Absence Of Cardiac Involvement Research Articles

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation.

Background: CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as long QT syndrome, Brugada syndrome and Timothy syndrome. Recent evidence has suggested the possible association between CACNA1C mutations and neurologically-isolated (in absence of cardiac involvement) phenotypes in children, giving birth to a wider spectrum of CACNA1C-related clinical presentations. However, to date, little is known about the variety of both neurological and non-neurological signs/symptoms in the neurologically-predominant phenotypes. Methods and Results: We conducted a systematic review of neurologically-predominant presentations without cardiac conduction defects, associated with CACNA1C mutations. We also reported a novel de novo missense pathogenic variant in the CACNA1C gene of a children patient presenting with constructional, dressing and oro-buccal apraxia associated with behavioral abnormalities, mild intellectual disability, dental anomalies, gingival hyperplasia and mild musculoskeletal defects, without cardiac conduction defects. Conclusions: The present study highlights the importance of considering the investigation of the CACNA1C gene in children's neurological isolated syndromes, and expands the phenotype of the CACNA1C related conditions. In addition, the present study highlights that, even in absence of cardiac conduction defects, nuanced clinical manifestations of the Timothy syndrome (e.g., dental and gingival defects) could be found. These findings suggest the high variable expressivity of the CACNA1C gene and remark that the absence of cardiac involvement should not mislead the diagnosis of a CACNA1C related disorder.

Frontal Plane QRS-T Angle as a Marker of Cardiac Iron Overload in Patients with Beta Thalassemia Major.

Cardiomyopathy due to myocardial iron deposition is the leading cause of death in transfusion- dependent beta-thalassemia major (β-TM) patients. Although cardiac T2* magnetic resonance imaging (MRI) can be used for the early detection of cardiac iron level before the onset of symptoms associated with iron overload, this expensive method is not widely available in many hospitals. Frontal QRS-T angle is a novel marker of myocardial repolarization and is associated with adverse cardiac outcomes. We aimed to investigate the relationship between cardiac iron load and f(QRS-T) angle in patients with β-TM. The study included 95 β-TM patients. Cardiac T2* values under 20 were considered to indicate cardiac iron overload. The patients were divided into two groups according to the presence or absence of cardiac involvement. Laboratory and electrocardiography parameters, including frontal plane QRS-T angle, were compared between the two groups. Cardiac involvement was detected in 33 (34%) patients. Multivariate analysis showed that frontal QRS-T angle independently predicted cardiac involvement (p < 0.001). An f(QRS-T) angle of ≥ 24.5° had a sensitivity of 78.8% and a specificity of 79% in detecting the presence of cardiac involvement. In addition, a negative correlation was found between cardiac T2* MRI value and f(QRS-T) angle. A widening f(QRS-T) angle could be considered a surrogate marker of MRI T2* to detect cardiac iron overload. Therefore, calculating the f(QRS-T) angle in thalassemia patients is an inexpensive and simple method for detecting the presence of cardiac involvement, especially when cardiac T2* values cannot be determined or monitored.

FP.21 Congenital myasthenic syndrome with Desmin aggregates: A novel association in recessive desminopathies due to a recurrent intronic DES mutation

Desminopathies (DES; OMIM: 125660) are highly variable presenting as cardiomyopathy, myofibrillar myopathy (MFM) or a combination of both. Dominant mutations are more common while a few severe cases of recessive myofibrillar myopathy were reported with complete loss of desmin. Here, we report three unsolved Limb girdle congenital myasthenic syndrome (LG-CMS) patients with a recurrent homozygous intronic DES mutation identified by systematic reanalysis through Solve-RD project. Three unrelated patients (M:F – 2:1) aged 16, 21 and 22 years presented with history of delayed motor milestones, childhood onset of progressive muscle involvement. Fatigable ptosis and limb weakness was reported in all three patients with gradually progressive speech and swallowing difficulty. Elevated serum creatine kinase was common finding and repetitive nerve stimulation showed decrement (>10%) in two patients. Clinical improvement of 25% with pyridostigmine and salbutamol was noted in one patient. Initial exome sequencing analysis did not reveal any significant variants in known CMS genes. On re-analysis, we identified a novel intronic homozygous substitution DES(NM_001927.4):c.1023+5G>A in all three patients. In-silico analysis predicted pathogenicity due to altered donor splice site. Muscle biopsy in one of the male patients showed mixed pattern with reduced sarcoplasmic Desmin staining along with Desmin positive aggregates. Neuromuscular junction involvement has been previously reported in severe desmin-null patients. The presence of a recessive CMS-MFM phenotype of moderate severity with desmin aggregates and absence of cardiac involvement in our patients expands the known spectrum of Desminopathies and reiterates the importance of early genetic diagnosis to identify treatable CMS phenotypes. Due to the presence of identical rare homozygous variant in three unrelated south Indian patients, we suspect a possibility of founder allele.

CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.225Clinical, genetic and neuropathological heterogeneity in a pediatric cohort with nemaline myopathy

Nemaline myopathies are a vast group of rare muscle diseases sharing a common pathognomonic histological marker: nemaline rods - dark-blue structures visualized in muscle fibers stained with Gomori Trichrome. A pediatric cohort from a reference center in the north of Portugal (between 2002-2017) was reassessed. Eight patients (4 of each gender) with ages between 1 and 18 yrs were diagnosed. Two patients were siblings and other two had family history. Six had a neonatal presentation with tetraparesis, distal arthrogryposis, and severe axial and bulbar involvement, 4 required invasive ventilatory support and 4 tube feeding. One patient died with 3m of age. All 8 patients needed ventilation support and one performed scoliosis surgery. Five were able to walk between 18 and 72m (34m average). Muscle biopsy was reviewed in 5: rods, mainly in the periphery, variable proportion of affected fibers, without correlation with clinical severity. In terms of their genetic etiology, the most frequent defective gene in this cohort was nebulin (NEB) affecting 5 patients (1 homozygous and 4 compound heterozygous). Six distinct pathogenic variants in NEB gene were identified: 3 affecting splice-sites, 2 causing frameshift and 1 nonsense. All give rise to premature termination codons. Several unrelated patients shared at least one NEB variant meaning that these could be preliminary targeted in future cases. One patient has a de novo pathogenic missense variant in ACTA1 gene. Finally, in the kindred with two affected siblings, a novel heterozygous missense variant in KLHL41 gene was identified. Further research is being carried-out to identify an eventual missing variant that would justify an autosomal recessive inheritance pattern. Considering the variability presented here and the size of the patient cohort, no genotype-phenotype correlations were drawn. Nevertheless, the absence of cardiac involvement in this cohort is concordant with previous reports.

Hypereosinophilic syndrome: endomyocardial biopsy versus echocardiography to diagnose cardiac involvement

ABSTRACTObjective: To compare echocardiograms and endomyocardial biopsies to diagnose cardiac involvement in hypereosinophilic syndrome.Methods: We examined the agreement between echocardiography and endomyocardial biopsies to detect cardiac involvement in hypereosinophilic syndrome by reviewing cases identified as hypereosinophilia or hypereosinophilic syndrome in Mayo Clinic databases from January 1978 through June 2009. Single-organ cases of eosinophilia such as eosinophilic fasciitis and eosinophilic gastroenteritis were excluded. We recorded echocardiogram and endomyocardial biopsy results including biopsy staining for eosinophil granule major basic protein (if performed). Clinical and laboratory features documented included presenting symptom(s), maximum total eosinophil count, dose of prednisone (if any) and eosinophil count at the time of endomyocardial biopsy, cardiac enzymes, serum tryptase level, electrocardiogram result, the result of testing for the FIP1L1-PDGFRA fusion gene, complications associated with the biopsy procedures and available follow-up information.Results: From a total of 387 patients’ records screened 288 met the criteria for hypereosinophilic syndrome and of these 240 had echocardiograms. Among these patients there were 138 normal echocardiograms, 67 had echocardiograms without findings of hypereosinophilic syndrome but with one or more other abnormalities, and 35 had echocardiograms with findings consistent with hypereosinophilic syndrome. Twenty-five patients from this group of 35 patients had both echocardiogram and endomyocardial biopsy. In 15 patients there was agreement between both endomyocardial biopsy and echocardiography as to the presence (n = seven) or absence (n = eight) for findings of cardiac involvement. In 10 of 25 patients test results diverged: 3 patients with positive echocardiographic changes did not have confirmatory findings by endomyocardial biopsy and seven patients with positive biopsy findings had echocardiograms without findings of hypereosinophilic syndrome.Conclusions: Echocardiograms and endomyocardial biopsies agree for presence or absence of cardiac involvement 60% of the time. Endomyocardial biopsy detected cardiac involvement in 7 patients in whom the echocardiogram was negative for findings of hypereosinophilic syndrome.

