Finite element analysis of mitral valve annuloplasty in Barlow's disease.

Barlow's Disease affects the entire mitral valve apparatus causing mitral regurgitation. Standard annuloplasty procedures lead to an average of 55% annular area reduction of the end diastolic pre-operative annular area in Barlow's diseased valves. Following annular reduction, mitral valvuloplasty may be needed, usually with special focus on the posterior leaflet. An in silico pipeline to perform annuloplasty by utilizing the pre- and -postoperative 3D echocardiographic recordings was developed. Our objective was to test the hypothesis that annuloplasty ring sizes based on a percentage (10%-25%) decrease of the pre-operative annular area at end diastole can result in sufficient coaptation area for the selected Barlow's diseased patient. The patient specific mitral valve geometry and finite element model were created from echocardiography recordings. The post-operative echocardiography was used to obtain the artificial ring geometry and displacements, and the motion of the papillary muscles after surgery. These were used as boundary conditions in our annuloplasty finite element analyses. Then, the segmented annuloplasty ring was scaled up to represent a 10%, 20% and 25% reduction of the pre-operative end diastolic annular area and implanted to the end diastolic pre-operative finite element model. The pre-operative contact area decrease was shown to be dependent on the annular dilation at late systole. Constraining the mitral valve from dilating excessively can be sufficient to achieve proper coaptation throughout systole. The finite element analyses show that the selected Barlow's diseased patient may benefit from an annuloplasty ring with moderate annular reduction alone.

[Mitral valve prolapse and mitral annulus disjunction: be aware of a potential arrhythmogenic substrate]. / Prolasso valvolare mitralico e disgiunzione mitro-anulare. La consapevolezza di un possibile substrato aritmico.

Mitral valve prolapse is a relatively common disease with a good overall prognosis. However, in specific clinical and instrumental contexts, patients at high risk of ventricular arrhythmias and sudden cardiac death can be identified. Female sex, history of palpitations or syncope, bi-leaflet myxomatous valve, ECG repolarization abnormalities in the inferior leads, complex ventricular arrhythmias, left ventricular fibrosis detected by cardiac magnetic resonance correlate with a higher risk clinical profile. Additionally, morpho-functional abnormalities of the mitral valve annulus, particularly mitral annulus disjunction, may cause a mechanical stretch at the inferior basal ventricular wall and posterior papillary muscles, predisposing to myocardial fibrosis and arrhythmias. A risk stratification strategy is needed to identify patients with mitral valve prolapse and/or mitral annulus disjunction at high risk of arrhythmias; however, few data are available. Further prospective multicenter studies are warranted, focusing on medical therapy, the role of implantable cardioverter-defibrillators for primary prevention, efficacy of targeted catheter ablation or mitral valve surgery.

Association of Mitral Annular Disjunction With Cardiovascular Outcomes Among Patients With Marfan Syndrome.

Importance: Mitral annular disjunction (MAD) has received particular interest in patients with mitral valve prolapse, ventricular tachycardia, and sudden cardiac death. The clinical significance of MAD for patients with Marfan syndrome (MFS) remains largely unexplored. Objective: To define the prevalence of MAD and examine its association with cardiovascular outcomes and arrhythmia among patients with MFS. Design, Setting, and Participants: This retrospective, single-center cohort study included 142 patients with a diagnosis of MFS based on the revised Ghent criteria and a confirmed (likely) pathogenic variant in the FBN1 gene who underwent regular follow-up between January 1, 2004, and December 31, 2019. Main Outcomes and Measures: The presence of MAD was assessed by echocardiography, and the extent of MAD was categorized in tertiles. Patients also underwent resting electrocardiography and 24-hour Holter monitoring. Outcomes included aortic events (aortic dissection or prophylactic aortic surgery), arrhythmic events (defined as sustained ventricular tachycardia or sudden cardiac death), and mitral valve surgery. Results: A total of 142 patients (72 female patients [51%]; median age at first examination, 25 years [range, 2-64 years]) were evaluated. Forty-eight patients (34%) had MAD. Patients with MAD had larger aortic root z scores than patients without MAD (4.1 [interquartile range, 2.8-5.7] vs 3.0 [interquartile range, 1.8-4.0]; P < .001) and more often had mitral valve prolapse (34 of 48 [71%] vs 14 of 94 [15%]; P < .001), ventricular ectopy (14 of 33 [42%] vs 15 of 70 [21%]; P = .03), and nonsustained ventricular tachycardia (13 of 33 [39%] vs 12 of 70 [17%]; P = .01). During follow-up, aortic events occurred at similar rates among patients with vs without MAD (15 of 43 [35%] vs 21 of 84 [25%]; P = .24), but patients in the upper MAD tertile (>10 mm) showed a higher occurrence of aortic events compared with patients with MAD of 10 mm or smaller (9 of 15 [60%] vs 6 of 28 [21%]; P = .01). Patients with arrhythmic events (n = 5) and patients requiring mitral valve surgery (n = 7) were observed exclusively in the group displaying MAD. Conclusions and Relevance: This study suggests that MAD among patients with MFS is associated with the occurrence of arrhythmic events, a higher need for mitral valve intervention, and, among patients with extensive MAD, more aortic events. Cardiac imaging for patients with MFS should consider the assessment of MAD as a potential marker for adverse outcomes.

