Cine-derived volumetric parameters were excluded. Particular attention was given to binary classification results from multi-variate regression models and ROC curve analyses. Bias assessment was performed with the Quality Assessment on Diagnostic Accuracy Studies. Five (5) studies were included in the systematic review, with a total of 284 athletes and 373 HCM patients. Several novel indices displayed discriminatory potential, such as native T1 mapping and T2 values, LV global longitudinal strain, late gadolinium enhancement and whole-LV fractal dimension. Diffusion tensor imaging enabled quantification of the secondary eigenvalue angle and fractional anisotropy in one study, which also proved capable of reliably detecting HCM in a mixed athlete/patient sample. Several novel CMR-derived parameters, most of which are currently under development, show promising results in discerning between athlete's heart and HCM. Prospective studies examining the discriminatory capacity of all promising modalities side-by-side will yield definitive answers on their relative importance; diagnostic models can incorporate the best performing variables for optimal results.

Arrhythmogenic cardiomyopathy and differential diagnosis with physiological right ventricular remodelling in athletes using cardiovascular magnetic resonance.

To describe the overlap between structural abnormalities typical of arrhythmogenic right ventricular cardiomyopathy (ARVC) and physiological right ventricular adaptation to exercise and differentiate between pathologic and physiologic findings using CMR. We compared CMR studies of 43 patients (mean age 49 ± 17 years, 49% males, 32 genotyped) with a definitive diagnosis of ARVC with 97 (mean age 45 ± 16 years, 61% males) healthy athletes. CMR was abnormal in 37 (86%) patients with ARVC, but only 23 (53%) fulfilled a major or minor CMR criterion according to the TFC. 7/20 patients who did not fulfil any CMR TFC showed pathological finding (RV RWMA and fibrosis in the LV or LV RWMA). RV was affected in isolation in 17 (39%) patients and 18 (42%) patients showed biventricular involvement. Common RV abnormalities included RWMA (n = 34; 79%), RV dilatation (n = 18; 42%), RV systolic dysfunction (≤ 45%) (n = 17; 40%) and RV LGE (n = 13; 30%). The predominant LV abnormality was LGE (n = 20; 47%). 22/32 (69%) patients exhibited a pathogenic variant: PKP2 (n = 17, 53%), DSP (n = 4, 13%) and DSC2 (n = 1, 3%). Sixteen (16%) athletes exceeded TFC cut-off values for RV volumes. None of the athletes exceeded a RV/LV end-diastolic volume ratio > 1.2, nor fulfilled TFC for impaired RV ejection fraction. The majority (86%) of ARVC patients demonstrate CMR abnormalities suggestive of cardiomyopathy but only 53% fulfil at least one of the CMR TFC. LV involvement is found in 50% cases. In athletes, an RV/LV end-diastolic volume ratio > 1.2 and impaired RV function (RVEF ≤ 45%) are strong predictors of pathology.

Role of the electrocardiogram in differentiating genetically determined dilated cardiomyopathy from athlete's heart.

BACKGROUND: Physiological cardiac remodelling in highly trained athletes may overlap with dilated cardiomyopathy (DCM). OBJECTIVES: The aim of this study was to investigate the role of the electrocardiogram (ECG) in differentiating between physiological and pathological remodelling. METHODS: The study population consisted of 30 patients with DCM who revealed a pathogenic variant at genetic testing and 30 elite athletes with significant cardiac remodelling defined by a left ventricular (LV) end-diastolic diameter >62 mm and/or LV ejection fraction between 45% and 50%. RESULTS: The ECG was abnormal in 22 (73%) patients with DCM. The most common abnormalities were low voltages (n = 14, 47%), lateral T-wave inversion (TWI) (n = 6, 20%), ventricular ectopic beats (n = 5, 17%) and anterior TWI (n = 4, 13). Two athletes revealed an abnormal ECG: complete left bundle branch block (LBBB) in one case and atrial flutter in the other. The sensitivity, specificity and accuracy of the ECG in differentiating DCM from physiological adaptation to exercise in athletes was 73% (confidence interval [CI]: 54%-88%), 93% (CI: 78%-99%) and 0.83 (CI: 0.71-0.92) respectively. CONCLUSIONS: While the ECG is usually normal in athletes exhibiting significant LV dilatation and/or systolic dysfunction, this test is often abnormal in patients with DCM harbouring a pathogenic variant. Low voltages in the limb leads and lateral TWI are the most common abnormalities.

