Shifts in Clinical Characteristics, Treatment, and Outcome for Rheumatic Mitral Stenosis: Insights From a 20-Year Multicentre Registry Study in Korea.

BACKGROUND: The rapid economic development of South Korea provides a unique model to study changes in the clinical characteristics, treatment approaches, and clinical outcomes of patients with rheumatic mitral stenosis (MS) relative to socioeconomic growth. METHODS: From the Multicenter mitrAl STEnosis with Rheumatic etiology (MASTER) registry, 2,337 patients diagnosed with moderate or severe rheumatic MS between January 2001 and December 2020 were analyzed. Patients were grouped into consecutive 5-year intervals based on their year of diagnosis. Clinical characteristics, echocardiographic data, and clinical outcomes were assessed. RESULTS: Over 20 years, the severity of mitral stenosis increased from 79.1% to 90.2%; similarly, the average age at diagnosis increased from 54.3 to 63.0 years (all P < 0.001). Comorbidities such as hypertension and atrial fibrillation increased (6.3% to 29.5% and 41.4% to 46.9%, respectively; all P for trend < 0.05). The rate of mitral intervention within five years after diagnosis increased from 31.2% to 47.4% (P for trend < 0.001). However, clinical outcomes of rheumatic mitral stenosis deteriorated over time in the composite outcomes (log-rank test, P < 0.001). Conversely, the incidence of stroke remained stable (60.6-73.7%; P < 0.001), which might be attributed to the increased use of anticoagulation therapy. CONCLUSION: This study observed an increase in patient age, comorbidities, and valve disease severity as the country transitioned from a developing to developed status. Despite a rise in mitral valve interventions, clinical outcomes deteriorated over 20 years, highlighting the need for modified treatment approaches to improve patient outcomes.

CD4+ T cells and TGFß1/MAPK signal pathway involved in the valvular hyperblastosis and fibrosis in patients with rheumatic heart disease.

The aim of this study was to investigate the roles of CD4+ T cells and transforming growth factor beta (TGFß1) in the pathological process of valvular hyperblastosis and fibrosis of patients with rheumatic heart disease (RHD). A total of 151 patients were enrolled, among whom, 78 patients were with RHD, and 73 were age and gender matched RHD negative patients. Blood samples and valve specimens were collected for analysis. Pathological changes and collagen fibers contents of valves were analyzed using HE and Masson staining. Percentage of peripheral blood CD4+ T cells was tested through flow cytometry. TGFß1 level in serum were identified by ELISA. CD4+ T cells infiltration and expression of TGFß1, p-p38, p-JNK, p-ERK in valves were detected by immunohistochemistry. The mRNA and protein levels of p38, JNK, ERK, TGFß1, I-collagen and α-SMA were detected by qRT-PCR and western blotting, respectively. The heart valve tissues of RHD patients showed higher degrees of fibrosis, calcification and lymphocytes infiltration, which were mainly CD4+ T cells. In addition, compared with control group, RHD patients had more total CD4+ T cells in peripheral blood and valve tissues. Expression of TGFß1, phosphorylation of JNK and p38, and synthesis of I-collagen in valve tissues of RHD patients were also significantly increased. Furthermore, we found a strong positive correlation between TGFß1 expression and phosphorylation of JNK and p38. CD4+ T cells, and fibrogenic cytokine TGFß1, which activate the intracellular MAPK signaling pathway may participate in the fibrosis of heart valve in RHD patients.

Rheumatic Mitral Stenosis: Long-Term Follow-Up of Adult Patients with Nonsevere Initial Disease.

INTRODUCTION: There is no consensus regarding the natural history of rheumatic mitral stenosis (MS) among adults presenting with nonsevere disease. This study aims to describe the progression of stenosis among adult rheumatic MS patients, to identify predictive factors for progression, and to assess the incidence of complications. METHODS: A retrospective cohort analysis was performed among patients with rheumatic MS treated at a single center. Eighty-five patients were included with mild to moderate MS, ≥30 years old on initial echocardiography. Demographics, medical history, echocardiographic reports over at least 10 years, and related complications were obtained from a computerized database. RESULTS: Over a period of 13.1 ± 2.38 years, 75 patients (88%) had no significant progression in stenosis severity. The final echocardiographic assessment demonstrated 2 groups with a significant difference between them regarding the mitral valve area (1.58 ± 0.44 vs. 1.1 ± 0.26 cm2, p = 0.001) and mean valvular pressure gradient (6.27 ± 2.52 vs. 8.5 ± 2.69 mm Hg, p = 0.01). Patients with indolent MS (group A) were compared to patients with progressive disease (group B), and a higher percent of Bedouin patients were found in group B (OR 8.036, p = 0.015). No significant differences were found in other parameters. Complications including atrial fibrillation, cerebral ischemic events, and impaired right ventricle function, although frequent, were not statistically different between the groups. CONCLUSIONS: An indolent natural progression of rheumatic MS was observed in our study. Despite this finding, it still has potentially deleterious effects. Bedouin patients have a higher risk for progressive disease.

