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Aims: Myocardial calcification is an unusual condition in which excess calcium is deposited in the myocardium. Herein, we report two cases of myocardial calcification from our clinical experience. Furthermore, we conduct a systematic review to examine the clinical course and associated pathologies of myocardial calcification. Methods and results: This systematic review was registered in PROSPERO (CRD42023463285). PubMed and Scopus were searched according to the following inclusion criteria: (i) case reports or case series describing patients with myocardial calcification; (ii) diagnosis of myocardial calcification by computed tomography (CT); (iii) adequate description of patients, including their chief complaint, medical history, evaluations, and treatments; and (iv) publication in English. Among the 75 patients, 24 had sepsis, 14 had myocarditis, and 37 had other pathologies. The mortality rate was 33% for patients with sepsis, 14% for patients with myocarditis, and 11% for patients with other pathologies. Follow-up CT findings beyond 2 years were reported in six patients, showing that the CT findings of myocardial calcification persisted but subsided over time. Autopsy was performed in seven patients, and extensive interstitial fibrosis and collection of inflammatory cells were observed in patients with myocarditis, sepsis, and ischaemic heart disease. Conclusion: While various medical conditions can cause myocardial calcification, accompanying conditions commonly reported with myocardial calcification were sepsis and myocarditis. The CT findings of myocardial calcification tend to regress over time if the underlying disease can be treated.
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Ventricular-assist device therapy for small patients with congenital heart disease is challenging due to its complex anatomy and hemodynamics. We describe a 3-year-old patient with heart failure with truncus arteriosus in the palliative stage. The patient underwent palliative right ventricular outflow tract reconstruction following bilateral pulmonary artery banding. At 6 months of age, the patient developed severe truncal valve regurgitation and left ventricular dysfunction. Emergent truncal valve replacement with a mechanical valve was performed, but left ventricular dysfunction persisted. At 3 years of age, the patient developed acute progression of heart failure triggered by influenza infection. The patient was intubated and transferred to our center to determine the indication for heart transplantation. On the second day after admission, signs of multiorgan failure appeared. Emergent ventricular-assist device implantation for both ventricles was performed with truncal valve closure, ventricular septal defect closure, atrial septal defect closure, and re-right ventricular outflow tract reconstruction. The right ventricular-assist device was successfully removed on the seventh postoperative day. Due to the small pulmonary arteries, severe pulmonary stenosis persisted after ventricular-assist device implantation, but it gradually improved with multiple pulmonary angioplasties. The patient was registered in the Japanese organ transplant network and is awaiting a donor organ in a stable condition.
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BACKGROUND: Restrictive cardiomyopathy (RCM) is characterized by impaired diastolic function with preserved ventricular contraction. Several pathogenic variants in sarcomere genes, including TNNI3, are reported to cause Ca2+ hypersensitivity in cardiomyocytes in overexpression models; however, the pathophysiology of induced pluripotent stem cell (iPSC)-derived cardiomyocytes specific to a patient with RCM remains unknown. METHODS AND RESULTS: We established an iPSC line from a pediatric patient with RCM and a heterozygous TNNI3 missense variant, c.508C>T (p.Arg170Trp; R170W). We conducted genome editing via CRISPR/Cas9 technology to establish an isogenic correction line harboring wild type TNNI3 as well as a homozygous TNNI3-R170W. iPSCs were then differentiated to cardiomyocytes to compare their cellular physiological, structural, and transcriptomic features. Cardiomyocytes differentiated from heterozygous and homozygous TNNI3-R170W iPSC lines demonstrated impaired diastolic function in cell motion analyses as compared with that in cardiomyocytes derived from isogenic-corrected iPSCs and 3 independent healthy iPSC lines. The intracellular Ca2+ oscillation and immunocytochemistry of troponin I were not significantly affected in RCM-cardiomyocytes with either heterozygous or homozygous TNNI3-R170W. Electron microscopy showed that the myofibril and mitochondrial structures appeared to be unaffected. RNA sequencing revealed that pathways associated with cardiac muscle development and contraction, extracellular matrix-receptor interaction, and transforming growth factor-ß were altered in RCM-iPSC-derived cardiomyocytes. CONCLUSIONS: Patient-specific iPSC-derived cardiomyocytes could effectively represent the diastolic dysfunction of RCM. Myofibril structures including troponin I remained unaffected in the monolayer culture system, although gene expression profiles associated with cardiac muscle functions were altered.