Prévalence des troubles respiratoires du sommeil dans une cohorte de 1112 patients hospitalisés pour exploration d’une HTA dans un service spécialisé

We studie 72 patients with renal amyloïdosis to evaluate prognostic factors. We used immunohistological techniques to classify in AL amyloïdosis and AA amyloïdosis. Several factors of better prognosis were determined : AA type, absence of cardiac involvement, young age, normal renal function.

European Collaborative Study of Treatment Outcomes in 347 Patients with Systemic AL Amyloidosis with Mayo Stage III Disease

Abstract 995N-terminal fragment of BNP (NT-proBNP) and cardiac troponin –T (TnT) or I (TnI) form a useful staging system in AL amyloidosis and poor outcomes have been reported in stage III patients treated before routine use of novel agents. These patients are routinely excluded from clinical trials and prospective outcome data is limited but recent studies suggest that some such patients may have better outcomes. We report the outcomes of 347 patients with Mayo stage III AL amyloidosis seen at the amyloid centres in London (UK), Pavia (Italy), Heidelberg (Germany) and Athens (Greece). Organ involvement and responses are defined according to 2005 amyloidosis consensus criteria. Presenting features were [n (%)/median (range)]: cardiac, renal and liver involvement in 338 (97%), 216 (62%) and 77 (22%) respectively, NT-proBNP 9106 ng/L (379–216187); TnI – 0.18 ng/ml (0.1–12); TnT −0.09 ng/ml (0.04–8.2) and IVS 15 mm (7–24). Treatments given were: Bortezomib combinations - 23 (7%), MDex - 150 (43%), thalidomide combinations - 96 (28%), lenalidomide combinations - 13 (4%). 30 (8%) were deemed too ill for treatment or died prior to treatment initiation. Only 37% completed the planned treatment course. The haematological responses on an intention to treat basis were seen in (Overall response rate/complete response (CR)/partial response (PR))(n(%)): MDex – 63(42%)/24 (16%)/39 (26%); Thalidomide combinations 31(32%)/11(12%)/20(21%), bortezomib combinations 10(43%)/6 (23%)/4 (17%), lenalidomide combination 5(38%)/0(0%)/5(38%).The median overall survival (OS) was 7.1 mos. The overall survival at 12 months from response evaluation was 74% for CR, 52% for PR and 18% for NR and from diagnosis was (median): CR – 59 mo, PR 28 mo, NR 10 mo and not assessable for response 2.9 mos. Stage III patients without echocardiographic evidence of cardiac involvement had excellent outcomes with 80% estimated 2 year OS. Using best fit cut-off, in multivariate model (including NT-proBNP., systolic blood pressure (SBP), ejection fraction, NYHA, ECOG, dFLC, LV wall thickness), NT-proBNP > 8000 ng/L (HR 2.3; p <0.0001) and SBP < 100 mm of Hg (HR 1.6; p<0.0001) were the only independent predictors of poor outcome. Using NT-proBNP >8000 ng/L and SPB <100 mm of Hg as high risk criteria, stage III patients can be further subdivided based on presence of none, one or two criteria with OS of 25 mo, 6 mo and 3 mo respectively. Using these criteria, on intent to treat basis, OS by CR/PR/NR was: no high risk factors – median not reached/69 mo/7 mo and one high risk factor - 59 mo/23 mo/4 mos respectively and too few patients for patients with two high risk factors making comparison unreliable.In conclusion, outcomes amyloidosis patients with stage III disease remain poor. However, stage III patients are heterogeneous and combination of NT-proBNP and SBP can usefully sub-classify these patients. Patients with abnormal biomarkers just due to renal failure in absence of cardiac involvement should be excluded from the current Mayo staging system. Although, treatment responses of stage III patients, on intent to treat basis, are poor with all regimes, it is encouraging that haematological responses improve outcomes and patients who achieve a CR have best outcomes. Clinical trials are urgently needed in patients with stage III disease to confirm these findings and define optimal treatment options. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Sarcoidosis does not belong to or overlap with immunoglobulin G4–related diseases based on an assessment of serum immunoglobulin G4 levels in cardiac and noncardiac sarcoidosis

