Cardiac disease in children and young adults with various lysosomal storage diseases: Comparison of echocardiographic and ECG changes among clinical groups.

BACKGROUND: Lysosomal storage disease (LSD) is a rare inherited disease group. Consecutively there are few data on cardiac changes in mucopolysaccharidosis (MPS), Anderson Fabry disease (AFD), and other LSD (oLSD) including Pompe disease (PD) and Danon disease (DD), I-cell disease ICD and mucolipidosis III (ML III). METHODS: Between 1994 and 2011, we identified 39 patients with LSD: 25 with MPS, 8 with AFD, and 6 with oLSD including PD (1), ML III (2), DD (1), and ICD (2) at our institution fulfilling the inclusion criteria of at least one echocardiogram and ECG. RESULTS: Median age was 11.4 years (range: 2-27), 22 were females (56%). Normal echocardiograms were present in 12 patients (31%): 4 with MPS (16%), 7 AFD (88%), and 1 oLSD (17%). Valvular heart disease was present in 23 patients (59%) occurring more often in MPS (76%) and oLSD (67%) than in AFD (0%) (p < 0.001). The most common ECG abnormality was a short PR interval in 10 of 35 patients (29%) occurring in all LSD groups. Median follow-up was 5.8 (0.2-22.2) years showing diminished 5-year survival compared to an age-matched group. However, no patient died due to a cardiac cause and no cardiovascular intervention was necessary. CONCLUSION: Echocardiographically detectable cardiovascular involvement in children with LSD is mostly confined to MPS and oLSD. Valve thickening in echo and a short PR interval in the ECG are the most frequent abnormalities. Routine repeat assessment is recommended in LSD. However, significant cardiac disease necessitating cardiac intervention is rare during a short follow-up.

Pectus excavatum: echocardiography and cardiac MRI reveal frequent pericardial effusion and right-sided heart anomalies.

AIMS: In patients with pectus excavatum (PEX), echocardiographic assessment can be difficult. There are little data on the impact of the chest deformity on echocardiographic findings and comparison of data obtained by echocardiography (echo) with cardiac magnetic resonance imaging (CMR) in PEX. METHODS AND RESULTS: In a prospective study, cardiac anomalies in PEX were analysed by echo and compared with CMR in consecutive patients with PEX referred for echo. If they agreed to participate, the patients were referred for CMR and included if the pectus index was ≥3.0 by CMR. Also, clinical data and electrocardiogram tracings were analysed. There were 18 patients (13 females; 72%), with a mean age of 53±16 years; mean pectus index was 4.7 (range: 3-7.3). Echo showed haemodynamically insignificant pericardial effusion in six patients (33%), tricuspid valve prolapse in five (28%), right ventricular (RV) localized wall motion anomalies (WMA) in five (28%) and diminished RV systolic function in two (11%); no patient had RV dilatation. CMR demonstrated cardiac displacement to the left in 9 patients (50%); minimal pericardial effusion was seen in 10 patients (56%; P value=0.13 compared with echo), RV localized WMA in 6 (44%; P value=1.0), diminished RV systolic function in 8 (44%; P=0.07), and RV dilatation in 5 (28%; P=0.06). A completely normal cardiac examination was found in six patients by echo (33%) and in 2 (11%) using CMR. Although some signs of arrhythmogenic RV cardiomyopathy (ARVC) were present, no patient fulfilled the ARVC criteria. CONCLUSION: In severe PEX, haemodynamically insignificant pericardial effusion, tricuspid valve prolapse and other RV anomalies possibly due to RV displacement are frequent as demonstrated by both CMR and echo. The cardiac assessment by echo and CMR did show discrepancies; however, they were not significant.

Hypertrophic cardiomyopathy due to beta-myosin heavy chain mutation with extreme phenotypic variability within a family.