Subject(s)
Cardiomyopathy, Restrictive , Induced Pluripotent Stem Cells , Child , Humans , Cardiomyopathy, Restrictive/genetics , Induced Pluripotent Stem Cells/metabolism , Mutation , Myocytes, Cardiac/metabolism , Troponin I/genetics , Troponin I/metabolismABSTRACT
Research on cardiomyopathy models using engineered heart tissue (EHT) created from disease-specific induced pluripotent stem cells (iPSCs) is advancing rapidly. However, the study of restrictive cardiomyopathy (RCM), a rare and intractable cardiomyopathy, remains at the experimental stage because there is currently no established method to replicate the hallmark phenotype of RCM, particularly diastolic dysfunction, in vitro. In this study, we generated iPSCs from a patient with early childhood-onset RCM harboring the TNNI3 R170W mutation (R170W-iPSCs). The properties of R170W-iPSC-derived cardiomyocytes (CMs) and EHTs were evaluated and compared with an isogenic iPSC line in which the mutation was corrected. Our results indicated altered calcium kinetics in R170W-iPSC-CMs, including prolonged tau, and an increased ratio of relaxation force to contractile force in R170W-EHTs. These properties were reversed in the isogenic line, suggesting that our model recapitulates impaired relaxation of RCM, i.e., diastolic dysfunction in clinical practice. Furthermore, overexpression of wild-type TNNI3 in R170W-iPSC-CMs and -EHTs effectively rescued impaired relaxation. These results highlight the potential efficacy of EHT, a modality that can accurately recapitulate diastolic dysfunction in vitro, to elucidate the pathophysiology of RCM, as well as the possible benefits of gene therapies for patients with RCM.
Subject(s)
Cardiomyopathies , Cardiomyopathy, Restrictive , Induced Pluripotent Stem Cells , Child , Child, Preschool , Humans , Cardiomyopathy, Restrictive/genetics , Cardiomyopathy, Restrictive/therapy , Mutation , Myocytes, Cardiac/physiologyABSTRACT
Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) and corrected disomy 21 (cDi21)-iPSCs. In T21-iPSC-derived ECs, apoptosis and mitochondrial reactive oxygen species (mROS) were significantly increased, and angiogenesis and oxygen consumption rate (OCR) were significantly impaired as compared with cDi21-iPSC-derived ECs. The RNA-sequencing identified that EGR1 on chromosome 5 was significantly upregulated in T21-ECs. Both EGR1 suppression by siRNA and pharmacological inhibitor could recover the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Alternately, the study also revealed that DYRK1A was responsible to increase EGR1 expression via PPARG suppression, and that chemical inhibition of DYRK1A could restore the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Finally, we demonstrated that EGR1 was significantly upregulated in the pulmonary arterial ECs from lung specimens of a patient with DS and PAH. In conclusion, DYRK1A/PPARG/EGR1 pathway could play a central role for the pulmonary EC functions and thus be associated with the pathogenesis of PAH in DS.
Subject(s)
Down Syndrome , Hypertension, Pulmonary , Induced Pluripotent Stem Cells , Pulmonary Arterial Hypertension , Humans , Induced Pluripotent Stem Cells/metabolism , Cell Differentiation/genetics , Endothelial Cells/metabolism , Down Syndrome/complications , Down Syndrome/genetics , Down Syndrome/metabolism , Hypertension, Pulmonary/genetics , PPAR gamma/metabolism , Pulmonary Arterial Hypertension/metabolism , Cells, Cultured , Early Growth Response Protein 1/genetics , Early Growth Response Protein 1/metabolismABSTRACT
Although pediatric pulmonary hypertension (PH) shares features and mechanisms with adult PH, there are also some significant differences between the two conditions. Segmental PH is a unique pediatric subtype of PH with unclear and/or multifactorial pathophysiological mechanisms, and is often associated with complex congenital heart disease (CHD), pulmonary atresia with ventricular septal defect, and aortopulmonary collateral arteries. Some cases of complex CHD, associated with a single ventricle after Fontan operation, show pathological changes in the small peripheral pulmonary arteries and pulmonary vascular resistance similar to those observed in pulmonary arterial hypertension (PAH). This condition is termed as the pediatric pulmonary hypertensive vascular disease (PPHVD). Recent advances in genetics have identified the genes responsible for PAH associated with developmental defects of the heart and lungs, such as TBX4 and SOX17. Targeted therapies for PAH have been developed; however, their effects on PH associated with developmental heart and lung defects remain to be established. Real-world data analyses on the anatomy, pathophysiology, genetics, and molecular biology of unique PPHVD cases associated with developmental defects of the heart and lungs, using nationwide and/or international registries, should be conducted in order to improve the treatments and prognosis of patients with these types of pediatric PH.
