Restrictive cardiomyopathy: from genetics and clinical overview to animal modeling.

Restrictive cardiomyopathy (RCM), a potentially devastating heart muscle disorder, is characterized by diastolic dysfunction due to abnormal muscle relaxation and myocardial stiffness resulting in restrictive filling of the ventricles. Diastolic dysfunction is often accompanied by left atrial or bi-atrial enlargement and normal ventricular size and systolic function. RCM is the rarest form of cardiomyopathy, accounting for 2-5% of pediatric cardiomyopathy cases, however, survival rates have been reported to be 82%, 80%, and 68% at 1-, 2-, and 5-years after diagnosis, respectively. RCM can be idiopathic, familial, or secondary to a systemic disorder, such as amyloidosis, sarcoidosis, and hereditary hemochromatosis. Approximately 30% of cases are familial RCM, and the genes that have been linked to RCM are cTnT, cTnI, MyBP-C, MYH7, MYL2, MYL3, DES, MYPN, TTN, BAG3, DCBLD2, LNMA, and FLNC. Increased Ca2+ sensitivity, sarcomere disruption, and protein aggregates are some of the few mechanisms of pathogenesis that have been revealed by studies utilizing cell lines and animal models. Additional exploration into the pathogenesis of RCM is necessary to create novel therapeutic strategies to reverse restrictive cardiomyopathic phenotypes.

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology.

Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.

Third time lucky: challenging secundum atrial septal defect.

Secundum atrial septal defect is the most common form of interatrial communication. Atrial septal defects can present in young adults with a variety of clinical presentations, including breathlessness on effort, palpitations, or stroke. Clinical heart failure and resting desaturation are both rarely seen in young patients. We present a case of a young man with a secundum atrial septal defect and a diagnosis of constrictive pericarditis, only made after two attempts at surgical correction of the atrial septal defect, with pericardiectomy at the third attempt and subsequent symptomatic improvement.

Stiff right atrial syndrome? A complex clinical case report utilizing multimodality imaging and invasive hemodynamics.

Background: Stiff left atrial syndrome is a well-established cause of heart failure symptoms. A parallel entity involving the right atrium (RA) has not previously been described. We present a case of refractory right heart failure (RHF) 12 years following orthotopic heart transplantation. Case summary: Patient underwent annuloplasty ring placement for severe tricuspid regurgitation in 2018 and kidney transplantation in 2020. The use of multimodality imaging and a multidisciplinary approach suggested a stiff RA as a potential etiology to refractory symptoms. Redo-heart and kidney transplantation in March 2021 led to the resolution of symptoms without recurrence. Discussion: We propose stiff right atrial syndrome that may need to be considered in the setting of refractory RHF primarily suggested by significant right atrial enlargement and restrictive physiology.

Coconut Atrium Causing Restrictive Physiology in the Right Ventricle.

We herein report a 61-year-old woman with a history of mitral valve replacement for rheumatic fever who presented with crural edema and ascites. Computed tomography showed massive left atrial (LA) calcification involving the interatrial septum, termed "coconut atrium." Catheterization revealed not only pulmonary artery hypertension but also a large V-wave in the pulmonary artery wedge pressure waveform and a dip-and-plateau pattern of right ventricular pressure. Three-dimensional transthoracic echocardiography confirmed the early attainment of peak LA volume and a decreased LA expansion index. Stiff LA syndrome due to coconut LA results in the development of restrictive right ventricular physiology.

Percutaneous Repair of Atrial Functional Tricuspid Regurgitation in Cardiac Amyloidosis: Combining Linear With Lateral Thinking.

Restrictive physiology, such as cardiac amyloidosis, compromises atrial and ventricular performance, often leading to "atrial" functional valvular regurgitation. While focusing on atrial functional tricuspid regurgitation we aimed at summarizing the pathophysiological characteristics of, and therapeutic options in, cardiac amyloidosis. (Level of Difficulty: Intermediate.).

End-diastolic forward flow in repaired tetralogy of Fallot: Mid-term outcomes from a single center.