Hypertrophic cardiomyopathy (HCM) affects 1 in 500 persons and shows high variability in severity of disease, in genetic heterogeneity and phenotypic patterns. Many affected individuals remain undetected throughout their lives. In this case report a family with proven beta-myosin heavy chain mutation (MYH7) with 3 affected family members with huge phenotypic variability is described. The index patient (male, age 21 years) has severe phenotypic expression with a pathological ECG and maximal septal wall thickness of 29 mm, there is no significant obstruction in the left ventricular outflow tract. The sister (age 16 years), mutation carrier, has no detectable hypertrophy and no ECG changes. The mother (age 44 years), also carrying the mutation, has a normal ECG and shows only mild septal hypertrophy of 12 mm and systolic anterior motion of her mitral valve chordae with no gradient. The maternal grandmother died suddenly at age 65 years of presumed coronary artery disease, and the maternal great-grandmother had a sudden cardiac death at age 50 years of unknown etiology. To conclude, this family shows impressively the wide spectrum of phenotypic presentation and outcome in one family.

Isolated left ventricular noncompaction as a cause for heart failure and heart transplantation: a single center experience.

OBJECTIVES: To determine the prevalence of isolated left ventricular noncompaction (IVNC) as a cause of heart failure and heart transplantation. METHODS: There were 960 patients seen in the heart failure clinic from 1987 to 2005, with a complete evaluation including echocardiography at our center (study population, 82% men, mean age 52 years). The following data were collected: type of heart disease, age at echocardiography and at heart transplantation, and frequency of heart transplantation. Echocardiographic diagnosis of IVNC was based on our published criteria. RESULTS: The etiologies of heart failure were coronary artery disease (CAD; 37%), idiopathic dilated cardiomyopathy (33%), valvular heart disease (11%), congenital heart disease (5%), IVNC (3%), hypertensive heart disease (3%), hypertrophic cardiomyopathy (2%), myocarditis (1%), and <1% other diagnoses. Heart transplantation was performed in 253 patients (26%) due to idiopathic dilated cardiomyopathy (42%), CAD (39%), valvular heart disease (5%), congenital heart disease (5%), IVNC (2%), or other etiologies (< or =1% each). CONCLUSIONS: The most common causes for heart failure remain idiopathic dilated cardiomyopathy, CAD and valvular heart disease. Strictly using the criteria for the definition of IVNC, IVNC is a rare underlying cardiomyopathy for both, heart failure (2.7%) and heart transplantation (2%) in our center.

Anderson-Fabry disease: long-term echocardiographic follow-up under enzyme replacement therapy.

AIMS: Anderson-Fabry disease affects various organ systems due to glycosphingolipid accumulation. Enzyme replacement therapy (ERT) has been reported to decrease left ventricular wall thickening (LVWT) and to improve diastolic dysfunction. METHODS AND RESULTS: This prospective study included 29 patients (patients; mean age 37 +/- 13 years) with genetically, enzymatically and/or biopsy-proven Anderson-Fabry disease and long-time ERT. Data on symptoms, cardiac medications and history of hypertension were collected and all patients had comprehensive echocardiographic examination prior to ERT and at follow-up. Disease was at an early stage with a total mean Mainz severity score index of only 18.6 +/- 13.0. Prior to ERT, 79% of patients reported acroparesthesia. The median creatinine level was 121 +/- 108 mcmol/L and LVWT was present in nine patients (31%). Binary appearance of the interventricular septum was found in 20% and posterobasal fibrosis in 83%. At median follow-up of 37 months, acroparesthesia decreased to 55% (P = 0.016). There was no change in creatinine levels. The incidence of LVWT was unchanged, only an increase in interventricular septal wall thickness from 11.7 +/- 0.4 to 12.5 +/- 0.5 was observed (P = 0.009). Left atrial size and the percentage of patients with binary appearance and posterobasal fibrosis were unchanged. There was a small improvement in diastolic function (29% decrease of E/Ea; P < 0.002). CONCLUSION: Our Anderson-Fabry cohort had successful long-time ERT with impressive amelioration of subjective symptoms. Although there was not much improvement in cardiac changes apart from a slight improvement of diastolic function, at least, there was no progression of cardiac disease. For complete reversibility of cardiac changes in Anderson-Fabry disease, ERT might have to be started earlier in life and/or prescribed for a longer time.