ABSTRACT
Background Dilated cardiomyopathy (DCM) is a major cause of heart failure in children. Despite intensive genetic analyses, pathogenic gene variants have not been identified in most patients with DCM, which suggests that cardiomyocytes are not solely responsible for DCM. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. They have several roles in maintaining cardiac function; however, the pathological role of CFs in DCM remains unknown. Methods and Results Four primary cultured CF cell lines were established from pediatric patients with DCM and compared with 3 CF lines from healthy controls. There were no significant differences in cellular proliferation, adhesion, migration, apoptosis, or myofibroblast activation between DCM CFs compared with healthy CFs. Atomic force microscopy revealed that cellular stiffness, fluidity, and viscosity were not significantly changed in DCM CFs. However, when DCM CFs were cocultured with healthy cardiomyocytes, they deteriorated the contractile and diastolic functions of cardiomyocytes. RNA sequencing revealed markedly different comprehensive gene expression profiles in DCM CFs compared with healthy CFs. Several humoral factors and the extracellular matrix were significantly upregulated or downregulated in DCM CFs. The pathway analysis revealed that extracellular matrix receptor interactions, focal adhesion signaling, Hippo signaling, and transforming growth factor-ß signaling pathways were significantly affected in DCM CFs. In contrast, single-cell RNA sequencing revealed that there was no specific subpopulation in the DCM CFs that contributed to the alterations in gene expression. Conclusions Although cellular physiological behavior was not altered in DCM CFs, they deteriorated the contractile and diastolic functions of healthy cardiomyocytes through humoral factors and direct cell-cell contact.
Subject(s)
Cardiomyopathy, Dilated , Fibroblasts , Heart Failure , Child , Humans , Fibroblasts/metabolism , Heart Failure/metabolism , Myocytes, Cardiac/metabolism , Signal TransductionABSTRACT
BACKGROUND: Restrictive cardiomyopathy in children is rare and outcomes are very poor. However, little information is available concerning genotype-outcome correlations. METHODS: We analyzed the clinical characteristics and genetic testing, including whole exome sequencing, of 28 pediatric restrictive cardiomyopathy patients who were diagnosed from 1998 to 2021 at Osaka University Hospital in Japan. RESULTS: The median age at diagnosis (interquartile range) was 6 (2.25-8.5) years. Eighteen patients received heart transplantations and 5 patients were on the waiting list. One patient died while waiting for transplantation. Pathologic or likely-pathogenic variants were identified in 14 of the 28 (50%) patients, including heterozygous TNNI3 missense variants in 8 patients. TNNT2, MYL2, and FLNC missense variants were also identified. No significant differences in clinical manifestations and hemodynamic parameters between positive and negative pathogenic variants were detected. However, 2- and 5-year survival rates were significantly lower in patients with pathogenic variants (50% and 22%) compared with survival in patients without pathogenic variants (62% and 54%; P=0.0496, log-rank test). No significant differences were detected in the ratio of patients diagnosed at nationwide school heart disease screening program between positive and negative pathogenic variants. Patients diagnosed by school screening showed better transplant-free survival compared with patients diagnosed by heart failure symptoms (P=0.0027 in log-rank test). CONCLUSIONS: In this study, 50% of pediatric restrictive cardiomyopathy patients had pathogenic or likely-pathogenic gene variants, and TNNI3 missense variants were the most frequent. Patients with pathogenic variants showed significantly lower transplant-free survival compared with patients without pathogenic variants.
Subject(s)
Cardiomyopathy, Restrictive , Heart Diseases , Humans , Child , Cardiomyopathy, Restrictive/diagnosis , Cardiomyopathy, Restrictive/genetics , Genetic Testing , Genotype , Heterozygote , Mutation, Missense , Heart Diseases/geneticsABSTRACT
Cardiac allograft vasculopathy (CAV) sometimes leads to restenosis, even after percutaneous transcatheter intervention. Recently, drug-coated balloons (DCBs) have been successfully used to treat coronary artery disease, especially CAVs, in adults. However, no studies have used DCBs in pediatric CAVs. We encountered a patient with CAV who underwent cardiac transplantation for restrictive cardiomyopathy at the age of 2 years. Nine years after the transplantation, severe stenosis of the proximal left anterior descending branch was observed. Considering the patient's young age and the possibility of restenosis, we performed an intervention with DCB. Follow-up conducted 7 months after the intervention showed no restenosis. Cardiac coronary artery lesions following transplantation are more likely to result in restenosis earlier than arteriosclerotic lesions. In pediatric patients, restenosis might require multiple stents and prolonged antiplatelet therapy. Our findings provide evidence supporting the possibility of an effective treatment of CAV in children.
