Combination anticoagulation strategy in pregnancy with mechanical valves: The KYBELE study.

BACKGROUND: Optimal first-trimester anticoagulation is still challenging in pregnant women with mechanical heart valves (MHVs) requiring high-dose warfarin. This multicenter prospective study aims to determine the optimal anticoagulation regimens for pregnant patients with MHVs. METHODS: All women were allocated to one of three treatment options during first trimester including lone low-molecular-weight heparin (LMWH), combination of LMWH + 2.5 mg warfarin, and LMWH+4 mg warfarin. Primary maternal outcome included a combination of death, thromboembolism, severe bleeding, and need for treatment of mechanical valve thrombosis (MVT). Any fetal loss was determined as primary fetal outcome. RESULTS: The study included 78 pregnancies in 65 women with MHVs. Primary maternal outcome rate was 44%, 12.5%, 3.5%, respectively. The rates of primary maternal outcome (44 vs 3.5%, P < .001), obstructive MVT (16 vs 0%, P = .04), MVT requiring treatment (28 vs 0%, P = .003), and cerebral embolism (24 vs 3.4%, P = .041) were found to be significantly higher in lone LMWH group compared to LMWH + 4 mg warfarin group. Moreover, the rates of primary maternal outcome (12.5 vs 44%, P = .015) and treatment for MHV thrombus (4.2 vs 28%, P = .049) were significantly lower in LMWH + 2.5 mg warfarin group compared to lone LMWH group. The incidences of fetal loss were 8 (32%) in the lone LMWH group, 8 (33.3%) in LMWH + 2.5 mg warfarin group, and 11 (37.9%) in LMWH + 4 mg warfarin group (P = .890 for 3-group).Warfarin related-embryopathy was not observed in any case. CONCLUSIONS: The combined anticoagulation strategy of LMWH plus low-dose warfarin during the first trimester of pregnancy may result in less maternal complications with comparable fetal outcomes in patients with MHVs. CONDENSED ABSTRACT: Low-molecular-weight heparin (LMWH) is thought to be safer for the fetus, however it is suspected to be less protective for the mother. To solve this dilemma, the authors suggested a novel anticoagulation strategy in pregnant women with prosthetic valves. Seventy-eight pregnancies of 65 women (median age 32 [27-35] years) were included in the study. A combination of LMWH and a reduced dose warfarin were associated with low rates of thrombus-related complications in pregnant patients with mechanical heart valves.

Lack of right ventricular hypertrophy is associated with right heart failure in patients with left ventricular failure.

Presence of right heart failure (RHF) is associated with a worse prognosis in patients with left ventricular failure (LVF). While the cause of RHF secondary to LVF is multifactorial, an increased right ventricular (RV) afterload is believed as the major cause of RHF. However, data are scarce on the adaptive responses of the RV in patients with LVF. Our aim was to understand the relationship of right ventricular hypertrophy (RVH) with RHF and RV systolic and diastolic properties in patients with LVF. 55 patients with a left ventricular ejection fraction of 40% or less were included in the present study. A comprehensive two-dimensional transthoracic echocardiographic examination was done to all participants. 12 patients (21.8%) had RHF, and patients with RHF had a significantly lower right ventricular free wall thickness (RVFWT) as compared to patients without RHF (5.3 ± 1.7 mm vs. 6.6 ± 0.9 mm, p = 0.02) and the difference remained statistically significant after adjusting for confounders (Δx̅:1.34 mm, p = 0.002). RVFWT had a statistically significant correlation with tricuspid annular plane systolic excursion (r = 0.479, p < 0.001) and tricuspid annular lateral systolic velocity (r = 0.360, p = 0.007), but not with the indices of the RV diastolic function. None of the patients with concentric RVH had RHF, while 22.2% of patients with eccentric RVH and 66.7% of patients without RVH had RHF (p < 0.01 as compared to patients with concentric RVH). In patients with left ventricular systolic dysfunction, absence of RVH was associated with worse RV systolic performance and a significantly higher incidence of RHF.

Association of red blood cell distribution width, systemic-immune-inflammation index and poor cardiovascular outcomes in patients with newly diagnosed hypertension.