Dynamic left ventricular outflow tract obstruction evoked by exercise echocardiography: prevalence and predictive factors in a prospective study.

AIMS: In patients without hypertrophic obstructive cardiomyopathy (HOCM), dynamic left ventricular outflow tract obstruction (DLVOTO) can cause ischaemia. Little is known about incidence and predictors of DLVOTO in patients without HOCM. METHODS AND RESULTS: In 300 patients referred for exercise echocardiography, assessment of DLVOTO at rest and with Valsalva and of the presence of systolic anterior motion of the mitral valve leaflets (SAM) was performed. Within 90 s post-exercise, wall motion, SAM, and DLVOTO were assessed again. A significant DLVOTO was defined as late-peaking Doppler velocity of >or=2.5 m/s (25 mmHg). Excluded were 7 patients with HOCM and 13 with inadequate image quality. There were 280 patients, aged 64(11) years. Coronary artery disease was found in 38% of patients; 44% were receiving beta-blocker therapy and 35% had hypertension. At rest, ejection fraction was 59 +/- 9%; left ventricular hypertrophy (LVH) was present in 21%, SAM in 16%, DLVOTO >or=25 mmHg at rest in 0.7%, and with Valsalva in 3%. At peak, echocardiographic signs of ischaemia occurred in 44%, and significant DLVOTO in 5% (13 patients). By multivariate analysis, it was found that independent predictors of significant DLVOTO at peak were chordal SAM at peak, smaller left ventricle at end-systole, higher systolic blood pressure at peak, younger age and increased septal wall thickness. Significant DLVOTO was a possible cause of symptoms and/or ischaemia in at least 6 of the 13 patients. CONCLUSION: Haemodynamically significant exercise-induced DLVOTO can occur without HOCM. Chordal SAM at peak, small, hyperdynamic left ventricles, increased septal wall thickness, and younger age are the best predictors.

[Heart murmur--auscultation or echocardiography in the diagnostic assessment of congenital or valvular heart disease?]. / Herzgeräusch--Auskultation oder Echokardiographie bei der Diagnose von Vitien und Herzklappenfehlern?

The incidence of patients with degenerative valvular but also of patients with congenital heart disease surviving until adulthood or even old age will increase in the next decades. Auscultation with the stethoscope remains an important diagnostic means in the detection and treatment of heart disease. Heart murmurs (especially systolic heart murmurs) are extremely common. There are helpful clues to differentiate heart murmurs. It can occasionally be relatively simple to differentiate a systolic murmur due to valvular heart disease from an innocent, ejection murmur; however, there are important limitations of auscultation. Overall, auscultation and clinical examination alone do not suffice to correctly diagnose and treat patients with heart failure or a murmur Clinically significant aortic stenosis, aortic regurgitation and mitral regurgitation as well as hypertrophic cardiomyopathy are not uncommonly missed or misinterpreted. An echocardiographic exam is mandatory in all patients with more than a soft systolic murmur, any diastolic murmur, cardiac symptoms and/or ECG changes.

Simple criteria for differentiation of Fabry disease from amyloid heart disease and other causes of left ventricular hypertrophy.