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OBJECTIVES: The goal of this study was to identify the clinical significance of the deoxyribonucleic acid (DNA) damage response marker, phosphorylated H2A histone variant X, on the bridge to recovery in low-weight paediatric patients with dilated cardiomyopathy (DCM) after having a Berlin Heart EXCOR implanted. METHODS: Consecutive paediatric patients with DCM who had an EXCOR implanted for DCM at our hospital between 2013 and 2021 were reviewed. Patients were classified into 2 groups according to the degree of DNA damage in the left ventricular cardiomyocytes-the low DNA damage group and the high DNA damage group-using the median value as the threshold. We examined and compared the preoperative factors and histologic findings associated with cardiac functional recovery following the explant procedure in the 2 groups. RESULTS: Competing outcome analysis of 18 patients (median body weight, 6.1 kg) showed that the incidence of an EXCOR explant was 40% at 1 year after the implant procedure. Serial echocardiography revealed significant left ventricular functional recovery in the low DNA damage group 3 months after the implant. The univariable Cox proportional hazards model revealed that the percentage of phosphorylated H2A histone variant X-positive cardiomyocytes was the significant factor associated with cardiac recovery and the EXCOR explant (hazard ratio, 0.16; 95% confidence interval, 0.027-0.51; P = 0.0096). CONCLUSIONS: The degree of DNA damage response to the EXCOR implant may aid in predicting the bridge to recovery with EXCOR among low-weight paediatric patients with DCM.
Subject(s)
Cardiomyopathy, Dilated , Heart Failure , Heart Transplantation , Heart-Assist Devices , Child , Humans , Heart Failure/surgery , Cardiomyopathy, Dilated/surgery , Myocytes, Cardiac , Histones , Heart-Assist Devices/adverse effects , DNAABSTRACT
Impella is a device effective for the treatment of cardiogenic shock. However, among small children, its application has limitations due to left ventricle size and vasculature and the turning diameter of the aortic arch. Herein, we report an 11-year-old girl with fulminant myocarditis who was successfully managed with Impella CP implantation via the right subclavian artery using a polyethylene terephthalate chimney graft. Compared with insertion via the femoral artery, this method has several advantages. That is, it can address limitations in aortic arch diameter and facilitate equable fixation of the Impella device in small pediatric patients.
Subject(s)
Heart-Assist Devices , Myocarditis , Female , Humans , Child , Myocarditis/complications , Myocarditis/surgery , Treatment Outcome , Shock, Cardiogenic/etiology , Shock, Cardiogenic/surgery , ArteriesABSTRACT
BACKGROUND: Although widely reported to affect older adults more, coronavirus disease 2019 (COVID-19) also affects adolescents, especially those with co-morbidities, including heart diseases. The safety and efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines has been established in healthy adolescents, yet there are few data for humoral and cellular immunogenicity in adolescents with cardiac diseases. METHODS: We evaluated anti-spike antibodies, neutralizing activities, and interferon-gamma production prior to and after SARS-CoV-2 vaccination in adolescents with cardiac diseases and healthy controls. RESULTS: Five healthy adolescents and 26 patients with cardiac diseases, including congenital heart disease (CHD, n = 10), dilated cardiomyopathy (DCM, n = 4), idiopathic pulmonary arterial hypertension (IPAH, n = 4), and those post-heart transplantation (post-HTx, n = 8) were enrolled. No severe adverse events, including myocarditis and pericarditis, were noted, even in patients with severe heart failure. Febrile events were noted after 21 of 62 injections (34%). All the healthy adolescents and 21 of the 26 patients (81%) showed sufficient elevation of neutralizing antibodies after the second dose of vaccination. Neutralizing antibodies and cellular immunity were absent in four of the eight post-HTx patients and one with single ventricle CHD. There was no correlation between the anti-spike and neutralizing antibody titers and interferon-gamma levels. When comparing the clinical characteristics of the patients post-HTx who did or did not acquire antibodies, there was no significant difference in the immunosuppressant types and trough levels. CONCLUSIONS: SARS-CoV-2 mRNA vaccine has efficient immunogenicity for adolescents with CHD, IPAH, and DCM. Half of post-HTx patients could not acquire sufficient humoral immunity.