Background: Pulmonary arterial end-diastolic forward flow (EDFF) following repaired tetralogy of Fallot (rTOF) is recognized as right ventricular (RV) restrictive physiology, which is closely related to poor prognosis. This study sought to review mid-term experience and investigate the risk factors of EDFF in the rTOF patients. Methods: From September 2016 to January 2019, 100 patients (age < 18 years old) who underwent complete tetralogy of Fallot (TOF) repair were enrolled and were divided into EDFF group (n = 52) and non-EDFF group (n = 48) based on the presence of postoperative EDFF. Elastic net analysis was performed for variable selection. Univariate and multivariate logistic analyses were used to analyze the correlation between risk factors and EDFF. Results: End-diastolic forward flow group had lower systolic blood pressure (P = 0.037), diastolic blood pressure (P = 0.027), and higher vasoactive-inotrope score within 24 h after surgery (P = 0.022) than non-EDFF group. Transannular patch (TAP) was an independent predictor of postoperative EDFF [P = 0.029, OR: 2.585 (1.102∼6.061)]. Patients were followed up for a median of 2.6 years [interquartile range (IQR) 1.6] after the first TOF repair. During follow-up, the prevalence of the EDFF was lower in those with pulmonary valve (PV) reconstructions than that in those undergoing patch enlargement without PV reconstructions in the primary TOF repair (P < 0.001). Conclusion: End-diastolic forward flow was associated with TAP. Patients with EDFF might have a transient hemodynamic instability in the early postoperative period. PV reconstructions in the TOF repair might reduce the incidence of EDFF in the mid-term follow-up.

End-Diastolic Forward Flow and Restrictive Physiology in Repaired Tetralogy of Fallot: A Systematic Review and Meta-Analysis.

Background Pulmonary arterial end-diastolic forward flow (EDFF) following repaired tetralogy of Fallot has been thought to represent right ventricular (RV) restrictive physiology, but is not fully understood. This systematic review and meta-analysis sought to clarify its physiological and clinical correlates, and to define a framework for understanding EDFF and RV restrictive physiology. Methods and Results PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for observational studies published before March 2021. Random-effects meta-analysis was performed to identify factors associated with EDFF. Forty-two individual studies published between 1995 and 2021, including a total of 2651 participants (1132 with EDFF; 1519 with no EDFF), met eligibility criteria. The pooled estimated prevalence of EDFF among patients with repaired tetralogy of Fallot was 46.5% (95% CI, 41.6%-51.3%). Among patients with EDFF, the use of a transannular patch was significantly more common, and their stay in the intensive care unit was longer. EDFF was associated with greater RV indexed volumes and mass, as well as smaller E-wave velocity at the tricuspid valve. Finally, pulmonary regurgitation fraction was greater in patients with EDFF, and moderate to severe pulmonary regurgitation was more common in this population. Conclusions EDFF is associated with dilated, hypertrophied RVs and longstanding pulmonary regurgitation. Although several studies have defined RV restrictive physiology as the presence of EDFF, our study found no clear indicators of poor RV compliance in patients with EDFF, suggesting that EDFF may have multiple causes and might not be the precise equivalent of RV restrictive physiology.

Cardiogenic Shock Due to Atrial Arrhythmia as the Initial Presentation of Transthyretin Cardiac Amyloidosis.

Atrial arrhythmias are common in transthyretin cardiac amyloidosis (ATTR-CA), with a prevalence of ≤80%. They are often not well tolerated. We describe 3 patients with decompensated heart failure and cardiogenic shock precipitated by atrial arrhythmias who ultimately received diagnoses of ATTR-CA. (Level of Difficulty: Intermediate.).

Quantification of end diastolic forward flow in two cases with pulmonary atresia with intact ventricular septum.

Similar to patients with repaired tetralogy of Fallot, patients with repaired pulmonary atresia with intact ventricular septum may need a reintervention at a later stage. Although the role of MRI in the long-term follow-up of patients with repaired tetralogy of Fallot has been established, the same has not been established for patients with repaired pulmonary atresia with intact ventricular septum. To define this role, we quantified the end-diastolic forward flow by fractioning it by the total flow of the main pulmonary artery in two cases during their long-term follow up after biventricular repair. In case 1, a male patient had hepatic congestion and a high end-diastolic forward flow fraction and underwent surgical take down to one and one-half ventricle repair at the age of 18 years. In case 2, a female patient, currently 13 years old, has an increasing end-diastolic forward flow fraction. She is under close observation as a potential candidate for one and one-half ventricle repair in the near future. Both patients had a high end-diastolic forward flow fraction of the total right ventricle output, suggesting that end-diastolic forward flow fraction may become a possible become a possible indicator of the adequacy of biventricular repair and the optimal timing for re-intervention.