Dilated cardiomyopathy in the era of precision medicine: latest concepts and developments.

Dilated cardiomyopathy (DCM) is an umbrella term entailing a wide variety of genetic and non-genetic etiologies, leading to left ventricular systolic dysfunction and dilatation, not explained by abnormal loading conditions or coronary artery disease. The clinical presentation can vary from asymptomatic to heart failure symptoms or sudden cardiac death (SCD) even in previously asymptomatic individuals. In the last 2 decades, there has been striking progress in the understanding of the complex genetic basis of DCM, with the discovery of additional genes and genotype-phenotype correlation studies. Rigorous clinical work-up of DCM patients, meticulous family screening, and the implementation of advanced imaging techniques pave the way for a more efficient and earlier diagnosis as well as more precise indications for implantable cardioverter defibrillator implantation and prevention of SCD. In the era of precision medicine, genotype-directed therapies have started to emerge. In this review, we focus on updates of the genetic background of DCM, characteristic phenotypes caused by recently described pathogenic variants, specific indications for prevention of SCD in those individuals and genotype-directed treatments under development. Finally, the latest developments in distinguishing athletic heart syndrome from subclinical DCM are described.

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.

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.

Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibrofatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. METHODS: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. After comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed antemortem with dilated cardiomyopathy (n=8) or ACM (n=7). Previous symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Postmortem genetic testing was undertaken in 24 of 202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics criteria. RESULTS: Of 202 ACM decedents (35.4±13.2 years; 82% male), no previous cardiac symptoms were reported in 157 (78%). Forty-one decedents (41/202; 20%) had been participants in competitive sport. The adjusted odds of dying during physical exertion were higher in men than in women (odds ratio, 4.58; 95% CI, 1.54-13.68; P=0.006) and in competitive athletes in comparison with nonathletes (odds ratio, 16.62; 95% CI, 5.39-51.24; P<0.001). None of the decedents with an antemortem diagnosis of dilated cardiomyopathy fulfilled definite 2010 Task Force criteria. The macroscopic appearance of the heart was normal in 40 of 202 (20%) cases. There was left ventricular histopathologic involvement in 176 of 202 (87%). Isolated right ventricular disease was seen in 13%, isolated left ventricular disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibrofatty infiltration were the left ventricular posterobasal (68%) and anterolateral walls (58%). Postmortem genetic testing yielded pathogenic variants in ACM-related genes in 6 of 24 (25%) decedents. CONCLUSIONS: SCD attributable to ACM affects men predominantly, most commonly occurring during exertion in athletic individuals in the absence of previous reported cardiac symptoms. Left ventricular involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM before death.

Electrocardiographic differentiation between 'benign T-wave inversion' and arrhythmogenic right ventricular cardiomyopathy.

AIMS: To characterize the most common electrocardiographic (ECG) abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), including anterior T-wave inversion (TWI) and to compare the characteristics of TWI in patients with ARVC and in a cohort of young healthy athletes and sedentary individuals. METHODS AND RESULTS: The study population consisted of 162 patients with a definite diagnosis of ARVC and 129 young controls with anterior TWI. Cardiac disease was excluded in all controls after a comprehensive diagnostic work-up. The ECG was abnormal in 131 patients with ARVC (81%). Abnormalities included anterior TWI (n = 82, 51%), QRS duration ratio V2:V5 >1.2 (n = 51, 31%), prolonged terminal S wave activation duration in V2 >55 ms (n = 42, 26%), inferior TWI (n = 30, 18%), and lateral TWI (n = 26, 16%). The J-point preceding anterior TWI was <0.1 mV in 80/82 (98%) patients with ARVC and in 98 (76%) controls. Among the ARVC patients with anterior TWI, 62 (77%) showed at least one additional abnormal feature, most commonly QRS duration ratio V2:V5 > 1.2 (52%) and inferior or lateral TWI (47%). CONCLUSION: The ECG is frequently abnormal in patients with ARVC and anterior TWI is the most common feature. Anterior TWI is usually accompanied by other abnormalities in ARVC, which are uncommon in healthy individuals. J point <0.1 mV preceding anterior TWI is not specific to ARVC and is observed in the majority of healthy individuals, including athletes, indicating a limited role for differentiating physiology or normal variants from ARVC.