Subject(s)
COVID-19 , Heart Diseases , Viral Vaccines , Adolescent , Humans , Aged , COVID-19 Vaccines , SARS-CoV-2 , COVID-19/prevention & control , Interferon-gamma , Antibodies, Viral , Viral Vaccines/adverse effects , Antibodies, Neutralizing , Vaccination , Heart Diseases/chemically induced , mRNA VaccinesABSTRACT
Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT-CHILD (NCT02562235), a multicenter, single-arm, 24-week, open-label, Phase 3 study. Patients aged 6-17 years in World Health Organization functional class (WHO-FC) I-III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5-2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty-four patients (mean age 12.8 years), 18 of whom were in WHO-FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study-drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6-minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT-proBNP was -66 ± 585 pg/ml (n = 14). There was no change in WHO-FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.
ABSTRACT
Restrictive cardiomyopathy (RCM) is a rare disease characterized by increased ventricular stiffness and preserved ventricular contraction. Various sarcomere gene variants are known to cause RCM; however, more than a half of patients do not harbor such pathogenic variants. We recently demonstrated that cardiac fibroblasts (CFs) play important roles in inhibiting the diastolic function of cardiomyocytes via humoral factors and direct cell-cell contact regardless of sarcomere gene mutations. However, the mechanical properties of CFs that are crucial for intercellular communication and the cardiomyocyte microenvironment remain less understood. In this study, we evaluated the rheological properties of CFs derived from pediatric patients with RCM and healthy control CFs via atomic force microscopy. Then, we estimated the cellular modulus scale factor related to the cell stiffness, fluidity, and Newtonian viscosity of single cells based on the single power-law rheology model and analyzed the comprehensive gene expression profiles via RNA-sequencing. RCM-derived CFs showed significantly higher stiffness and viscosity and lower fluidity compared to healthy control CFs. Furthermore, RNA-sequencing revealed that the signaling pathways associated with cytoskeleton elements were affected in RCM CFs; specifically, cytoskeletal actin-associated genes (ACTN1, ACTA2, and PALLD) were highly expressed in RCM CFs, whereas several tubulin genes (TUBB3, TUBB, TUBA1C, and TUBA1B) were down-regulated. These results implies that the signaling pathways associated with cytoskeletal elements alter the rheological properties of RCM CFs, particularly those related to CF-cardiomyocyte interactions, thereby leading to diastolic cardiac dysfunction in RCM.
Subject(s)
Cardiomyopathy, Restrictive , Actins , Child , Fibroblasts , Heart Murmurs , Humans , Microscopy, Atomic Force , Myocytes, Cardiac , RNA , Rheology , TubulinABSTRACT
Pulmonary atresia and ventricular septal defect (PA/VSD) demonstrate a wide variety of pulmonary and coronary artery abnormalities; additionally, coronary-to-pulmonary artery fistula (CPAF) is a rare manifestation of PA/VSD and is seldom detected during pregnancy. In this report, we present a case of prenatal diagnosis of CPAF in PA/VSD and impactful images in a neonate, which were obtained using fetal echocardiography and postnatal electrocardiography-gated 320-row CT. Prenatal diagnosis of CPAF can facilitate the provision of better therapeutic strategies after birth.