Hypertrophic Cardiomyopathy and Primary Restrictive Cardiomyopathy: Similarities, Differences and Phenocopies.

Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These "sarcomeric cardiomyopathies" also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy.

Echocardiographic predictors of severe right ventricular diastolic dysfunction in tetralogy of Fallot: Relations to patient outcomes.

BACKGROUND: Previous studies have described echocardiographic indices of right ventricular (RV) diastolic function in patients with tetralogy of Fallot (TOF) but these indices have not been validated against invasive hemodynamic data. The purpose of this study was to determine echocardiographic predictors of severe RV diastolic dysfunction, and the impact of severe RV diastolic dysfunction on transplant-free survival. METHODS: Cohort study of TOF patients that underwent non-simultaneous cardiac catheterization and echocardiogram at Mayo Clinic. Based on prior studies we selected these indices for assessment: tricuspid E/A, E/e', deceleration time, pulmonary artery forward flow, dilated inferior vena cava (IVC), and hepatic vein diastolic flow reversal (HVDFR). RV diastolic function classes (normal, mild/moderate and severe dysfunction) were created using arbitrary cut-off points of the median values of right ventricular end-diastolic pressure (RVEDP) and right atrial pressure (RAP) for the cohort. RESULTS: Among 173 patients (age 40 ± 13 years), 68 patients were classified as normal (RVEDP≤14 and RAP≤10), 37 as mild/moderate dysfunction (either RVEDP>14 or RAP>10), and 69 as severe dysfunction (RVEDP>14 and RAP>10). Of the indices assessed, dilated IVC had the best sensitivity of 95% (area under the curve [AUC] 0.689) while HVDFR had the best specificity of 69% (AUC 0.648) for detecting severe RV diastolic dysfunction. Severe RV diastolic dysfunction was an independent risk factor for death/transplant (hazard ratio 2.83, p = 0.009). CONCLUSION: Severe RV diastolic dysfunction, as defined by invasive hemodynamic indices, was associated with poor prognosis. Echocardiographic indices can identify these high risk patients, and hence improve risk stratification in clinical practice.

Early signs of right ventricular systolic and diastolic dysfunction in acute severe respiratory failure: the importance of diastolic restrictive pattern.

BACKGROUND: The incidence and pathophysiology of right ventricular failure in patients with severe respiratory insufficiency has been largely investigated. However, there is a lack of early signs suggesting right ventricular systolic and diastolic dysfunction prior to acute cor pulmonale development. METHODS: We conducted a retrospective analytical cohort study of patients for acute respiratory distress syndrome undertaking an echocardiography during admission in the cardiothoracic intensive care unit. Patients were divided according to treatment: conventional protective ventilation (38 patients, 38%); interventional lung assist (23 patients, 23%); veno-venous extracorporeal membrane oxygenation (37 patients, 37%). Systolic and diastolic function was studied assessing, respectively: right ventricular systolic longitudinal function (tricuspid annular plane systolic excursion) and systolic contraction duration (tricuspid annular plane systolic excursion length); right ventricular diastolic filling time and right ventricular diastolic restrictive pattern (presence of pulmonary valve presystolic ejection wave). Correlation between the respiratory mechanics and systo-diastolic parameters were analysed. RESULTS: In 98 patients studied, systolic dysfunction (tricuspid annular plane systolic excursion <16 mm) was present in 33.6% while diastolic restrictive pattern was present in 64%. A negative correlation was found between tricuspid annular plane systolic excursion and tricuspid annular plane systolic excursion length (P<0.0001; r -0.42). Tricuspid annular plane systolic excursion and tricuspid annular plane systolic excursion length correlated with right ventricular diastolic filling time (P<0.001; r -0.39). Pulmonary valve presystolic ejection wave was associated with tricuspid annular plane systolic excursion (P<0.0001), tricuspid annular plane systolic excursion length (P<0.0001), right ventricular diastolic filling time (P<0.0001), positive end-expiratory pressure (P<0.0001) and peak inspiratory pressure (P<0.0001). CONCLUSION: Diastolic restrictive pattern is present in a remarkable percentage of patients with respiratory distress syndrome. Bedside echocardiography allows a mechanistic evaluation of systolic and diastolic interaction of the right ventricle.