The Mitral Annular Disjunction of Mitral Valve Prolapse: Presentation and Outcome.

OBJECTIVES: The aim of this study was to assess in patients with mitral valve prolapse (MVP) mitral annular disjunction (MAD) prevalence, phenotypic characteristics, and long-term outcomes (clinical arrhythmic events and excess mortality). BACKGROUND: Clinical knowledge regarding MAD of MVP remains limited and controversial, and its potential link with untoward outcomes is unsubstantiated. METHODS: A cohort of 595 (278 women, mean age 61 ± 16 years) consecutive patients with isolated MVP, with comprehensive clinical, rhythmic, Doppler echocardiographic, and consistent MAD assessment, were examined. MAD prevalence, associated MVP phenotypes, and outcomes (survival, clinical arrhythmic events) starting at diagnostic echocardiography were analyzed. To balance important baseline differences, propensity scoring matching was conducted among patients with and those without MAD. RESULTS: The presence of MAD was common (n = 186 [31%]) in patients with MVP, generally in younger patients, and was not random but was independently associated with severe myxomatous disease involving bileaflet MVP and marked leaflet redundancy (both P ≤ 0.0002). The presence of MAD was also independently associated with a larger left ventricle (P = 0.005). Age-matched cohort survival after MVP diagnosis was not worse with MAD (10-year survival 93% ± 2% for patients without MAD and 97% ± 1% for those with MAD; P = 0.40), even adjusted comprehensively for MVP characteristics (P = 0.80) and accounting for time-dependent mitral surgery (P = 0.60). During follow-up, 170 patients had clinical arrhythmic events (ventricular tachycardia, n = 159; arrhythmia ablation, n = 14; cardioverter-defibrillator implantation, n = 14; sudden cardiac death, n = 3). MAD was independently associated with higher risk for arrhythmic events (adjusted HR: 2.60; 95% CI: 1.87-3.62; P < 0.0001). The link between MAD and arrhythmic events persisted with time-dependent mitral surgery (adjusted HR: 2.54; 95% CI: 1.84-3.50; P < 0.0001), was strong under medical management (adjusted HR: 3.21; 95% CI: 2.03-5.06; P < 0.0001) but was weaker after mitral surgery (adjusted HR: 2.07; 95% CI: 1.24-3.43; P = 0.005). CONCLUSIONS: This large cohort with MVP comprehensively characterized shows that MAD is frequent at MVP diagnosis and is strongly linked to advanced myxomatous degeneration. The presence of MAD was independently associated with long-term excess incidence of clinical arrhythmic events. However, within the first 10 years post-diagnosis, MAD was not linked to excess mortality, and although reassurance should be provided from the survival point of view, careful monitoring for arrhythmias is in order for MAD.

The chromogranin A-derived peptides catestatin and vasostatin in dogs with myxomatous mitral valve disease.