First Experience of Sutureless Redo on Mitral Valve Using Valve-in-Valve Technique: Two-Stage Implantation on a Large Animal.

Sutureless implantation of the mitral valve bioprosthesis using the valve-in-valve method was performed on a large animal (sheep). According to the results of a two-stage implantation (primary implantation of a xenopericardial 26-mm framed bioprosthesis and reimplantation of the developed 23-mm bioprosthesis), minor changes in quantitative indicators were revealed: an increase in the transprosthetic gradient by 1.3 mm Hg and a decrease in the area of the mitral orifice by 21.6%. Considerable reduction in the intervention time by 18 min was achieved (by 40% in comparison with the primary prosthesis). The absence of adverse events in the animal and complications in the post-operative period, as well as physiological hemodynamic indicators indicate the safety of the developed medical device.

Unrecognized Cardiac Amyloidosis at the Time of Mitral Valve Surgery: Incidence and Outcomes.

OBJECTIVE: It is increasingly recognized that cardiac amyloidosis can occur in patients with severe aortic stenosis undergoing both surgical and transcatheter valve replacements. We aimed to investigate whether unrecognized cardiac amyloidosis may also occur in patients with severe mitral valve disease undergoing surgery. METHODS: The pathology department database at our center was retrospectively analyzed over a 10-year period for cases in which the mitral valve or another type of cardiac tissue removed at the time of mitral surgery demonstrated incidental amyloidosis. Clinical and echocardiographic variables were collected from the electronic medical record and the echocardiographic database. RESULTS: Between 2007 and 2016, a total of 7,733 mitral valve surgical specimens were received. Of these, there were 15 cases in which the mitral valve, or another type of cardiac tissue removed at surgery, demonstrated incidentally detected amyloidosis. The most frequent comorbidities were hypertension (87%) and atrial fibrillation (80%); 13 patients (87%) underwent bioprosthetic mitral valve replacement, and 2 patients (13%) underwent mitral valve repair. Sites of amyloid deposition were the mitral valve (80%), left atrial appendage (33%), and subaortic tissue (7%); 14 patients (93%) had wild-type transthyretin amyloid. The mean duration of follow-up was 1,023 days (range: 29-2,811 days). There were no surgical complications in the follow-up period. CONCLUSIONS: Over a 10-year period, incidentally detected cardiac amyloidosis occurred in 0.2% of the mitral valve surgical cases. The outcomes for these patients undergoing mitral valve surgery were excellent, with no complications or deaths attributable to surgery at a mean follow-up of 1,023 days.

Quantification of rheumatic mitral stenosis severity with three-dimensional vena contracta area.

INTRODUCTION: Rheumatic mitral stenosis (MS) is an important health issue in developing countries. Assessment of the correct mitral valve area (MVA) is essential for the timing of intervention. Most of the parameters for the assessment of rheumatic MS are derived from Two-dimensional (2D) echocardiography. Three-dimensional (3D) echocardiography is commonly used in our daily practice at the present time. The aim of this study was to assess the value of 3D echocardiography mitral valve vena contracta area (VCA) in predicting the severity of Rheumatic MS by comparing 3D planimetry. METHODS: The patients, who had been diagnosed as mild, moderate, and severe rheumatic MS with conventional methods (pressure half time, planimetry) by 2D transesophageal echocardiography (TEE)/ transthoracic echocardiography (TTE), underwent 3D TEE evaluation. Also, the patients who had an atrial fibrillation and more than moderate aortic regurgitation were included in the study. 3D TEE full volume mitral valve VCA was measured in end-diastole during its largest dimensions. 3D TEE full volume and 3D zoom MVA planimetry were measured at the end-diastole during the mitral valve`s largest opening. RESULTS: We studied 40 patients (the mean age: 51.1 ± 11.6 years, 31 females) with rheumatic MS. 3D TEE VCA was found to be highly correlated with the 3D TEE MVA (r = 0.82, P < 0.001). CONCLUSION: Our study findings provide evidence that 3D TEE mitral valve VCA can be additionally used in detecting the severity of rheumatic MS.