Etiology of right ventricular restrictive physiology early after repair of tetralogy of Fallot in pediatric patients.

BACKGROUND: Right ventricular restrictive physiology (RVRP) is a common finding after repair of Tetralogy of Fallot (TOF). The characteristic feature of RVRP is the presence of a direct end-diastolic flow (EDFF) during atrial contraction in the main pulmonary artery. This end-diastolic forward flow is caused by increased right ventricular end-diastolic pressure due to right ventricular myocardial stiffness and decreased right ventricular compliance. OBJECTIVE: Our main objective is to found out the etiology of RVRP in pediatrics patients who underwent for complete repair of Tetralogy of Fallot (TOF). METHODS: A total of 50 TOF patients have registered for this study in our hospital from January 2017 to September 2018. The patients were divided in two groups, group A with restrictive physiology and group B without restrictive physiology. The patients selected for this study includes TOF patients, TOF patients with atrial septal defect (ASD), and TOF patients with patent ductus arteriosus (PDA). Ventricular hypertrophy and right heart enlargement were evaluated by electrocardiogram and echocardiography. The other parameters we used to compare between these two groups were sex, age, weight, cardio pulmonary bypass (CPB) time, aortic cross clamping time, transannular patch, SP02, RV/LV pressure, ventricular hypertrophy, right heart (RH) enlargement, tricuspid annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure (PASP), TAPSE/PASP ratio, pulmonary annular diameter, intubation time, PICU stay and hematocrit (HCT). RESULTS: RVRP was identified in 28 patients (58%). Lower SP02 (mean: 84.3 ± 7.9%) with p-value 0.015, transannular patch repair (n = 22, 78.5%) with p-value< 0.001, longer cardiopulmonary bypass (CPB) time (mean: 117.6 ± 23 min) with p-value< 0.001, longer aortic cross clamping time (mean: 91.4 ± 20.26 min) with p-value< 0.001, lower TAPSE, lower PASP,lower TAPSE/PASP ratio and presence of hypertrophy (p-value < 0.001) were identified as etiology for restrictive physiology. It was also found that 77% TOF patients with ASD have a higher risk of RVRP in our study. CONCLUSIONS: In TOF patient's etiology for right ventricular restrictive physiology are associated with lower SP02, transannular patch repair, longer CPB and longer aortic cross clamping time, hypertrophy, lower TAPSE, lower PASP and lower TAPSE/PASP ratio.

Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease.

OBJECTIVES: The aim of this study was to identify a unifying cardiac pathophysiology that explains the cardiac pathological features in sickle cell disease (SCD). BACKGROUND: Cardiopulmonary complications, the leading cause of adult death in SCD, are associated with heart chamber dilation, diastolic dysfunction, elevated tricuspid regurgitant jet velocity (TRV), and pulmonary hypertension. However, no unifying cardiac pathophysiology has been identified to explain these findings. METHODS: In a 2-part study, we first examined patients with SCD who underwent screening echocardiography during steady state at our institution. We then conducted a meta-analysis of cardiac studies in SCD. RESULTS: In the 134 patients with SCD studied (median age 11 years), significant enlargement of the left atrial volume was present (z-score 3.1, p = 0.002), shortening fraction was normal (37.6 ± 4.7%), and lateral and septal ratios of mitral velocity to early diastolic velocity of the mitral annulus (E/e') were severely abnormal in 8% and 14% of patients, respectively, indicating impaired diastolic function. Both TRV and lateral E/e' correlated with enlarged left atrial volume in SCD (p = 0.003 and p = 0.006, respectively). Meta-analysis of 68 studies confirmed significant left atrial diameter enlargement in patients with SCD compared with controls, evidence of diastolic dysfunction and enlarged left ventricular end-diastolic dimension with normal shortening fraction. The majority of patients with catheter-confirmed pulmonary hypertension had mild pulmonary venous hypertension consistent with restrictive cardiac physiology. CONCLUSIONS: Patients with SCD have a unique form of cardiomyopathy with restrictive physiology that is superimposed on hyperdynamic physiology and is characterized by diastolic dysfunction, left atrial dilation, and normal systolic function. This combination results in mild, secondary, pulmonary venous hypertension and elevated TRV. Sudden death is common in other forms of restrictive cardiomyopathy. Our finding of this unique restrictive cardiomyopathy may explain the increased mortality rates and sudden death seen in patients with SCD with mildly elevated TRV.