BACKGROUND: The protein chromogranin A (CgA) is stored and co-released with catecholamines from the stimulated adrenal glands. Increased plasma concentrations of CgA have been shown in people with heart disease. The aim of the study was to investigate whether plasma concentrations of the CgA-derived biologically active peptides catestatin and vasostatin were associated with the severity of myxomatous mitral valve disease (MMVD) in dogs and to assess potential associations between these blood variables and dog characteristics, echocardiographic variables, heart rate (HR), blood pressure (BP) and plasma N-terminal-proBNP (NT-proBNP) concentration. Sixty-seven privately owned dogs with or without MMVD were included. The dogs underwent physical examination, blood pressure measurement, blood sample collection, and echocardiographic examination. Plasma concentrations of catestatin and vasostatin were analyzed using radioimmunoassay. RESULTS: Catestatin concentration decreased with increasing left atrial and ventricular size (R2 ≤ 0.09, P ≤ 0.019), and increased with increasing systolic and diastolic blood pressures (R2 ≤ 0.08, P ≤ 0.038). Regression analyses showed no significant associations for vasostatin. No differences in plasma concentrations of catestatin or vasostatin were found between the disease severity groups used in the study. CONCLUSIONS: In the present dog population, the catestatin concentration showed weak negative associations with left atrial and ventricular sizes, both of which are known to increase with increasing severity of MMVD. Furthermore, the catestatin concentration showed weak positive associations with blood pressure.

Very long-term outcomes of twisted auto-pericardial mitral annuloplasty.

OBJECTIVES: During mitral annuloplasty, we twisted the harvested auto-pericardium to enable adequate ring sizing and implanted it to prevent ring-related complications. Indication for twisted auto-pericardial band (APB) was limited to patients with less than severe annular dilation to ensure high reproducibility and durability. The aim of this study was to investigate the long-term outcomes of twisted APB annuloplasty. METHODS: From 1999 to 2009, 107 patients (62 ± 12 years, degenerative 92 and infective endocarditis 15) with isolated posterior mitral leaflet (PML) prolapse with inter-commissural distance of 32 mm or smaller underwent twisted APB annuloplasty. Of these, 104 patients without early leaflet repair failure were studied. Leaflet repairs were predominantly performed by quadrangular resection. Median APB size was 28 mm. RESULTS: Follow-up rate was 98.1% and duration was 10.9 ± 4.8 years. There were two early and 34 late deaths. Survival and freedom from cardiac-related death at 15 years were 61.7% ± 5.6% and 83.8% ± 4.7%, respectively. Age and male sex were independent predictors of mortality. There were four late reoperations for recurrent severe mitral regurgitation (MR), three of which were due to new chordal rupture. Freedom from reoperation and freedom from moderate or severe MR at 15 years were 93.1% ± 3.5% and 81.3% ± 6.2%, respectively. No patients developed hemolysis, ring dehiscence, or infective endocarditis. CONCLUSIONS: The long-term outcomes of twisted APB for isolated PML prolapse without severe annular dilation are satisfactory. Twisted APB annuloplasty may be a preferable option to reduce ring-related complications with sufficient durability.

The Association Between Keratoconus and Mitral Valve Prolapse: A Meta-Analysis.

OBJECTIVE: The debate pertaining to the association between Keratoconus (KC) and Mitral Valve Prolapse (MVP) continues to occur among physicians. The results of cross-sectional studies attempting to present the co-existing prevalence of these two diseases remain indeterminate. We compiled the first meta-analysis to determine the pattern of prevalence between the two diseases. METHODS: Two separate literature searches for cross-sectional studies were performed for this metaanalysis. The first search encompassed finding literature comparing the prevalence of KC between patients with MVP and a control group. The second search pertained to finding studies comparing the prevalence of MVP patients with KC and a control group. RESULTS: Six studies reported the prevalence of MVP in patients with KC and a control group. The prevalence was 41.6% in patients with KC and 11.5% in patients without KC (OR = 7.06 [95% CI = 2.41-20.64]). There was a significant heterogeneity among the studies (I2 = 84%). Two studies showed the prevalence of KC in patients with MVP and a control group. The prevalence was 17.0% in patients with KC and 2.9% in the control group (OR = 5.07 [95% CI = 1.08-23.83]). There was no heterogeneity within the analysis (I2 = 0%). CONCLUSION: There is a statistically significant co-existing prevalence between MVP and KC. Patients with KC are more likely to present with MVP, and patients with MVP are more likely to present with KC.