Involvement of Apelin/APJ Axis in Thrombogenesis in Valve Heart Disease Patients with Atrial Fibrillation.

The mechanism underlying thrombosis in atrial fibrillation (AF) is not yet clearly understood. The apelin/APJ axis parallel and counter-regulate with the angiotensin system. The present study hypothesizes that apelin/APJ axis exert its anti-thrombus effect in normal left atrial tissue and is disrupted by up-regulated renin-angiotensin-aldosterone system (RAAS) signaling during AF. The specimens of left atrial appendages collected from patients with rheumatic mitral stenosis who underwent valve replacement were divided into 3 groups: sinus rhythm, AF+/thrombus-, and AF+/thrombus+. The amounts of angiotensin II receptor subtype 1 (AT1), apelin/APJ and its downstream plasminogen activator inhibitor-1 (PAI-1) were detected by western blot. The expression of apelin/APJ was significantly decreased in the AF+/thrombus+ group compared with the sinus rhythm and AF+/thrombus- groups. Meanwhile the expressions of AT1 and PAI-1 were highest in the AF+/thrombus+ group compared to the other two groups. Taken together, the present study reveals apelin/APJ axis might be correlated with thrombosis in patients with AF mediated by PAI-1.

Association of matrix metalloproteinase 3 and endogenous inhibitors with inflammatory markers in mitral valve disease and calcification.

Calcific mitral valve stenosis (MVS) is a common disease characterized by extensive remodeling of the extracellular matrix via matrix metalloproteinases (MMPs). The mechanism of calcification due to extensive matrix remodeling remains unclear. In this study, we investigated the relationship between MMP-3, tissue inhibitors of metalloproteinases (TIMPs) as well as pro-inflammatory cytokines and the phenomenon of calcification in MVS. 212 patients having rheumatic mitral stenosis (RMS) and 155 healthy control subjects were recruited in the Cardiology Department of La Rabta Hospital University. Levels of MMP-3, TIMPs, IL-6 and TNF-α were measured by ELISA sandwich assay, hs-CRP was measured by immunoturbidimetry. Plasma levels of MMP-3, TIMP-1 and MMP-3/TIMP-2 ratio were lower only in RMS women in comparison to the control group. Calcification degree correlated positively with MMP-3 in women and men. In addition, calcification was correlated positively with MMP-3/TIMPs ratio in women patients. The inflammatory parameters were positively associated with extracellular matrix turnover biomarkers in men patients. In patients, the level of MMP-3 was increased in men and women with a calcification score ≥ 5. In addition, MMP-3 level predicted the occurrence of calcification. At ROC curves analysis, the cut-off MMP-3 level was in women was 9.21 ng/ml (sensitivity 51.1%, specificity 89.3%) and in men was 12.84 ng/ml (sensitivity 78.6%, specificity 77.8%). The high levels of MMP-3 and the biomarkers of inflammation contribute to valvular remodeling and calcification of the mitral valve.

A Rare Case of Rheumatic Heart Disease with Stenosis and Incompetence of Three Valves in a Nigerian Woman.

BACKGROUND: Though valve disease resulting from rheumatic heart disease is common, triple valve involvement is uncommon; with a bleak survival outlook Objective: To report a 38-year-old patient with both stenosis and incompetence of 3 valves, who lived till adulthood and went into heart failure after child-birth. No such report has come from Nigeria Methods: Case report of a Nigerian woman who lived with multiple valve disease up to adulthood when after delivery she developed hypertension and went into heart failure. Recurrent atrial fibrillation kept her in and out of heart failure. Three of her valves: mitral, aortic and tricuspid were both stenosed and incompetent. The consequent pulmonary hypertension and later development of arterial hypertension and atrial fibrillation worsened her morbidity till surgical intervention. CONCLUSION: Mixed triple valve disease of rheumatic origin tough rare, can occur; and is amenable to specialist surgical intervention.

Histopathological Study of Left and Right Atria in Isolated Rheumatic Mitral Stenosis With and Without Atrial Fibrillation.

