Activation of activin/Smad2 and 3 signaling pathway and the potential involvement of endothelial­mesenchymal transition in the valvular damage due to rheumatic heart disease.

Rheumatic heart disease (RHD) is an autoimmune disease caused by rheumatic fever following group A hemolytic streptococcal infection and primarily affects the mitral valve. RHD is currently a major global health problem. However, the exact pathological mechanisms associated with RHD­induced cardiac valve damage remain to be elucidated. The endothelial­mesenchymal transition (EndMT) serves a key role in a number of diseases with an important role in cardiac fibrosis and the activin/Smad2 and 3 signaling pathway is involved in regulating the EndMT. Nevertheless, there are no studies to date, to the best of the authors' knowledge, investigating the association between RHD and EndMT. Thus, the aim of the current study was to investigate the potential role of EndMT in cardiac valve damage and assess whether activin/Smad2 and 3 signaling was activated during RHD­induced valvular injury in a rat model of RHD induced by inactivated Group A streptococci and complete Freund's adjuvant. Inflammation and fibrosis were assessed by hematoxylin and eosin and Sirius red staining. Serum cytokine and rheumatoid factor levels were measured using ELISA kits. Expression levels of activin/Smad2 and 3 signaling pathway­related factors [activin A, Smad2, Smad3, phosphorylated (p­)Smad2 and p­Smad3], EndMT­related factors [lymphoid enhancer factor­1 (LEF­1), Snail1, TWIST, zinc finger E­box­binding homeobox (ZEB)1, ZEB2, α smooth muscle actin (α­SMA) and type I collagen α 1 (COL1A1)], apoptosis­related markers (BAX and cleaved caspase­3) and valvular inflammation markers (NF­κB and p­NF­κB) were detected using reverse transcription­quantitative PCR and western blot analyses. Compared with the control group, the degree of valvular inflammation and fibrosis, serum levels of IL­6, IL­17, TNF­α and expression of apoptosis­related markers (BAX and cleaved caspase­3) and valvular inflammation marker (p­NF­κB), activin/Smad2 and 3 signaling pathway­related factors (activin A, p­Smad2 and p­Smad3), EndMT­related factors (LEF­1, Snail1, TWIST, ZEB 1, ZEB2, α­SMA and COL1A1) were significantly increased in the RHD group. These results suggested that the activin/Smad2 and 3 signaling pathway was activated during the development of valvular damage caused by RHD and that the EndMT is involved in RHD­induced cardiac valve damage.

Dietary intervention reduces left atrial enlargement in dogs with early preclinical myxomatous mitral valve disease: a blinded randomized controlled study in 36 dogs.

BACKGROUND: Myxomatous mitral valve disease (MMVD), the most common naturally-occurring heart disease in dogs, is associated with alterations in energy metabolism, oxidative stress and inflammation. Energy deprivation plays a causal role in the development of heart failure. This study was designed to determine if a cardiac protection blend (CPB) of nutrients containing medium-chain triglycerides as an alternative energy source, fish oil to reduce inflammation, antioxidants, and other key nutrients important to cardiac health and function could slow or prevent MMVD progression. Nineteen dogs with early stage MMVD and 17 breed-, age-, and sex-matched healthy dogs were enrolled for a 6-month blinded, placebo-controlled study. Dogs in each cardiac health group were randomly assigned to either control diet (CON) or CPB-supplemented diet. Echocardiography was performed at baseline, 3 months and 6 months. RESULTS: No changes were found in healthy dogs. While MMVD-CON dogs had an average 10% increase over baseline in left atrial diameter (LAD) and left atrial to aortic root ratio (LA/Ao) at 6 months, MMVD-CPB dogs showed 3% decreases, resulting significant diet by time interactions (P = 0.037, P = 0.005, respectively). More MMVD-CON dogs progressed from stage B1 to B2 during the study. A positive correlation was found between 6-month changes in LAD and blood pressures in MMVD-CPB dogs (systolic: P = 0.050, diastolic: P = 0.035) but not MMVD-CON dogs. CONCLUSIONS: Our results demonstrated efficacy of CPB-based dietary intervention in reducing LA size and mitral regurgitation, and in slowing or preventing the progression of early MMVD in dogs.

Postoperative atrial tachycardias after mitral valve surgery: Mechanisms and outcomes of catheter ablation.