Primary cilia defects causing mitral valve prolapse.

Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1 A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.

Repair of bileaflet prolapse in Barlow syndrome: The 4-chord technique.

Barlow syndrome is a form of degenerative mitral valve (MV) disease found in a subset of patients with bileaflet prolapse. The hallmark of Barlow's disease includes excessive and billowing leaflet tissue caused by myxomatous tissue proliferation, elongated chordae, and pronounced annular dilatation. Surgical repair of patients with Barlow's disease is challenging due to the extent of the leaflet and annular abnormalities. Several techniques have been described to repair Barlow's MV including currently popular "non-resectional" approaches. Repair with neochordae has been associated with excellent results and includes the advantage of preserved leaflet mobility and a large surface of coaptation. We describe a simple approach to the use of neochordae to repair bileaflet prolapse in patients with Barlow syndrome and avoid systolic anterior motion.

Characteristics of mitral valve leaflet length in patients with pectus excavatum: A single center cross-sectional study.

The mitral valve morphology in patients with pectus excavatum (PE) has not been fully investigated. Thirty-five patients with PE, 46 normal controls, and patients with hypertrophic cardiomyopathy (HCM) who underwent 2 leaflet length measurements of Carpentier classification P2 and A2 using a transthoracic echocardiography were retrospectively investigated. The coaptation lengths and depths, papillary muscle tethering length, and mitral annular diameters were also measured. The P2 and A2 lengths were separately compared between 2 groups: older than 16 years and 16 years or younger. Furthermore, the correlations between actual P2 or A2 lengths and Haller computed tomography index, an index of chest deformity, were investigated in patients with PE exclusively. Among subjects older than 16 years, patients with PE had significantly shorter P2, longer A2, shorter copatation depth, and longer papillary muscle tethering length compared with normal controls. Similarly, patients with PE had significantly shorter P2 and shorter coaptation depth even compared with patients with HCM, while no significant difference was found in A2 length and papillary muscle tethering length. The same tendency was noted between 4 normal controls and 7 age- and sex-matched patients with PE ≤ 16 years old. No significant difference regarding A2/P2 ratio was found between patients with PE older and younger than 16 years. No significant correlation between the Haller computed tomography index and actual mitral leaflet lengths in patients with PE older than 16 years was noted; the same was observed for A2/P2 in all patients with PE. In conclusion, the characteristic features of the shorter posterior mitral leaflet, the longer anterior mitral leaflet, the shorter coaptation depth, and the longer papillary muscle tethering length in patients with PE was demonstrated. This finding might provide a clue regarding the etiology of mitral valve prolapse in PE at its possible earliest form.

Pattern of Rheumatic valvular involvement and its contribution towards valvular malfunction in young adults

Objective: To study the different patterns of valvular malfunction in Rheumatic heart disease (RHD) and assess the factors contributing towards it. Methods: This is an observational study among patients with chronic RHD. One hundred patients (female 81 and 19 males) within ages 12 to 40 years (Mean age 27.3) were analyzed. A relevant clinical history including that of an initial episode of acute rheumatic fever (ARF) and recurrent episodes was obtained. 2D echo assessment of the cardiac valves was performed with an estimation of Wilkins score for the mitral valve (MV). Results: Among the study population female: male ratio was 4:1. 30% had recurrent episodes of ARF. Only 60% had at least some evidence of ARF at any time in their life. The posterior mitral valve appears to be affected more than the anterior leaflet giving an average Wilkins score of 9.7 and 6.7 respectively. The total score had a positive correlation with Mitral stenosis (MS) (p <0.05). MV involvement was noted in 97%. 44% had significant mitral valve prolapse (MVP) but no statistical correlation was noted with mitral regurgitation (MR) (p>0.05). A regurgitant grade of 2 or more was found in 41%. High sensitive C reactive protein of more than 1mg/dl was noted in 55% of patients. Conclusion: Chronic rheumatic MV disease can exist as MS, MR, MVP or simply an elevated valve score. Apart from recurrent streptococcal infections and chronic sub clinical inflammation, a number of different components of valve damage contribute towards the end result.