Subject(s)
Coronary Artery Disease , Fistula , Heart Septal Defects, Ventricular , Pulmonary Atresia , Female , Fetus , Heart Septal Defects, Ventricular/diagnostic imaging , Humans , Infant, Newborn , Pregnancy , Prenatal Diagnosis , Pulmonary Artery/abnormalities , Pulmonary Artery/diagnostic imaging , Pulmonary Atresia/diagnostic imagingSubject(s)
Aortic Coarctation , Aorta, Thoracic , Aortic Coarctation/complications , Aortic Coarctation/diagnosis , Child , Heart , Humans , Male , Schools , ThoraxABSTRACT
OBJECTIVES: High concentrations of low-density lipoprotein cholesterol (LDL-C) are a risk factor for cardiovascular disease. We validated the efficacy of the Martin method is useful in the estimation of LDL-C concentrations was validated in Japanese populations and derived a modified Martin method for easy laboratory information system applications. METHODS: We created 3 subject groups, including 2664 health check-up participants registered with the Resource Center for Health Science, 29,806 clinical patients (A) in the Gifu University Hospital, and 113,716 clinical patients (B) in the Fujita Health University Hospital. Each method to estimate serum LDL-C concentrations (Friedewald formula, Martin method and modified Martin method) was validated by correlation analysis with serum LDL-C concentrations measured using a direct method. RESULTS: The correlation coefficients with the direct method in terms of the Friedewald formula, Martin method, and modified Martin method were 0.963, 0.972 and 0.970 in the health check-up participants; 0.946, 0.962 and 0.961 in clinical patients A; and 0.961, 0.979 and 0.978 in clinical patients B, respectively. Concordance ratios with using the direct method in the Friedewald formula, Martin method and modified Martin method were 82.8%, 85.5% and 85.3% in the health check-up participants; 76.4%, 80.5% and 80.2% in clinical patients A; and 76.1%, 82.6% and 82.6% in clinical patients B, respectively. CONCLUSION: Our results show that the Martin and modified Martin methods display good performance in terms of the estimation of LDL-C concentrations among triglyceride concentrations of a wide range, and they may thus be useful for estimating LDL-C concentrations.
Subject(s)
Cardiovascular Diseases , Clinical Laboratory Information Systems , Cardiovascular Diseases/diagnosis , Cholesterol, LDL , Humans , Japan , TriglyceridesABSTRACT
BACKGROUND: There has been no nationwide survey on the prognosis of pediatric restrictive cardiomyopathy (RCM) in Japan; therefore, this retrospective multicentered study was designed to investigate the long-term survival rate of pediatric patients with RCM in Japan.MethodsâandâResults: A multicentered, retrospective observational study was performed between 1990 and 2014 and included patients diagnosed with RCM who were aged <18 years from 18 Japanese institutions. A total of 54 patients were diagnosed with RCM. The median age at diagnosis was 4.4 years, and the median duration of observation was 2.2 years at the time of this study. Of these patients, 54% had symptoms, including heart failure. Twelve patients died without heart transplantation, mostly due to heart failure. The median time to death from diagnosis was 2.5 years. Freedom from death at 1, 5, and 10 years was 91%, 68%, and 62%, respectively. Death occurred within 5 years of diagnosis in most patients. Twenty-two patients underwent heart transplantation. Freedom from heart transplantation at 1, 5, and 10 years was 77%, 58%, and 53%, respectively. Freedom from death or heart transplantation at 1, 5, and 10 years was 72%, 40%, and 34%, respectively. The presence of symptoms was a risk factor for death or transplantation. CONCLUSIONS: The prognosis of pediatric RCM is poor, and the heart transplantation rate is low in Japan.
Subject(s)
Cardiomyopathy, Restrictive , Heart Failure , Heart Transplantation , Humans , Child , Cardiomyopathy, Restrictive/therapy , Cardiomyopathy, Restrictive/etiology , Retrospective Studies , Japan/epidemiology , Heart Transplantation/adverse effects , Heart Failure/therapy , Heart Failure/complicationsABSTRACT
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature neonates. Classical BPD is caused by hyperoxia and high-pressure mechanical ventilation, whereas BPD in recent era is caused by impaired pulmonary angiogenesis and alveolarization in extreme prematurity. Although sildenafil was reported to be effective in a hyperoxia-induced rat BPD model, several clinical trials could not demonstrate any significant improvement in the respiratory statuses of BPD infants. Riociguat is a soluble guanylate cyclase stimulator that increases cyclic guanosine monophosphate activity in a nitric oxide independent manner. However, a beneficial effect in BPD has not been established yet. METHODS AND RESULTS: We established BPD model in rats by injection of SU5416 on day 1 followed by maintenance under normoxia, which resulted in oversimplified alveoli, sparse pulmonary capillary vessels, severe pulmonary hypertension, and growth retardation, which mimicked the features observed in recent clinical management of BPD. We administered riociguat from day 10, when BPD rats exhibited growth retardation. Histological analyses demonstrated that riociguat treatment significantly but partially ameliorated lung alveolarization, vascularization, and pulmonary hypertension. However, the survival rate was not significantly improved by riociguat treatment. CONCLUSIONS: Riociguat could ameliorate pulmonary alveolarization, vascularization, and hypertension in the SU5416 induced BPD rat model, but could not improve the overall survival.