BACKGROUND: Atrial tachycardias (ATs) including atrial fibrillation are common arrhythmias occurring late after mitral valve (MV) surgery, and their management is challenging. OBJECTIVE: The purpose of this study was to determine the electrophysiological mechanisms of ATs in patients with prior MV surgery and the long-term outcomes of catheter ablation. METHODS: We studied 67 consecutive patients (mean age 59.4 ± 10.6 years; 41 men [61%]) with prior MV surgery who presented with ATs postoperatively between 2007 and 2015. RESULTS: AT was clinically documented before the electrophysiology study in 55 patients, whereas in the remaining 12 patients AT was inducible at the study. A total of 99 ATs (35 spontaneous and 64 inducible) were characterized. Overall, the right atrium (RA) was the chamber of origin in 56%. The underlying mechanism was macroreentry in 91 cases and included typical RA flutter (n = 37), mitral annular flutter (n = 21), incisional right AT (n = 16), roof-dependent reentry (n = 12), and local left atrial reentry (n = 5). Eight focal ATs were also documented: 6 from the left atrium and 2 from the RA. Left-sided ATs were more common in patients with prior Maze procedure (53%), and mitral annular flutter was twice as prevalent in this group (42% vs 21%; P = .05). The ablation was acutely successful in 98.5%. Freedom from atrial arrhythmias was 62% at 12 months, with 42% requiring more than 1 procedure. CONCLUSION: Macroreentry is the predominant AT mechanism in patients with prior MV surgery. Circuits are most often localized to the RA, with left-sided ATs more common in patients with prior Maze procedure. Repeat procedures are common and outcomes with 1 year complete AT control good.

Thrombotic thrombocytopenic purpura and cardiac papillary fibroelastoma: a 'unique coexistence'.

Thrombotic thrombocytopenic purpura (TTP), a complex thrombotic microangiopathy, remains an evolving enigma. A 49-year-old African-American woman presented with acute left hemiplegia, an ischemic cerebrovascular accident involving the right middle cerebral artery. Sequential appearance of thrombocytopenia and evidence of microangiopathic haemolysis led to the diagnosis of acquired idiopathic autoimmune TTP. This was managed with plasma exchange (PEX) and steroids. Early haematologic relapse within a month was managed with the addition of rituximab attaining sustained remission. The patient presented 3 years later with acute confusion and expressive aphasia due to multiple infarcts involving the left parieto-occipital cortex. Transoesophageal echocardiography demonstrated a pedunculated 6 mm mitral valvular mass consistent with a papillary fibroelastoma. Anticoagulation was instituted and the patient was continued on therapeutic oral warfarin. A haematologic relapse of TTP eventually emerged and was managed with PEX, steroids and rituximab. This vignette demonstrates several dilemmas in the clinical presentation, diagnosis and management of TTP in current day practice. Rituximab has adjuvant benefits to PEX and is being investigated as potential first-line therapy. Monitoring ADAMTS13 activity and inhibitor titre, as in our case, prove to have prognostic significance. Cardiac fibroelastomas are rare benign cardiac tumours usually arising from valvular endocardium with thromboembolic potential. One of the proposed mechanisms of origin of these masses is organizing thrombi in the setting of endocardial injury and inflammation questioning a possible link to thrombotic microangiopathy. To the best of our knowledge, this is the first report of this unique coexistence.

Spatial relationship between high-dominant-frequency sites and the linear ablation line in persistent atrial fibrillation: its impact on complex fractionated electrograms.