AIMS: Fabry disease may be difficult to differentiate from other causes of left ventricular hypertrophy such as other myocardial storage diseases (including amyloidosis), hypertrophic cardiomyopathy (HCM), or hypertensive heart disease (HHD). We sought to determine simple criteria to best differentiate the above mentioned cardiac diseases. METHODS AND RESULTS: All patients in a six-year time period with left ventricular hypertrophy due to Fabry disease (13 patients), biopsy proven cardiac amyloidosis (16 patients), non-obstructive HCM (17 patients), and 22 randomly selected patients with advanced HHD were compared. Retrospective analysis of clinical characteristics, findings of electrocardiogram (ECG) and echocardiography by blind review was performed. RESULTS: No single clinical characteristic or findings of ECG or echocardiography could reliably differentiate between the various diseases. Increased echogenicity/granular sparkling, valvular abnormalities, abnormal renal function, and diastolic function were not helpful discriminators. In a univariate analysis, four criteria (acroparesthesia, anhydrosis, absence of hypertension and presence of Sokolow criteria for left ventricular hypertrophy in the ECG) were significant for Fabry disease. By logistic regression analysis, the following most suitable discriminative parameters were identified: hypertension in HHD (specificity 82%), orthostasis and/or pericardial effusion for amyloidosis (specificity 93%), papillary muscle anomaly in non-obstructive HCM (specificity 92%), and Fabry disease if neither hypertension orthostatis, pericardial effusion nor a papillary muscle anomaly was present (specificity 87%). CONCLUSION: A combination of symptoms, echocardiographic findings and ECG in unexplained left ventricular hypertrophy may help to differentiate amyloidosis, non-obstructive HCM and hypertensive heart disease from Fabry disease. The results of this preliminary study will have to be confirmed in a prospective study.

Ebstein's anomaly - review of a multifaceted congenital cardiac condition.

Ebstein's anomaly (EA) is a rare but fascinating congenital heart disorder accounting for <1% of all congenital heart defects. Since its description in 1866, dramatic advances in diagnosis and therapy have been made. In this review, we describe current diagnostic criteria and classification, natural history, clinical features, and prognosis, typical echocardiographic features and pathologic findings, and the spectrum of associated cardiac malformations including left heart anomalies associated with EA. Differences between Ebstein-like changes associated with congenitally corrected transposition and EA are described. The spectrum of typical ECG and conduction system changes, arrhythmias including accessory pathways and ectopic atrial tachycardias related to EA are also reviewed. Differential diagnosis of EA is discussed including tricuspid valve dysplasia and prolapse as well as arrhythmogenic right ventricular cardiomyopathy. The review describes management options in EA including catheter interventions, indication for operation and surgical options including tricuspid valve repair and replacement. Overall, EA is a complex congenital anomaly with a broad pathologic-anatomical and clinical spectrum and no two patients are alike. Therefore, precise knowledge of the different anatomic and hemodynamic variables, associated malformations and management options are essential. Management of EA patients is complex. Thus it is important that these patients are regularly seen by a cardiologist with expertise in congenital heart disease.

Symptomatic mechanical heart valve thrombosis: high morbidity and mortality despite successful treatment options.

BACKGROUND: Recommendations for treatment of mechanical prosthetic heart valve thrombosis (PVT) include systemic thrombolysis and/or reoperation. Data on complications and outcome are limited. METHODS: Clinical and echocardiographic findings of 17 patients with mechanical PVT were reviewed. Complications and outcome of surgery and/or thrombolysis were analysed. Prospective follow-up was obtained. RESULTS: Symptomatic PVT occurred 8.4 +/- 7.2 years after mechanical valve replacement at mean age 55 +/- 15 years. Thrombosis involved the mitral valve in 12 patients (71%), the aortic valve in 4 (24%) and the tricuspid valve in one (6%). The reason for PVT was inadequate anticoagulation in 11 patients (65%), endomyocardial fibrosis in 2 (12%) and unknown in 4 (24%). Prior to diagnosis, systemic emboli occurred in 6 patients (35%). Thirteen patients (76%) presented in functional class NYHA IV. Haemodynamic valve obstruction was documented by echocardiography in 15 patients (88%). Treatment included primary reoperation in 12 patients (71%), thrombolysis with urokinase in 3 (18%) (with reoperation in 1), reinstitution of adequate anticoagulation in one (6%); death occurred before treatment in one (6%). Intraoperatively, both pannus and thrombus were found in 5 of 13 patients (38%). Treatment-related emboli occurred in 5 patients (29%), to the brain in 3, to the legs in one and to a coronary artery in one. Five patients died (mortality 29%) within 30 days due to multiorgan failure/septicaemia (3 patients), congestive heart failure (1), or cerebral emboli (1). Follow-up after 28 +/- 28 months in the 12 surviving patients was unremarkable. CONCLUSIONS: The most common aetiology for obstructive PVT is thrombus formation due to inadequate anticoagulation. PVT remains a serious complication with high morbidity and mortality despite aggressive treatment by thrombolysis and/or surgery. Surgery is often needed due to the frequent presence of pannus and/or large thrombi. However, long-term prognosis after successful treatment of PVT is excellent.