BACKGROUND: Mitral stenosis (MS) has the highest incidence of atrial fibrillation (AF) in chronic rheumatic valvular disease. There are very few studies in isolated MS comparing histopathological changes in patients with sinus rhythm (SR) and AF. OBJECTIVES: To analyze the histological changes associated with isolated MS and compare between changes in AF and SR. METHODS: This was a prospective study in patients undergoing valve replacement surgery for symptomatic isolated MS who were divided into 2 groups, Group I AF (n = 13) and Group II SR (n = 10). Intra-operative biopsies performed from 5 different sites from both atria were analyzed for 10 histopathologic changes commonly associated with AF. RESULTS: On multivariate analysis, myocytolysis (odds ratio [OR]: 1.48, P = 0.05) was found to be associated with AF, whereas myocyte hypertrophy (OR: 0.21, P = 0.003), and glycogen deposition (OR: 0.43, P = 0.002) was associated with SR. Interstitial fibrosis the commonest change was uniformly distributed across both atria irrespective of the rhythm. CONCLUSION: In rheumatic MS, SR is associated with myocyte hypertrophy whereas AF is associated with myocytolysis. Endocardial inflammation is more common in left atrial appendage irrespective of rhythm. Interstitial fibrosis is seen in >90% of patients distributed in both the atria and is independent of the rhythm. Amyloid and Aschoff bodies are uncommon and the rest of the changes are uniformly distributed across both the atria.

Assessment of insulin-like growth factor-1 (IGF-I) level in patients with rheumatic mitral stenosis.

OBJECTIVES: Insulin-like growth factor-1 may serve some regulatory function in the immune system. Rheumatic mitral stenosis is related to autoimmune heart valve damage after streptococcal infection. The aim of this study was to assess the level of insulin-like growth factor-1 and its correlation with the Wilkins score in patients with rheumatic mitral stenosis. METHODS: A total of 65 patients with rheumatic mitral stenosis and 62 age- and sex-matched control subjects were enrolled in this study. All subjects underwent transthoracic echocardiography. The mitral valve area and Wilkins score were evaluated for all patients. Biochemical parameters and serum insulin-like growth factor-1 levels were measured. RESULTS: Demographic data were similar in the rheumatic mitral stenosis and control groups. The mean mitral valve area was 1.6±0.4 cm2 in the rheumatic mitral stenosis group. The level of insulin-like growth factor-1 was significantly higher in the rheumatic mitral stenosis group than in the control group (104 (55.6-267) versus 79.1 (23.0-244.0) ng/ml; p=0.039). There was a significant moderate positive correlation between insulin-like growth factor-1 and thickening of leaflets score of Wilkins (r=0.541, p<0.001). CONCLUSIONS: The present study demonstrated that serum insulin-like growth factor-1 levels were significantly higher in the rheumatic mitral stenosis group compared with control subjects and that insulin-like growth factor-1 level was also correlated with the Wilkins score. It can be suggested that there may be a link between insulin-like growth factor-1 level and immune pathogenesis of rheumatic mitral stenosis.

Cor triatriatum or divided atriums: which approach provides the better understanding?

It is frequent, in the current era, to encounter congenital cardiac malformations described in terms of "cor triatriatum". But can hearts be truly found with three atrial chambers? The morphological method, emphasised by Van Praagh et al, states that structures within the heart should be defined on the basis of their most constant components. In the atrial chambers, it is the appendages that are the most constant components, and to the best of our knowledge, hearts can only possess two appendages, which can be of either right or left morphology. The hearts described on the basis of "cor triatriatum", nonetheless, can also be analysed on the basis of division of either the morphologically right or the morphologically left atriums. In this review, we provide a description of cardiac embryology, showing how each of the atrial chambers possesses part of the embryological body, along with an appendage, a vestibule, a venous component, and a septum that separates them. We then show how it is, indeed, the case that the hearts described in terms of "cor triatriatum" can be readily understood on the basis of division of these atrial components. In the right atrium, it is the venous valves that divide the chamber. In the left atrium, it is harder to provide an explanation for the shelf that produces atrial division. We also contrast the classic examples of the divided atrial chambers with the vestibular shelf that produces supravalvar stenosis in the morphologically left atrium, showing that this form of obstruction needs to be distinguished from the fibrous shelves producing intravalvar obstruction.

Elevated fibrinogen and lowered homocysteine-vitamin determinants and their association with left atrial thrombus in patients with rheumatic mitral stenosis.