AIMS: Complex fractionated electrograms (CFEs) and high-dominant-frequency (DF) sites theoretically represent abnormal substrates and targets for atrial fibrillation (AF) ablation. The relationship between the high-DF sites in the left atrium (LA) and commonly used linear ablation line to the distribution of the CFEs in patients with persistent AF is unknown. METHODS AND RESULTS: This study enrolled 62 persistent AF patients who underwent construction of LA CFE and DF maps (>350 points/map). Circumferential pulmonary vein isolation and linear ablation including that at the septum, roof, mitral-annulus, and ridge of the appendage were performed. Multipolar catheter mapping identified sites with high DFs (≥ 8 Hz) in all patients (9.8 ± 4.6/patient). In 47 patients in whom AF persisted despite ablation, there was a significant reduction in the continuous CFE (<50 ms) burden after the linear ablation (62 vs.11%; P < 0.0001), with a decrease in both the DF within the coronary sinus (6.9 ± 0.9 vs. 5.9 ± 0.8 Hz; P < 0.0001) and CFE surface area (42.8 ± 18.8 vs. 12.6 ± 10.5 cm(2); P < 0.0001). Comparing the high-DF sites with the ablated lesions, 64% of the high-DF sites (324 of 507) were on or adjacent to the ablation lines. Residual CFEs were observed in the infero-posterior regions in 83% of the patients. Almost half of the high-DF sites away from the linear ablation line were identified in the inferior (34%) and posterior (14%) LA regions. CONCLUSION: Linear ablation resulted in the localization of the continuous CFE regions and reduced the global LA DF in patients with persistent AF. This may be related to the proximity relationship between the linear ablation lines and high-DF sites except for in the infero-posterior regions.

Ablation of atrial fibrillation with concomitant cardiac surgery.

Atrial fibrillation is present in approximately 35% of patients presenting for mitral valve surgery and in 1 to 6% of adult patients undergoing other forms of cardiac surgery. If left untreated, atrial fibrillation is associated with increased morbidity, and, in some subgroups, increased mortality. Therefore, concomitant management of the arrhythmia is indicated in most cardiac surgery patients with preexisting atrial fibrillation. Although the cut-and-sew Cox-maze III procedure is extremely effective, it has been supplanted by newer operations that rely on alternate energy sources to create lines of conduction block. Early and mid-term results are good with a variety of technologies. Choice of lesion set remains a matter of debate, but results of ablation appear to be enhanced by a biatrial lesion set. Targeted areas for improvement in concomitant ablation include acceptance of uniform standards for reporting results, development of improved technology for ablation and intraoperative assessment, and creation of instrumentation that facilitates minimally invasive approaches.

Idiopathic ventricular arrhythmia arising from the mitral annulus: a distinct subgroup of idiopathic ventricular arrhythmias.

OBJECTIVES: We sought to clarify the prevalence and characteristics of idiopathic ventricular tachycardia or premature ventricular contraction originating from the mitral annulus (MAVT/PVC). BACKGROUND: Recent case reports have presented patients with MAVT/PVC. METHODS: Electrocardiographic (ECG) characteristics and the results of electrophysiologic investigation and radiofrequency catheter ablation (RFCA) were analyzed in 352 patients with symptomatic idiopathic ventricular tachycardia (IVT)/premature ventricular contraction (PVC). RESULTS: Nineteen cases of IVT/PVC (5%) represented MAVT/PVC. Of these, 11 (58%) originated from the anterolateral portion of the mitral annulus (AL-MAVT/PVC), and 2 (11%) arose from the posterior portion (Pos-MAVT/PVC). The remaining six cases of MAVT/PVC (31%) had posteroseptal origin (PS-MAVT/PVC). In all patients, an S-wave was present in lead V(6). The QRS polarity in inferior leads and leads I and aVL was useful for differentiating AL-MAVT/PVC from Pos-MAVT/PVC or PS-MAVT/PVC. The Pos-MAVT/PVC had an Rs pattern in lead I and an R pattern in lead V(1), whereas PS-MAVT/PVC invariably had an R pattern in lead I and a negative QRS component in lead V(1). The AL-MAVT/PVC and Pos-MAVT/PVC showed a longer QRS duration than the PS-MAVT/PVC (p < 0.001), and all had late-phase "notching" of the QRS complex in inferior leads. In all patients, RFCA eliminated MAVT/PVC, with no recurrences during follow-up for 21 +/- 15 months. CONCLUSIONS: Mitral annular VT/PVC is a rare but distinct subgroup of IVT/PVC. MAVT/PVC origin could be determined by ECG analysis. The AL and PS sites of the MA were preferential.

Identifying patients with degenerative mitral regurgitation for mitral valve repair and replacement: a transesophageal echocardiographic study.

