Background.
Patients with congenital heart defects (CHD) and chronic pressure overload of the right ventricle (RV) are prone to long-term RV dysfunction and failure. The exact mechanism of RV dysfunction is unknown, but both pressure overload and pressure-independent factors are believed to play an important role. While myocardial ischemia and fibrosis are well known factors in acquired left-heart disease, their exact role in RV dysfunction and failure due to chronic pressure overload remains unknown. Imaging methods nowadays allow accurate non-invasive evaluation of both myocardial ischemia and fibrosis. The aim of our study was to assess myocardial ischemia and fibrosis in patients with CHD and chronic pressure overload of the RV and their possible association with clinical, laboratory, functional and imaging markers of RV function.
Hypotheses.
1. Right ventricular ischaemia and fibrosis are present and related findings in adults with congenital heart disease and chronic right ventricular pressure overload.
2. Ischaemia and fibrosis are associated with right ventricular systolic and diastolic dysfunction in adults with congenital heart disease and chronic right ventricular pressure overload.
3. Serum biomarkers of cardiac fibrosis, electrocardiographic and echocardiographic parameters are associated with right ventricular ischaemia and fibrosis in adults with congenital heart disease and chronic right ventricular pressure overload.
Research design and methods.
This was a single centre cohort study, approved by the Slovenian Medical Ethics Committee. All patients with CHD and chronic RV pressure overload, including those with systemic RV (patients with transposition of the great arteries after atrial switch operation (TGA-AS) or patients with congenitally corrected transposition of the great arteries (CCTGA)) and patients with pulmonary arterial hypertension (PAH) and Eisenmenger syndrome, followed at the national referral centre for ACHD patients were invited to participate. Patients with acute or advanced chronic heart failure, uncontrolled arrhythmias, physical limitation precluding exercise testing or known genetic syndrome were excluded. After obtaining informed consent, each patient underwent a comprehensive multimodality study protocol that included echocardiography for assessment of RV systolic and diastolic function, single-photon emission computerized tomography (SPECT) for evaluation of RV ischemia and contrast enhanced cardiac magnetic resonance (CMR) for assessment of both focal (late gadolinium enhancement (LGE)) and diffuse (RV extracellular volume fraction (ECV)) RV fibrosis. Additionally, venous blood sampling for evaluation of different serum biomarkers (high-sensitivity troponin I, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and collagen turnover biomarkers) and cardiopulmonary exercise testing were also performed. Statistical analysis investigated the differences in clinical, laboratory, functional and imaging markers of the RV in patients with and without RV ischemia or fibrosis.
Results.
The final analysis included 32 adult patients with chronic RV pressure overload, including 15 patients with TGA-AS, 8 with CCTGA and 9 with ES. The mean age was 40 ± 10 years and 12 (33%) were women. Myocardial perfusion imaging with SPECT revealed reversible perfusion defects indicating RV ischemia in 12 patients (37%). No patient had chest pain, ischemic ECG changes or clinically important arrhythmias during exercise testing. In patients with RV ischemia, reversible perfusion defects were detected in a median of 1.5 (IQR [1-2]) RV segments and were most commonly observed in the anterior and free RV wall. There was no significant difference in RV ischemia between different patient subgroups (TGA-AS: 5 (33%), CCTGA: 2 (22%), ES: 5 (55%); p=0.41).
Contrast enhanced CMR was possible in 25 (78%) patients and late gadolinium enhancement (LGE) indicating focal RV fibrosis was detected in 12 patients (48%). There was no significant difference in focal RV fibrosis between different patient subgroups (TGA-AS: 5 (42%), CCTGA: 2 (33%), ES: 5 (71%); p=0.35). Average values of RV ECV, representing a marker of diffuse RV fibrosis, did not differ between patient subgroups (p=0.152) and 28% of patients had abnormal RV ECV.
Patients with confirmed RV ischemia more commonly had focal RV fibrosis, while there was no difference in the presence of diffuse RV fibrosis. Areas of LGE indicating focal RV fibrosis were present in 5 (31%) patients with normal RV perfusion and 7 (78%) patients with RV ischemia; p=0.041). Notably, subgroup analysis revealed that this association between RV ischemia and focal fibrosis was observed exclusively in patients with SRV (2 (15%) with normal RV perfusion vs 5 (100%) with RV ischemia, p=0.002), while patients with ES did not show the same relationship (3 (100%) vs 2 (50%), p=0.43).
Comparison of clinical characteristics of all included patients revealed that patients with RV ischemia were significantly older than those with normal RV perfusion (42.6 ± 11.0 vs 38.4 ± 10.6 years; p= 0.049). There were no significant differences in other clinical parameters, such as history of arrhythmias or heart failure. Patient subgroup analysis of laboratory, imaging and functional parameters showed that patients with ES and confirmed RV ischemia had significantly lower exercise capacity compared to those without RV ischemia (percent-predicted peak oxygen consumption 45.0±5.1 vs 56.7±2.9%, p=0.005). However, there was no other association between RV ischemia or focal RV fibrosis and other echocardiographic or CMR parameters of RV systolic or diastolic function in both groups of patients. Laboratory markers were also similar.
Conclusions.
Our single centre, multimodality study demonstrated that RV ischemia and focal RV fibrosis are prevalent in adult patients with CHD and chronic RV pressure overload. These findings support limited previous studies on this topic. The observed association between RV ischemia and focal RV fibrosis in patients with SRV suggests a possible pathophysiological link. However, due to the small sample size and other study limitations, larger studies are necessary to gain a better understanding of this concept, which could potentially lead to targeted therapy for preventing myocardial fibrosis. Interestingly, RV ischemia or fibrosis did not show any association with various imaging markers of RV systolic or diastolic dysfunction. This finding emphasizes the intricate and multifaceted nature of RV dysfunction, necessitating further investigation to uncover the precise underlying mechanisms. A better understanding of the interconnected relationship between RV ischemia, fibrosis, and dysfunction may pave the way for targeted therapies aimed at preventing the development of myocardial dysfunction in these patients.
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