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A 46- year-old man was admitted on April 2005 due to atypical chest pain not effort related. He was asymptomatic until 3 months before admission when he presented with exertional dypsnea (class II NYHA), several episodes of atypical chest pain and palpitations.
Physical examination was normal. The ECG (fig. 1) showed sinus rhythm, left anterior hemiblock and frequent monofocal ventricular premature beats that could be originated from the right ventricular outflow tract.
The echocardiogram showed a slightly dilated left ventricle with an end-diastolic diameter of 57mm. The interventricular septal thickness was 9 mm, and the left ventricular posterior wall thickness was 10 mm (Fig 2a). The left ventricular ejection fraction was 45%. The right ventricle was markedly dilated (fig 2 b, fig 2c) with an end-diastolic diameter of 50mm and a normal systolic function (TAPSE 24mm, fig. 2d). Both atria were dilated with a left atrial diameter of 45 mm. A moderate tricuspid regurgitation was observed and the pulmonary pressure was slightly increased. The atrial septum was intact.
At this time, a pulmonary thromboembolism (PE) was suspected, thus a Computerized Tomographic Pulmonary Angiography and a thoracic CT were performed. PE was discarded and it was evidenced a repletion defect in the superior vena cava that might be produced by a “vascular steal” phenomenon. The exercise stress echocardiogram following the Bruce protocol lasted 4.4 minutes, reached 97% of the predicted maximum heart rate and 10 METS. It was negative for ischemia and showed an abnormal relaxation pattern at rest and during exercise.
Family history was remarkable. His 78 year-old father had exertional dypsnea (class II NYHA). Past medical history revealed the presence of several syncopal episodes beginning at 18 years old and episodes of atypical chest pain in the last ten years. The patient had hypertension and presented chronic atrial fibrillation. The echocardiogram showed a slightly dilated left ventricle (end-diastolic diameter 56mm) with global hypokinesia and an ejection fraction of 44%. The right ventricle was slightly dilated with normal systolic function. The aortic valve showed leaflets calcification and a grade III/IV aortic regurgitation was observed. Myocardial ischaemia was discarded by stress echocardiography.
The proband’s paternal grandfather had died suddenly at 32 years-old. No further details were available. The patient’s mother was unaffected.
After initial evaluation, the proband was referred to our centre due to a suspected familial cardiomyopathy.
Fig 3. Family pedigree.
At this moment only patients III.1(proband),
II: 1 and II: 2 had been clinically evaluated
• What would be the differential diagnosis in this patient?
• What would be the diagnostic strategy that you propose?
ANSWER FOR THE CASE
Differential diagnosis and diagnostic strategy
Our case, a 46-year-old male patient, presented with exertional dyspnea and palpitations, a severe right ventricular and atrial dilatation, monomorphic ventricular extrasystolia, mild left ventricular dilatation, systolic dysfunction (EF 45%) and a family history of DCM (father). Causes of right chambers dilatation include pressure overload, volume overload, and myocardial dysfunction, which may be secondary to ischemic heart disease or to primary cardiomyopathies (mainly ARVC) (1). Several possible aetiologies such as ischemic heart disease, right side valvulopathies, atrial septal defect, proximal vascular abnormalities, pulmonary thromboembolism and congenital causes had been acceptably discarded by 2D, Doppler and stress echocardiography, Computerized Tomographic Pulmonary Angiography and a thoracic CT. The presence of mild left ventricular enlargement and dysfunction (LV end diastolic diameter was increased by 11% above the maximum predicted by the Henry´s formula) would not explain the severity of the right chambers compromise. However, the left ventricular involvement and the family history of DCM would suggest the presence of a primary cardiomyopathy with biventricular compromise.
Although ARVC would be the cardiomyopathy that best fit with the patient's characteristics (severe right ventricular dilatation with left ventricle involvement), our patient did not fulfil the current ARVC diagnostic criteria (2). The possibility of an extracardiac shunt should also be considered, even thought it would not explain the left ventricular involvement. This hypothesis was also supported by the finding of a repletion defect in the superior vena cava that might be produced by a “vascular steal” phenomenon.
With the hypothesis of a familial cardiomyopathy with biventricular involvement we performed a genetic study of the main ARVC disease-causing genes (desmosomal genes: PKP2, DSP, DSG2 and DSC2).
We also performed a MRI, which is the procedure of choice to study extracardiac shunts (3) and could help to evaluate the structural and functional characteristic of the right ventricle, reducing subjective bias associated with echocardiography (4).