OBJECTIVE: We sought to preoperatively identify the suitability of patients with degenerative mitral valve (MV) regurgitation for MV repair (MVR) and MV replacement. BACKGROUND: MVR is the preferred method of treatment over MV replacement, if surgically feasible. MVR preserves left ventricular function and decreases risk of hemolysis, thromboembolism, and-in the absence of anticoagulation-hemorrhage. However, the ability to identify patients suitable for MVR preoperatively is somewhat limited. METHODS: In all, 76 patients underwent MV operation for severe symptomatic mitral regurgitation. The decision to operate was at the discretion of the referring physician in consultation with respective cardiothoracic surgeons at two separate, nonrelated institutions. All patients underwent preoperative and/or intraoperative transesophageal echocardiographic studies. RESULTS: In all, 35 patients (46%) underwent MVR and 41 (54%) underwent MV replacement. There was no difference in the percentage of MVRs between the two institutions: 17 cases (41%) at Hahnemann University Hospital, Philadelphia, Pa, versus 18 cases (53%) at Northwestern University Memorial Hospital, Chicago, Ill (P = not significant). Age was found to be a significant univariate predictor with older age favoring MV replacement. On average, patients who underwent MVR were 11 years younger then those who underwent MV replacement. Heart failure was also found to be a significant univariate predictor: as New York Heart Association functional class worsened, MV replacement was more likely. Echocardiographic variables favoring MVR included chordal length (>29 mm, P <.001), length of posterior mitral leaflet (>17 mm, P <.008), and length of anterior leaflet (>25 mm, P <.01). The only echocardiographic parameter favoring replacement was the presence of anterior mitral annular calcification. Using multivariate analysis, older age (>63 years) was again a significant predictor favoring MV replacement (P <.002; odds ratio [OR] 20). Longer chordal length (>29 mm) was the strongest predictor favoring MVR (P <.001; OR 11.2). Longer length of the posterior leaflet (>17 mm; OR 5.07) and mitral annulus size > 35 mm (OR 7.75) were also significant multivariate predictors favoring MVR. The presence of anterior mitral annular calcification favored MV replacement using multivariate analysis (OR 25). CONCLUSIONS: Patients suitable for MVR can be identified preoperatively using a combination of clinical and echocardiographic parameters.

Histopathogenesis of early-stage mitral annular calcification.

Mitral annular calcification (MAC) is a common condition in elderly subjects that sometimes causes degenerative mitral valvular diseases. To investigate the early histopathogenesis of MAC, we examined 180 consecutive autopsies of elderly subjects. After a macroscopic and radiological examination, 5-mm-thick serial tissue blocks obtained from the mitral annulus were examined in all MAC cases. Five cases without MAC were also studied using histology, immunostaining, electron microscopy, analytical electron microscopy and the TUNEL method. The incidence of MAC in females (23%) was higher than that in males (15%). Most MAC was located at the posterior cusp (91%). The mitral annulus showed signs of microscopic calcification and lipid-deposition in some degenerated areas in all of the cases without MAC. The interstitial cells were positive for vimentin and partially positive for smooth muscle actin, indicating the myofibroblastic differentiation. Ultrastructural studies showed an abundance of cellular degradation products and foci of calcium- and phosphorus-deposition on these products in the interstitium. Several interstitial cells tested positive for both single-stranded DNA immunostaining and the TUNEL reaction. In conclusion, the microscopic calcification of mitral annulus is an early stage of MAC and caused by calcium-deposition on cellular degradation products, probably released from apoptotic or necrotic interstitial cells.

Compositional changes of human mitral valves with aging.

To elucidate compositional changes of the mitral valve with aging, the authors investigated the relationships among element contents in the mitral valves. The subjects consisted of 10 men and 15 women, ranging in age from 65 to 102 yr. After the ordinary dissection, mitral valves, lower parts of the interventricular septa, and terminal crests containing the sinoatrial nodes were resected and the element contents were determined by inductively coupled plasma-atomic emission spectrometry. The interventricular septa and sinoatrial nodes were used to compare with the mitral valves. With regard to the mitral valve, it was found that extremely significant correlations were found among the contents of Ca, P, Mg, and Na, but no significant correlations were found between the contents of S and elements such as Ca, P, or Mg. Regarding the interventricular septum, it was found that an extremely significant correlation was found between P and S contents; very significant correlations were found between Ca and Mg contents and between Mg and S contents; and a significant correlation was found between P and Mg contents. However, no significant correlation was found between Ca and P contents in the interventricular septa. In the terminal crest containing the sinoatrial node, significant correlations were found among the contents of Ca, P, Mg, and S. The present study revealed that with regard to the relationships among element contents, the compositional change of the mitral valve was intermediate between those of the thoracic aorta and the interventricular septum.