Mitral valve prolapse.

Introduction: Mitral valve prolapse (MVP) is a common valve pathology with a spectrum of disease from isolated prolapse to myxomatous, multi-scallop Barlow's disease. The main complications relate to progression of mitral regurgitation, endocarditis, sudden death, and stroke. The timing of intervention in patients with asymptomatic severe mitral regurgitation is controversial. Areas covered: This article reviews the pathophysiology, genetics, clinical features, diagnostic imaging, complications, long-term outcomes, and indications for intervention in MVP. Expert commentary: Several key dilemmas in the management of MVP remain. Factors which influence progression of mitral regurgitation are unclear and therefore, we have no therapeutic targets to prevent progression. Evidence-based methods to reduce the risk of sudden death, stroke, and endocarditis have not been identified. In symptomatic patients with severe mitral regurgitation valve surgery is recommended. In asymptomatic patients, careful risk stratification incorporating markers of left ventricular dysfunction, atrial fibrillation, pulmonary hypertension, and valve reparability is required to identify the optimal timing of intervention.

Possible mechanism of late systolic mitral valve prolapse: systolic superior shift of leaflets secondary to annular dilatation that causes papillary muscle traction.

Progressive superior shift of the mitral valve (MV) during systole is associated with abnormal papillary muscle (PM) superior shift in late systolic MV prolapse (MVP). The causal relation of these superior shifts remains unclarified. We hypothesized that the MV superior shift is related to augmented MV superiorly pushing force by systolic left ventricular pressure due to MV annular dilatation, which can be corrected by surgical MV plasty, leading to postoperative disappearance of these superior shifts. In 35 controls, 28 patients with holosystolic MVP, and 28 patients with late systolic MVP, the MV coaptation depth from the MV annulus was measured at early and late systole by two-dimensional echocardiography. The PM tip superior shift was monitored by echocardiographic speckle tracking. MV superiorly pushing force was obtained as MV annular area × (systolic blood pressure - 10). Measurements were repeated after MV plasty in 14 patients with late systolic MVP. Compared with controls and patients with holosystolic MVP, MV and PM superior shifts and MV superiorly pushing force were greater in patients with late systolic MVP [1.3 (0.5) vs. 0.9 (0.6) vs. 3.9 (1.0) mm/m2, 1.3 (0.5) vs. 1.2 (1.0) vs. 3.3 (1.3) mm/m2, and 487 (90) vs. 606 (167) vs. 742 (177) mmHg·cm2·m-2, respectively, means (SD), P < 0.001]. MV superior shift was correlated with PM superior shift ( P < 0.001), which was further related to augmented MV superiorly pushing force ( P < 0.001). MV and PM superior shift disappeared after surgical MV plasty for late systolic MVP. These data suggest that MV annulus dilatation augmenting MV superiorly pushing force may promote secondary superior shift of the MV (equal to late systolic MVP) that causes subvalvular PM traction in patients with late systolic MVP. NEW & NOTEWORTHY Late systolic mitral valve prolapse (MVP) is associated with mitral valve (MV) and papillary muscle (PM) abnormal superior shifts during systole, but the causal relation remains unclarified. MV and PM superior shifts were correlated with augmented MV superiorly pushing force by annular dilatation and disappeared after surgical MV plasty with annulus size and MV superiorly pushing force reduction. This suggests that MV annulus dilatation may promote secondary superior shifts of the MV (late systolic MVP) that cause subvalvular PM traction.

New insights into mitral heart valve prolapse after chordae rupture through fluid-structure interaction computational modeling.