Genetic analysis informed the presence of four genetic variants (Table1): DSG2 variant I85N (g42507C>G or Ile85Asn) has not been previously described either in patients or in healthy controls thus, taking in account the thousands of samples analysed so far, it was considered a mutation. At functional level, this variant affects a residue slightly conserved (I85) producing an amino acid change from a nonpolar (isoleucine, I) to another uncharged polar aminoacid (asparagine, N). This may produce important physicochemical changes in the mass, the hydrophobicity and polarity (Grantham distance: 149 [0-215]). We performed an in silico analysis to predict the effect of amino acid substitution at residue 85 (I to N) using two softwares: Polyphen (= Polymorphism phenotyping) and Sorting Intolerant From Tolerant (SIFT). Polyphen predicted that the change may affect the function of the protein and SIFT was not conclusive. This data, however, was insufficient to ascertain the pathogeniciy of I85N.
DSP variant A2294G (g42507C>G or Ala2294Gly) has been identified in three families (Dr van der Zwaag, personal communication).
Only one has been partially published and appeared in a database of mutations and benign variants related to dysplasia / arrhythmogenic right ventricular cardiomyopathy (ARVC). In this family, the variant was the only one found in the proband diagnosed with ARVC (5 genes related to this phenotype were analyzed), but showed no cosegregation with the disease as the proband’s mother, who also presented this phenotype, did not present this variant. In the second family, the proband (currently 72 years old) carried a second confirmed pathogenic mutation in desmoplakin (DSP). In the last family, this variant was identified in the father of a male patient who died suddenly at the age of 25, although the latter patient did not carry the variant. Both, however, were carriers of a confirmed pathogenic mutation in another gene. Finally, Polyphen software predicted that this variant may not affect the protein function. With this data, we considered A2294G as a probably non pathogenic variant.
The other genetic variants found in the plakophilin (PKP2) gene, L366P and the intronic IVS12+(13-14)insC were polymorphism frequently identified in healthy controls.
Genetic variants identified in the proband. The variants are name by aminoacid code and below by nucleotide code. See text for description.
Next, we performed the familial study, for which the I85N and A2294G variants were tested on the affected proband’s father but he did not carry any of them (as in consequence neither did the affected grandfather, figure 2). The proband’s mother could not be genotyped but despite she could be an obligate carrier of at least one variant, she was clinically unaffected. Hence, we could not demonstrate cosegregation of these variant with disease.
Familiar pedigree. Genetic study was available only for patients II.1 and III.1 (proband). Filled symbols means clinical affected individuals. Genetic test result is drawn below each symbol. +/- means heterozygous for the mutation and -/- means wild type.
The cardiac MRI (Fig. 1a and 1b) confirmed the presence of a dilatation of both right chambers with a mild depressed right ventricular function (ventricular end diastolic diameter: 60mm, end diastolic volume: 356ml; right atrium diameter 64 mm and ejection fraction of 47%). It also showed the dilatation and functional impairment of the left ventricle (end diastolic diameter: 60mm, end diastolic volume: 243ml and ejection fraction decreased by 40%). No regional structural or functional right ventricle abnormalities were observed. However, the most relevant finding was the demonstration (by Angio MRI, 3D shaded surface display) of a partial anomalous pulmonary venous return (PAPVR), producing a shunt from the right superior pulmonary lobe to the superior vena cava (white arrow, Fig. 1c). This explained the right high cardiac output of 8 l/m calculated by MRI.
In conclusion, we consider that the right chambers dilatation would be explained by the presence of an extracardiac shunt (PAPVR). We cannot exclude that the genetic variants identified in the DSG2 and DSP genes could contribute to the biventricular moderate dysfunction, but they could also be non-pathogenic. In any case, the familial antecedents of DCM would not be explained by the presence of these genetic variants. ARVC diagnosis was not supported by clinical criteria and we cannot confirm that the identified genetic variants are associated with the development of disease. The left ventricular compromise in the proband and in his father may have two different etiologies (in the case of the proband’s father DCM could be secondary to hypertension and valvular disease), but it may also be possible that they have a familial DCM caused by other still unknown genetic cause. In the latter case the substantial differences in phenotypic manifestations would be due to the presence of PAPVR in the proband. We consider that this case is still open and we are evaluating other genes that have been associated with the development of familial DCM. For example, mutations in sarcomeric genes have already been associated with the development of congenital abnormalities, such as atrial septal defects.
Acknowledgements: We gratefully acknowledge the excellent technical assistance of Dr Rafaela Soler Fernandez, Dr. Esther Rodriguez and Dr. Cristina Mendez from the radiology service, Complejo Hospitalario, Universitario de A Coruña. Spain.
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