Resolution of protein-losing enteropathy with standard high molecular heparin and urokinase after Fontan repair in a patient with tricuspid atresia.

At 6 years of age, a girl with tricuspid atresia underwent a Björk modified Fontan procedure with implantation of a Carpentier Edwards bioprosthesis between the right atrium and the right ventricle. Ten years later she developed increasing edema, ascites and pleural effusions. The work-up showed severe stenosis of the bioprosthesis and protein losing enteropathy with a massive decrease of the albumin level to 14 g/l (normal 40-50 g/l). At 17 years of age, the bioprosthesis was replaced with a direct anastomosis between the cavoatrial junction and the right pulmonary artery. Within one month post-operatively, extensive thrombosis of the superior vena cava, anonymous and subclavian veins occurred. Protein-losing enteropathy persisted with an albumin level of 17 g/l. Parallel to the successful treatment of these thrombi with high molecular heparin and urokinase, protein losing enteropathy and hypoalbuminemia resolved completely as long as the antithrombotic treatment with high molecular heparin was continued. Oral anticoagulation was ineffective. Chronic antithrombotic treatment with high molecular heparin may thus be the treatment of choice in these forms of protein-losing enteropathy associated with venous thrombosis.

Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis.

OBJECTIVES: We sought to describe characteristics and outcome in adults with isolated ventricular noncompaction (IVNC). BACKGROUND: Isolated ventricular noncompaction is an unclassified cardiomyopathy due to intrauterine arrest of compaction of the loose interwoven meshwork. Knowledge regarding diagnosis, morbidity and prognosis is limited. METHODS: Echocardiographic criteria for IVNC include-in the absence of significant heart lesions-segmental thickening of the left ventricular myocardial wall consisting of two layers: a thin, compacted epicardial and an extremely thickened endocardial layer with prominent trabeculations and deep recesses. Thirty-four adults (age >16 years, 25 men) fulfilled the diagnostic criteria and were followed prospectively. RESULTS: At diagnosis, mean age was 42 + 17 years, and 12 patients (35%) were in New York Heart Association class III/IV. Left ventricular end-diastolic diameter was 65 + 12 mm and ejection fraction 33 + 13%. Apex and/or midventricular segments of both the inferior and lateral wall were involved in >80% of patients. Follow-up was 44 + 40 months. Major complications were heart failure in 18 patients (53%), thromboembolic events in 8 patients (24%) and ventricular tachycardias in 14 patients (41%). There were 12 deaths: sudden in six, end-stage heart failure in four and other causes in two patients. Four patients underwent heart transplantation. Automated cardioverter/defibrillators were implanted in four patients. CONCLUSIONS: Diagnosis of IVNC by echocardiography using strict criteria is feasible. Its mortality and morbidity are high, including heart failure, thrombo-embolic events and ventricular arrhythmias. Risk stratification includes heart failure therapy, oral anticoagulation, heart transplantation and implantation of an automated defibrillator/cardioverter. As IVNC is a distinct entity, its classification as a specific cardiomyopathy seems to be more appropriate.

Extensive thrombus formation in the right ventricle due to a rare combination of arrhythmogenic right ventricular cardiomyopathy and heterozygous prothrombin gene mutation G20210 A.