Mitral stenosis (MS) causes stagnation of blood flow, leading to thrombus formation in the left atrium (LA), which may lead to systemic thrombo-embolic complications and stroke. We compared the alterations in echocardiographic and procoagulant parameters in patients with severe rheumatic MS with and without LA thrombus. The study was a cross-sectional study of patients with rheumatic MS, being evaluated for percutaneous mitral commisurotomy. Group 1 patients comprised of patients with rheumatic MS with LA thrombus (n=35) and Group 2 patients had rheumatic MS without LA thrombus (n = 45). Platelet aggregability, fibrinogen, homocysteine, vitamin B12 and folate; mitral valve area (MVA), mean mitral gradient and pulmonary artery pressure (PAP) were assessed in all study subjects. Significant increase in fibrinogen, homocysteine and platelet aggregation and fall in homocysteine-associated determinants were seen in Group 1, as compared with Group 2. Raised fibrinogen, lowered homocysteine-vitamin determinants and lowered mitral valve area were associated independently, with presence of LA thrombus in rheumatic MS. In this study, fibrinogen, vitamin B12 and folate were independently associated with the occurrence of thrombus in patients with rheumatic MS. Hence, our results suggest that increase in procoagulant mechanisms contribute to increased risk of thrombosis in the left atrium in patients with rheumatic MS.

Pathology Image of the Month: Mitral Stenosis at Autopsy.

A 52-year-old woman decedent was presented to the hospital autopsy service for a coroner authorized complete autopsy following an admit urine toxicology screen that was positive for cannabinoids. Prior to admission, she was found unresponsive at home after a two month history of increasingly progressive shortness of breath. She was transported to the emergency department and resuscitated after prolonged arrest. She was then admitted to the intensive care unit and subsequently was documented to have significant anoxic brain injury. Care was withdrawn by the family and death was declared on hospital day five. Medical history was reported for type 2 diabetes mellitus, and bipolar schizoaffective disorder with multiple prior psychiatric admissions. Her medical record review revealed a transthoracic echocardiogram two months prior to admission that documented mild mitralregurgitation, moderate mitral valve stenosis and a thickened valvular and subvalvular mitral apparatus with restricted motion of the posterior leaflet. Left atrial enlargement was marked, left ventricular hypertrophy was moderate, and pulmonary hypertension was graded as severe. The ejection fraction was estimated at 70 percent. She was discharged with outpatient follow-up to the cardiology department but was noncompliant with recommendations.

Mitral and Aortic Valvulitis in Primary Chronic Septic Endocarditis.

Results of long-term prospective follow-up of patients with early stages of mitral and aortic valvulitis and primary chronic septic endocarditic are presented. Clinical diagnostics of the diseases is described and the key role is assigned to pathognomic (absolute) clinical symptoms. The tendency to progressive fibrosis of endocardial structures with subsequent gradual development of valve dysfunction and stenosis (especially for the mitral valve) is revealed. It is shown that early treatment increases the effective valve area and promotes reversion of mitral stenosis. The possibility of early diagnostics of primary chronic septic endocarditis in combination with adequate etiopathogenetic therapy provide the basis for prevention of acquired valvular disease.

Mitral valve disease.

In industrially developed countries, moderate or severe mitral valve disease is relatively common and is usually caused by prolapse or is secondary to left ventricular disease. Mitral stenosis (MS), however, is uncommon and usually a sequela of rheumatic fever. This article discusses the natural history of mitral regurgitation and MS and their medical and surgical management.

Comparative study of human aortic and mitral valve interstitial cell gene expression and cellular function.

Valve interstitial cells (VICs) are essential for valvular pathogenesis. However, the transcriptional profiles and cellular functions of human aortic VICs (hAVICs) and mitral VICs (hMVICs) have not been directly compared. We performed NimbleGen gene expression profiling analyses of hAVICs and hMVICs. Seventy-eight known genes were differentially expressed between hAVICs and hMVICs. Higher expression of NKX2-5, TBX15, OGN, OMD, and CDKN1C and lower expression of TBX5, MMP1, and PCDH10 were found in hAVICs compared to hMVICs. The differences in these genes, excepting OGN and OMD, remained in rheumatic VICs. We also compared cell proliferation, migration, and response to mineralization medium. hMVICs proliferated more quickly but showed more calcium deposition and alkaline phosphatase activity than hAVICs after culture in mineralization medium, indicating that hMVICs were more susceptible to in vitro calcification. Our findings reveal differences in the transcription profiles and cellular functions of hAVICs and hMVICs.

Liquefaction necrosis of mitral annulus calcification.

Liquefaction necrosis of the mitral annulus is a rare form of peri-annular calcification that the cardiologist must be able to differentiate from other cardiac masses. It classically looks like a round or semilunar hyperdense mass with a denser peripheral rim, located mainly in the posterior mitral annulus. The case we report here was diagnosed in a 78-year-old female patient who presented with an embolic cerebral vascular accident, which raises the question of its etiopathogenic responsibility.