Mitral valve (MV) dynamics depends on a force balance across the mitral leaflets, the chordae tendineae, the mitral annulus, the papillary muscles and the adjacent ventricular wall. Chordae rupture disrupts the link between the MV and the left ventricle (LV), causing mitral regurgitation (MR), the most common valvular disease. In this study, a fluid-structure interaction (FSI) modeling framework is implemented to investigate the impact of chordae rupture on the left heart (LH) dynamics and severity of MR. A control and seven chordae rupture LH models were developed to simulate a pathological process in which minimal chordae rupture precedes more extensive chordae rupture. Different non-eccentric and eccentric regurgitant jets were identified during systole. Cardiac efficiency was evaluated by the ratio of external stroke work. MV structural results showed that basal/strut chordae were the major load-bearing chordae. An increased number of ruptured chordae resulted in reduced basal/strut tension, but increased marginal/intermediate load. Chordae rupture in a specific scallop did not necessarily involve an increase in the stress of the entire prolapsed leaflet. This work represents a further step towards patient-specific modeling of pathological LH dynamics, and has the potential to improve our understanding of the biomechanical mechanisms and treatment of primary MR.

The Mitral Annulus Disjunction Arrhythmic Syndrome.

BACKGROUND: Mitral annulus disjunction (MAD) is an abnormal atrial displacement of the mitral valve leaflet hinge point. MAD has been associated with mitral valve prolapse (MVP) and sudden cardiac death. OBJECTIVES: The purpose of this study was to describe the clinical presentation, MAD morphology, association with MVP, and ventricular arrhythmias in patients with MAD. METHODS: The authors clinically examined patients with MAD. By echocardiography, the authors assessed the presence of MVP and measured MAD distance in parasternal long axis. Using cardiac magnetic resonance (CMR), the authors assessed circumferential MAD in the annular plane, longitudinal MAD distance, and myocardial fibrosis. Aborted cardiac arrest and sustained ventricular tachycardia were defined as severe arrhythmic events. RESULTS: The authors included 116 patients with MAD (age 49 ± 15 years; 60% female). Palpitations were the most common symptom (71%). Severe arrhythmic events occurred in 14 (12%) patients. Longitudinal MAD distance measured by CMR was 3.0 mm (interquartile range [IQR]: 0 to 7.0 mm) and circumferential MAD was 150° (IQR: 90° to 210°). Patients with severe arrhythmic events were younger (age 37 ± 13 years vs. 51 ± 14 years; p = 0.001), had lower ejection fraction (51 ± 5% vs. 57 ± 7%; p = 0.002) and had more frequently papillary muscle fibrosis (4 [36%] vs. 6 [9%]; p = 0.03). MVP was evident in 90 (78%) patients and was not associated with ventricular arrhythmia. CONCLUSIONS: Ventricular arrhythmias were frequent in patients with MAD. A total of 26 (22%) patients with MAD did not have MVP, and MVP was not associated with arrhythmic events, indicating MAD itself as an arrhythmogenic entity. MAD was detected around a large part of the mitral annulus circumference and was interspersed with normal tissue.

Mitral valve prolapse and aortic root dilation in adults with hypermobile Ehlers-Danlos syndrome and related disorders.

Ehlers-Danlos syndromes (EDSs) are a group of inherited connective tissue disorders, and among them, classical EDS (cEDS) and hypermobile EDS (hEDS) are the most common. Mitral valve prolapse (MVP) and aortic root dilation (ARD) have previously been reported to occur at an increased frequency within cEDS and hEDS. More recently, a study performed in the pediatric population did not show increased prevalence (Ritter et al., American Journal of Medical Genetics Part A, 173(6), 1467-1472, 2017). The purpose of this study was to review a large population of individuals with cEDS, hEDS, and hypermobility spectrum disorders to determine the frequency of MVP and ARD. A retrospective chart review of 209 individuals with echocardiograms was performed. Overall, 6.4% (13/209) had MVP and 1.6% (3/189) were found to have ARD. Although the presence of MVP is higher than what has been reported in the general population, no patients had severe MVP or required surgical intervention. No patients in this cohort had an aortic root diameter requiring surgical repair. Based on the results of this study and previous studies, routine echocardiograms to assess for valvular diseases and ARD may not be necessary unless warranted by presence of symptoms or family history.