Arrhythmogenic right ventricular cardiomyopathy is a rare heart muscle disease characterized by right and often left ventricular myocardial atrophy and fibrofatty replacement. Heart failure, arrhythmias and sudden death are characteristic complications. We observed a female in whom arrhythmogenic right ventricular cardiomyopathy was diagnosed due to presyncopes and dyspnea on exertion. A left ventricular thrombus was found echocardiographically, which disappeared with oral anticoagulation. Subsequently, however, extensive thrombus formation in the dilated akinetic right ventricle occurred which was resistant to combined treatment with heparin and oral anticoagulation. Thrombophilia screening showed a mutant prothrombin 20210A allele which is an inherited coagulopathy associated with increased plasma levels of prothrombin and increased risks of mainly venous thrombosis. The patient developed endstage biventricular heart failure and underwent heart transplantation within 3 months after thrombus formation in the right ventricle was diagnosed. In the explanted heart, the thrombus in the right ventricle was impressively large and calcified. In patients with unusual thrombus formation in the heart, coagulopathy may be associated and should be excluded.

[Stress echocardiography: analysis of results in 100 coronary angiography patients]. / Stress-Echokardiographie: Analyse der Resultate bei 100 koronarangiographierten Patienten.

Stress echocardiography is increasingly accepted as a reliable, noninvasive method for assessment of coronary artery disease. We retrospectively analysed the results of the first 100 consecutive patients (79 males, 62 +/- 10 years), who had both stress echocardiography and coronary angiography within 3 months without intercurrent revascularisation. In 71% of the patients treadmill- was performed and in 29% dobutamine-stress echocardiography. No patient had severe side effects. In the 100 patients, positive predictive accuracy for detection of significant coronary artery disease was 95% and for multivessel disease 80%. There was no significant difference in positive predictive value for detection of significant stenosis in the posterior perfusion territory (left circumflex, right coronary artery), with 79% compared to the anterior perfusion territory (86%, p = ns). Sensitivity for the left circumflex (60%) tended to be lower compared to the right coronary artery (76%) or left anterior descending coronary artery (82%) (p = ns). Despite poorer echocardiographic image quality in dobutamine-stress echocardiography patients, there was no significant difference between treadmill- and dobutamine-stress echocardiography regarding the positive predictive value for detection of coronary artery disease (98 vs 92%) or for recognition of multivessel disease (79 vs 79%) (p = ns). False results of stress echocardiography were rare (7%): false positive results were more common in the presence of wall motion abnormalities at rest, false negative results after an insufficient stress-induced increase in heart rate. Gender or left ventricular hypertrophy had no impact on stress echocardiography results (p = ns). In conclusion, both dobutamine- and treadmill-stress echocardiography are reliable, sensitive methods for non-invasive assessment of coronary artery disease; this is also valid in women and in left ventricular hypertrophy.

Left ventricular end-diastolic pressure can be estimated by either changes in transmitral inflow pattern during valsalva maneuver or analysis of pulmonary venous flow.

We directly compared the transmitral inflow pattern during preload reduction and pulmonary venous flow velocities to determine left ventricular end-diastolic pressure (LVEDP) in 78 patients who underwent left heart catheterization. Transmitral inflow indexes (A-wave duration, ratio of peak flow velocity of early diastole [E] to peak flow velocity of late diastole during atrial contraction [A] [E/A ratio]) at rest and during the Valsalva maneuver (30 mm Hg for 15 seconds) and indexes of pulmonary venous flow (velocity and duration of the atrial reversal) were obtained. Fair correlations existed between LVEDP (mean 15+/-6 mm Hg) and the percentage decrease in the E/A ratio (r = 0.72), increase in duration of A wave during the Valsalva maneuver (r = 0.60), flow velocity of atrial reversal (r = 0.58), and difference of duration of atrial flow reversal and A wave (r = 0.62) (all P<.001). While sensitivity, specificity, and diagnostic accuracy to detect an elevated LVEDP were comparable, technically adequate Doppler recordings were obtained more often for the mitral inflow during the Valsalva maneuver than for the pulmonary venous flow (72 versus 66 patients, P< 0.05).