Although sarcoidosis may exhibit histopathologic features similar to those of a newly emerging clinical entity, immunoglobulin G4-related sclerosing disease, sarcoidosis is currently not considered to be associated with immunoglobulin G4-related immunoinflammation. Not many studies on this association have been reported. We investigated serum immunoglobulin G4 levels among patients with sarcoidosis with or without cardiac involvement (cardiac sarcoidosis and non-cardiac sarcoidosis patients). The mean serum immunoglobulin G4 level among the 65 patients with sarcoidosis was 56.8 ± 43.0 mg/dL, which did not significantly differ between patients with cardiac sarcoidosis (54 ± 48 mg/dL, n = 12) and patients without cardiac sarcoidosis (58 ± 42 mg/dL; n = 53). Serum level of soluble interleukin 2 receptor, a potent marker that may reflect sarcoidosis activity, was elevated in cardiac sarcoidosis (910 ± 683 U/L) and noncardiac sarcoidosis (689 ± 399 U/L) but did not significantly differ between the groups. Immunohistochemistry of cardiac or lymph node specimens from patients with cardiac sarcoidosis showed only sparse or no infiltration of immunoglobulin G4-positive lymphocytes, in contrast to the moderate to severe infiltration of CD68-positive macrophages and CD45-positive lymphocytes. Although the number of study subjects was small, these findings collectively suggest that regardless of the presence or absence of cardiac involvement, sarcoidosis does not belong to or overlap with immunoglobulin G4-related sclerosing disease.

AL Amyloidosis: Prognosis of Cardiac Involvement Reconsidered.

Abstract 4872 BackgroudPrognosis in AL amyloidosis is commonly viewed as dichotomous, based on the presence or absence of cardiac involvement. Patients with cardiac AL amyloidosis are reported to have a dismal prognosis, with a median survival of approximately 6 months. Furthermore, cardiac involvement is often considered a contraindication to hematopoietic cell transplant. AimsTo compare the prognosis of patients with cardiac AL amyloidosis with and without presenting symptoms of congestive heart failure (CHF). MethodsThe study population consisted of individuals with biopsy-proven AL amyloidosis and cardiac involvement seen at the Stanford University Amyloid Center. Cardiac involvement was defined by the presence of amyloid deposits on endomyocardial biopsy or the combination of increased ventricular mass with reduced electrocardiographic voltage. ResultsA total of 27 patients (median age 64 years, 37% female) were evaluated. The 16 patients with CHF symptoms had a median age of 65 years with a median of 2 organs involved with amyloidosis. The 11 patients without CHF symptoms had a median age of 59 years with a median of 3 organs involved. At diagnosis, NT-proBNP was significantly higher in the group with CHF symptoms (15,938 vs. 2,538 pg/ml, P<0.001), as was the likelihood of detectable troponin I (86% s. 36%, P<0.02). Mean levels of the involved serum free light chain (179.7 vs. 47.9 mg/dL) were nonsignificantly higher in the cohort with CHF. Though there was no difference in the mean interventricular septal width between the two groups (1.5 cm), the mean systolic blood pressure (sBP) (91 vs. 115 mm Hg, P<0.001) and left ventricular ejection fraction (45 vs. 59%, p=0.02) were significantly lower in the group with CHF symptoms. A total of 6 patients (4 without CHF symptoms, 2 with CHF symptoms) received hematopoietic cell transplants, and 3 patients received heart transplants. Other therapies employed included oral melphalan (6 patients), dexamethasone (19 patients), lenalidomide (17 patients), and bortezomib (4 patients). After a median follow-up of 24 months, there were 9 deaths in the cohort with CHF symptoms vs. 0 in the group without CHF symptoms. Six-month survival (50% vs. 100%, P<0.01) and one-year survival (42% vs. 100%, P<0.01) were significantly lower in the group with CHF symptoms. DiscussionCHF at presentation is the primary factor which predicts a poor prognosis in patients with cardiac AL amyloidosis. In our cohort, no patient without CHF symptoms at diagnosis later developed CHF, and thus new CHF symptoms do not appear to be a typical consequence of progressive disease. ConclusionNot all patients with cardiac AL amylodosis have an exceptionally poor prognosis. Many patients have ‘incidental' cardiac involvement in the absence of CHF symptoms and appear to do well with both standard and intensive therapies. DisclosuresWitteles:Celgene: Research Funding. Off Label Use: Melphalan, lenalidomide & bortezomib as therapy for AL amyloidosis.. Witteles:Celgene: Research Funding. Schrier:Celgene: Research Funding.

Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis

Primary prevention of acute rheumatic fever is accomplished by proper identification and adequate antibiotic treatment of group A β-hemolytic streptococcal (GAS) tonsillopharyngitis. Diagnosis of GAS pharyngitis is best accomplished by combining clinical judgment with diagnostic test results, the criterion standard of which is the throat culture. Penicillin (either oral penicillin V or injectable benzathine penicillin) is the treatment of choice, because it is cost-effective, has a narrow spectrum of activity, and has long-standing proven efficacy, and GAS resistant to penicillin have not been documented. For penicillin-allergic individuals, acceptable alternatives include a narrow-spectrum oral cephalosporin, oral clindamycin, or various oral macrolides or azalides. The individual who has had an attack of rheumatic fever is at very high risk of developing recurrences after subsequent GAS pharyngitis and needs continuous antimicrobial prophylaxis to prevent such recurrences (secondary prevention). The recommended duration of prophylaxis depends on the number of previous attacks, the time elapsed since the last attack, the risk of exposure to GAS infections, the age of the patient, and the presence or absence of cardiac involvement. Penicillin is again the agent of choice for secondary prophylaxis, but sulfadiazine or a macrolide or azalide are acceptable alternatives in penicillin-allergic individuals. This report updates the 1995 statement by the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee. It includes new recommendations for the diagnosis and treatment of GAS pharyngitis, as well as for the secondary prevention of rheumatic fever, and classifies the strength of the recommendations and level of evidence supporting them.

Parasympathetic dysautonomia precedes left ventricular systolic dysfunction in Chagas disease

Background Parasympathetic dysautonomia is an established feature of advanced Chagas cardiomyopathy. However, in the absence of cardiac involvement, the presence of vagal dysfunction remains controversial. In a cross-sectional study, we compared patients with Chagas disease without cardiac involvement and healthy individuals by three different methods to determine whether vagal dysfunction is present in the early phase of Chagas disease. Methods Sixty-one patients with Chagas disease without cardiac involvement and 38 controls were submitted to respiratory sinus arrhythmia test and 24-hour Holter monitoring. Vagal heart influences were assessed by the expiratory/inspiratory (E/I) ratio, time-domain indexes of heart rate variability (HRV), and by the quantification of a 3-dimensional return map. Results The two groups were comparable in terms of left ventricular ejection fraction and left ventricular end-diastolic dimension. Compared with the control group, patients with Chagas disease had significantly lower values of the E/I ratio (mean ± SD: 1.38 ± 0.02 and 1.25 ± 0.02, P <.004) and short-term indexes of HRV (median [interquartile range]—rMSSD: 23 [18-27] and 17 [13-23], P =.00; pNN50: 11 [7-17] and 6 [2-12], P =.00). P3, a beat-to-beat HRV index derived from the 3-dimensional return map, also was significantly reduced in the Chagas disease group (mean ± SD: 118 ± 5 vs 100 ± 4, P =.00). None of these indexes of vagal heart control were significantly correlated with left ventricular function or to the presence of esophageal radiologic abnormalities. Conclusion Parasympathetic dysautonomia is an independent and early phenomenon in Chagas disease and may precede left ventricular systolic dysfunction. (Am Heart J 2001;141:260-5.)

Amyloidosis: Recognition, Confirmation, Prognosis, and Therapy

Amyloidosis: Recognition, Confirmation, Prognosis, and Therapy

Treatment of Acute Streptococcal Pharyngitis and Prevention of Rheumatic Fever: A Statement for Health Professionals

Primary prevention of acute rheumatic fever is accomplished by proper identification and adequate antibiotic treatment of group A β-hemolytic streptococcal (GAS) tonsillopharyngitis. Diagnosis of GAS pharyngitis is best accomplished by a throat culture. Penicillin (either oral penicillin V or injectable benzathine penicillin) remains the treatment of choice, because it is cost effective, has a narrow spectrum of activity, has long-standing proven efficacy, and GAS resistant to penicillin have not been documented. Various macrolides, oral cephalosporins, and other β-lactam agents are acceptable alternatives, particularly in penicillin-allergic individuals. The individual who has had an attack of rheumatic fever is at very high risk of developing recurrences after subsequent GAS pharyngitis and needs continuous antimicrobial prophylaxis to prevent such recurrences (secondary prevention). The duration of prophylaxis depends on the number of previous attacks, the time lapsed since the last attack, the risk of exposure to streptococcal infections, the age of the patient, and the presence or absence of cardiac involvement. Penicillin is again the agent of choice for secondary prophylaxis, but sulfadiazine or erythromycin are acceptable alternatives in penicillin-allergic individuals. This report is an update of a 1988 statement by this committee. It expands on the previous statement, includes more recent therapeutic modalities, and makes more specific recommendations for the duration of secondary prophylaxis.