Invasive hemodynamics of constrictive pericarditis.

Cardiac catheterization and hemodynamic study is the gold standard for the diagnosis of pericardial constriction. Careful interpretation of the hemodynamic data is essential to differentiate it from other diseases with restrictive physiology. In this hemodynamic review we shall briefly discuss the physiologic basis of various hemodynamic changes seen in a patient with constrictive pericarditis.

"Pulmonary valve replacement diminishes the presence of restrictive physiology and reduces atrial volumes": a prospective study in Tetralogy of Fallot patients.

Pulmonary valve replacement (PVR) reduces right ventricular (RV) volumes in the setting of long-term pulmonary regurgitation after Tetralogy of Fallot (ToF) repair; however, little is known of its effect on RV diastolic function. Right atrial volumes may reflect the burden of RV diastolic dysfunction. The objective of this paper is to evaluate the clinical, echocardiographic, biochemical and cardiac magnetic resonance (CMR) variables, focusing particularly on right atrial response and right ventricular diastolic function prior to and after elective PVR in adult patients with ToF. This prospective study was conducted from January 2009 to April 2013 in consecutive patients > 18 years of age who had undergone ToF repair in childhood and were accepted for elective PVR. Twenty patients (mean age: 35 years; 70% men) agreed to enter the study. PVR was performed with a bioporcine prosthesis. Concomitant RV reduction was performed in all cases when technically possible. Pulmonary end-diastolic forward flow (EDFF) decreased significantly from 5.4 ml/m(2) to 0.3 ml/m(2) (p < 0.00001), and right atrial four-chamber echocardiographic measurements and volumes by 25% (p = 0.0024): mean indexed diastolic/systolic atrial volumes prior to surgery were 43 ml/m(2) (SD+/-4.6)/63 ml/m(2) (SD+/-5.5), and dropped to 33 ml/m(2) (SD+/-3)/46 ml/m(2) (SD+/-2.55) post-surgery. All patients presented right ventricular diastolic and systolic volume reductions, with a mean volume reduction of 35% (p < 0.00001). Right ventricular diastolic dysfunction was common in a population of severely dilated RV patients long term after ToF repair. Right ventricular diastolic parameters improved as did right atrial volumes in keeping with the known reduction in RV volumes, after PVR.

Coronary flow dynamics in children after repair of Tetralogy of Fallot.

OBJECTIVES: To assess the possible effect of a stiff right ventricle on the coronary flow (CF) in patients with post-operative Tetralogy of Fallot (TOF). BACKGROUND: Right ventricular restrictive physiology i.e. forward flow during atrial contraction (RVRP), is characteristic to many patients with post-operative TOF. METHODS: A total of 34 patients with TOF anatomically corrected through transatrial repair were included. Coronary flow parameters were registered with transthoracic Doppler echocardiography from posterior descending (PDCA) and left anterior descending (LAD) coronary arteries in the same patient in 24/34 (71%) patients. Twenty age-matched healthy children were used as controls. Cardiac magnetic resonance (CMR) imaging was used to detect myocardial fibrosis, RV volume, and RVRP. RESULTS: The mean age at investigation was 10.2 ± 2.8 years. RV end diastolic and end systolic volumes indexed for BSA were larger in patients with RVRP (p=0.002 and 0.008 respectively). Peak flow velocity in diastole and flow velocity time integral was increased in patients compared to controls. They were increased in the LAD in patients with fibrosis of RV (n=11) compared to patients without fibrosis (n=9) (p=0.01 and 0.047 respectively). LAD coronary flow was especially increased in patients with RVRP (n=9) as compared with those without (n=11), (p=0.006). CONCLUSIONS: Patients at mid-term followup after correction of TOF show increase of coronary flow. This increase is more pronounced in patients with fibrosis and RVRP of the RV.