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.

Sudden unexplained death in the young: epidemiology, aetiology and value of the clinically guided genetic screening.

Aims: To determine the incidence and the causes of sudden death (SD) in persons aged 1-35 years old and the diagnostic yield of clinically guided genetic screening in the sudden arrhythmic death syndrome (SADS) victims' families. Methods and results: Incidence and causes of SD in the Attica region of Greece in 2002-10 were determined using death certificates and autopsy reports. We evaluated clinically consecutive families of SADS victims and if a clinical diagnosis was established, we proceeded to targeted genetic analysis. Out of 6030 deaths, 56% were due to traumatic or violent causes, 40.5% were natural deaths, and 3.3% were of undetermined cause. There were 349 SD cases. Cardiovascular causes accounted for 65%, non-cardiovascular causes for 17%, and SADS for 18%. Clinical evaluation identified an inherited heart disease in 5/20 SADS families (25%). Targeted genetic analysis identified a causative mutation in all of the five screened families and reconfirmed the diagnosis in three of five proband victims. Clinical and genetic evaluation of 28 family members identified eight affected carriers and eight non-affected carriers. Molecular autopsy failed to identify any of these families. Conclusion: Sudden death in the young is of cardiovascular origin in the majority of cases. A considerable rate of SD cases remains of unknown cause on post-mortem. Apart from channelopathies, subclinical forms of inherited structural heart diseases would appear to be implicated in SADS. Clinically guided genetic screening has a significant diagnostic yield and identifies affected families that would have been missed by the current suggested molecular autopsy panel.

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome.

BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. RESULTS: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. CONCLUSIONS: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

Fabry disease and cardiovascular involvement.

Fabry disease (FD, OMIM 301500) is a rare X-linked lysosomal storage disorder of the glycosphigolipid metabolism caused by total or partial deficiency of the lysosomal enzyme alpha-galactosidase A (α-gal A). Progressive intralysosomal accumulation of neutral glycosphingolipids in a variety of cell types triggers a cascade of pathophysiological events including cellular death, compromised energy metabolism, small vessel injury, K(Ca)3.1 channel dysfunction in endothelial cells, oxidative stress, impaired autophagosome maturation, tissue ischemia and, importantly, development of irreversible cardiac and renal tissue fibrosis, leading to major multisystemic manifestations. Cardiovascular complications of the disease are very frequent and contribute substantially to disease-related morbidity and mortality in men. Cardiovascular involvement is the leading cause of premature death in heterozygous female patients with FD. Left ventricular hypertrophy is the most prominent cardiac manifestation followed by conduction system disease, valve dysfunction, arrhythmias, vessel disease and coronary microvascular dysfunction. The diagnosis of subclinical forms of the disease, before the development of cardiac hypertrophy, using newer techniques (tissue doppler imaging, strain rate and cardiac magnetic resonance) is crucial to the early initation of the treatment. Greatest benefit of the enzyme replacement treatment is achieved when started at an early stage of the disease before extensive fibrosis or other irreversible tissue damage takes place. Fabry disease should be included in the differential diagnosis algorithm of idiopathic hypertrophy. Determination of Alpha-Gal A activity on plasma and peripheral leukocytes in males and genetic testing in females are the diagnostic gold-standards.