Amylose : étude des facteurs du pronostic chez 72 patients avec atteinte rénale

We studie 72 patients with renal amyloïdosis to evaluate prognostic factors. We used immunohistological techniques to classify in AL amyloïdosis and AA amyloïdosis. Several factors of better prognosis were determined : AA type, absence of cardiac involvement, young age, normal renal function.

Early-onset benign autosomal-dominant limb-girdle myopathy with contractures (Bethlem myopathy)

We report the first Japanese patients, a mother and son, with early-onset, benign, autosomal-dominant, limb-girdle myopathy with contractures (Bethlem myopathy). The clinical features revealed predominantly proximal muscle weakness — especially in the limb-girdle muscles — joint contractures increasing with age, a benign course, and the absence of cardiac involvement. Muscle histology revealed nonspecific myopathic changes without dystrophic features. Electromyogram revealed a reduced interference pattern with a giant spike suggesting a neurogenic process.

The natural history of rheumatic fever in the first three decades

Summary An analysis of the clinical course exhibited by 225 rheumatic subjects who have lived to their present ages of sixteen to thirty years, and 112 individuals who have succumbed to the disease during a twenty-year period of observation, has been presented. The onset of the disease from childhood is characterized by protean manifestations of activity and by a varied number of years of freedom from recurrence or continuous years of manifestations of active infection. After puberty, about the age of sixteen years, the majority of the subjects (66 per cent) were free from recurrence of symptoms, compared with 13 per cent before this age period. The practical importance of consideration of the age factor in this disease has been discussed. From a comparison of the course of the disease in the living and in the deceased series of subjects, it appears that the disease is self-limited, death being due in most instances to fatal active carditis. While the first attack of carditis may be severe and fatal, the majority of the deceased subjects survived subsequent recurrent active carditis. The average age of death was 12.6 years, and the greatest incidence was in the age group of twelve to sixteen years, inclusive, for the series. The care and management of these patients during the period of observation is not within the scope of this report. It is, however, of some interest to note that the children who experienced several intercurrent years of freedom from manifestations of rheumatic activity, remained in the same environment. Those who succumbed to the disease and those who survived with minimal degree of cardiac damage received comparable medical supervision. It is difficult to reconcile some current etiologic hypotheses with the observed course of the disease in these subjects. The type of rheumatic manifestation, exclusive of active carditis, did not appear to be of prognostic significance. The incidence of heart disease was comparable whether patients exhibited joint pains alone or chorea or polyarthritis with or without joint pains. All of the subjects presented evidence of cardiac involvement, although in only 39 per cent were the symptoms of carditis above the clinical horizon and capable of recognition. When the symptoms of active carditis were of sufficient degree to be diagnosed, the subsequent amount of cardiac damage, that is the multiple valvular lesions and marked cardiac enlargement, was greater and the mortality higher. During the course of the disease physical signs of valvular involvement may disappear, may be inconstant or uncharacteristic, leading to the erroneous opinion that the heart is left unscathed. The presence of considerable cardiac enlargement, established by adequate roentgenologic examination in a large series of these children who were under continuous careful observation, indicates the limitations of a diagnosis of the absence of cardiac involvement in rheumatic individuals based on physical examination alone. It is of some prognostic importance to note that the majority of these rheumatic individuals who survived were able to carry on their work and play without circulatory symptoms, particularly after puberty. The future course of the disease in these individuals must await a further period of continued observation for final comment. It would seem likely, however, that the usual unfavorable prognostic opinion that the majority succumb during the third and fourth decades is influenced by observations which are limited to adult patients who are under observation because of symptoms or by postmortem statistics. There may well be in the general population a considerable number of rheumatic individuals in whom the disease has been mild or unrecognized and the presence of heart disease unknown. Our own observations, as well as the frequent accidental discovery of mitral stenosis during routine physical examination or postmortem examination, favor this view. Accumulation of adequate data as to the true incidence, morbidity, and mortality of this disease is a vital need. Such information can only be collated from studies of representative series of subjects under continuous observation from the onset of the disease throughout its course to its end. An adequate comprehension of the natural history of rheumatic fever is the only reliable criterion available at the present time for considering critically current etiologic hypotheses and for evaluating various therapeutic measures.