Radiofrequency ablation of sustained ventricular tachycardia related to the mitral isthmus in Chagas' disease.

This case report describes the electrophysiological findings of a 62-year-old patient with chronic Chagas' disease and two distinct morphologies of sustained ventricular tachycardia that involved a mitral isthmus. Multiple RF applications were necessary to obtain a bidirectional conduction block in the mitral isthmus that was related to the interruption of both tachycardias. After the procedure, the patient presented massive cerebral infarction that progressed to coma and death. Autopsy showed acute and old lesions at the mitral isthmus and recent mitral annulus thrombosis.

The influence of severe bone loss on mitral annular calcification in postmenopausal osteoporosis of elderly Japanese women.

We assessed the influence of aging bone calcium metabolism on mitral annular calcification (MAC) and aortic valve calcification (AVC) in 239 septua- and octogenarians (62 men, 177 women; 80.2 +/- 4.4 years). Osteoporosis was diagnosed by vertebral bone fracture. Both MAC and AVC were derived by 2-dimensional echocardiography. Bone mineral content (BMC) of the lumbar vertebral body was obtained by single-energy quantitative computed tomography using a calibration phantom. Serum calcium, phosphorus, parathyroid hormone, calcitonin, and osteocalcin were examined. Patients were classified into 3 age-matched groups in each sex: Group-C included patients with MAC (-) and AVC (-) (n = 96); Group-A was those with AVC (+) and MAC (-) (n = 80); Group-M consisted of those with MAC (+) and AVC (-) or AVC (+) (n = 63). Osteoporosis-frequency and BMC in women were significantly higher (p < 0.01) and lower (p < 0.001) respectively than those in men. Among men, osteoporosis-frequency and BMC showed no difference between the 3 groups. Among women, osteoporosis-frequency (52%) and BMC (32 +/- 23 mg/cm3) in Group-M were higher (NS) and significantly less (p < 0.01) than those (37%, 49 +/- 36) in Group-C, respectively. In both sexes, serum examinations revealed no differences between the 3 groups. These results suggest that: 1) MAC in elderly women can be attributed to ectopic calcium deposits, related to the severe bone loss caused by postmenopausal osteoporosis; 2) there is no significant relationship between the incidence of MAC or AVC and the humoral factors of calcium metabolism; and 3) AVC may be mainly caused by pressure or stress loading.

Effect of lanthanum chloride on established atherosclerosis in the cholesterol-fed rabbit. Mitral valve as a site for assessment of treatment effects.

The ability of lanthanum chloride (LaCl3) to retard the progression of established atherosclerosis was investigated in cholesterol-fed rabbits. Rabbits were initially maintained on a high-fat plus cholesterol-supplemented diet for 10 weeks to induce lesions and were then changed to a low-fat diet or a low-fat diet supplemented with LaCl3 for an additional 24 weeks to permit their serum cholesterol levels to normalize. LaCl3 did not affect the rate at which serum cholesterol levels returned to normal. The dose of LaCl3 was approximately 30 mg/kg body weight/day. In comparison with controls, LaCl3-treated rabbits exhibited histologically less severe coronary artery and mitral valve atherosclerosis. Lesion severity in the carotid arteries was unaffected by LaCl3 treatment. Although statistically significant, the salutary effects of LaCl3 were relatively small. The data support the hypothesis that calcium antagonists can retard the progression of established atherosclerotic lesions. The data also illustrate the value of the mitral valve as a site to assess treatment effects on monocyte/macrophages in vivo.

Mitral anular calcification in chronic renal failure.

In order to determine the incidence and pathogenesis of mitral anular calcification (MAC) in chronic renal failure, we analyzed biochemical, hemodynamic and echocardiographic data in 168 patients on long-term hemodialysis. Mitral anular calcification is more common in patients with chronic renal failure than in other patients of similar age. Its pathogenesis appears to be due to abnormal calcium-phosphorus homeostasis in the setting of secondary hyperparathyroidism. Hypertension did not appear to be an important etiologic factor in our patients. Meticulous control of hyperphosphatemia would appear to be the most important therapeutic measure in preventing this complication.