BACKGROUND: Red cell distribution width (RDW) and the systemic immune-inflammation index (SII) have been extensively studied as predictors of morbidity and mortality in several cardiovascular diseases. This prospective study aimed to investigate the relationship between long term major adverse cardiac events (MACEs) and simple hematological parameters in hypertensive patients. METHODS: The study included a total of 1202 patients with newly diagnosed HT. Of the patients, 662 (55.1%) were female and 540 (44.9%) were male, with a mean age of 53.0 ± 11.4 years. The primary endpoint of the study was long term MACE, including cardiac death, stroke, and myocardial infarction. This is the first study focusing on the association of SII with major adverse cardiovascular outcomes in patients with HT. RESULTS: Eighty-nine patients (8.7%) developed at least one MACE during a mean follow-up period of 82.2 ± 1.3 months. RDW (13.0 ± 0.9 vs. 13.5 ± 1.2%, p < .001) and SII [465.0 (353.4-609.4) vs. 584.4 (468.9-794.0) x103/µL, p < .001] were significantly higher in patients with MACEs. The prevalence of MACEs was significantly higher in patients with RDW>13.1% (10.4 vs. 5%; p < .001) and in patients with SII>465 x103/µL (11.8 vs. 3.1%; p < .001). The multivariate logistic regression analysis showed SII and RDW were independent predictors of MACEs. CONCLUSION: The results of the study demonstrated that the RDW and SII were independent predictors of long-term cardiovascular events in hypertensive patients. These simple hematological parameters may be used as prognosticators of MACE in patients with newly diagnosed HT.

The relationship between incomplete surgical obliteration of the left atrial appendage and thromboembolic events after mitral valve surgery (from the ISOLATE Registry).

Left atrial appendage (LAA) is a common site of thrombus formation especially in patients with atrial fibrillation (AF). Complete surgical LAA closure (cSLC) is the surgical aim, however incomplete surgical LAA closure (iSLC) is not rare. In this study, we aimed to evaluate the risk of thromboembolic complications (TEC) in AF patients with iSLC after mitral valve surgery. A total of 101 AF patients (mean age: 61.8 ± 11.8 years; male:32), who underwent surgical suture ligation during mitral valve surgery were enrolled in this retrospective study. All patients underwent transthoracic and transesophageal echocardiography (TEE) at least 3 months after surgery. The primary outcome was the occurrence of TEC including any ischemic stroke, transient ischemic attack, coronary or peripheral embolism. TEE examination revealed cSLC in 66 (65.3%) and iSLC in 35 patients (34.6%). A total of 12 TECs (11.9%) occurred during a mean follow-up time of 41.1 ± 15.6 months. TECs were found to be significantly higher in the iSLC group (25.7% vs 4.5%, p = 0.002). The prevalence of iSLC was significantly higher in patients with TEC (75 vs. 29.2%, p = 0.002). High CHA2DS2-VASc Score and iSLC were found to be independent predictors of TEC. Long term TEC free survival was found to be significantly decreased in patients with iSLC. The presence of iSLC was associated with a significantly increased risk of TEC in AF patients after mitral valve surgery. Routine intraoperative and postoperative screening for iSLC by TEE and long-term strict anticoagulation therapy are recommended in these patients.

Evaluation of the potential predictors of embolism in patients with left atrial myxoma.

INTRODUCTION: Cardiac myxomas are the most common primary intracardiac tumors. Although myxomas are histologically benign, they are potentially dangerous due to potential risk of systemic and cerebral embolism. In this study, we aimed to investigate the potential predictors of embolism in patients with left atrial myxoma. METHODS: This single-center retrospective study enrolled 93 patients (mean age: 52.9 ± 15.3 years, female: 70 [75.3%]) with left atrial myxomas between 2014 and 2018. The patients were classified into two groups (embolic vs nonembolic) to investigate possible predictors of embolism. Demographic, laboratory, and echocardiographic parameters were recorded into a dataset and compared between patients with and without embolism. RESULTS: The study population was composed of 13 (14%) patients in embolic (11 cerebrovascular and 2 peripheral) and 80 (86%) patients in nonembolic group. Demographic and laboratory parameters were similar between the groups. Tumor sizes were significantly higher in the embolic group than in the nonembolic group (5.59 ± 1.08 vs 4.29 ± 0.61; P = 0.001). By multivariate analysis, increased tumor size, increased left atrial diameter, and the presence of atrial fibrillation and irregular tumor surface were identified as independent predictors of embolism. In ROC curve analyses, tumor size above 4.6 cm predicted embolism with a sensitivity of 77% and a specificity of 73% (AUC: 0.858; 95% CI: 0.752-0.964; P < 0.001). CONCLUSION: The presence of atrial fibrillation, irregular tumor surface, increased tumor size, and increased left atrial diameter is associated with increased risk of embolism in patients with left atrial myxoma. Early surgery should be scheduled for such patients due to increased potential for embolism.

Relationship Between Pulmonary Venous Flow and Prosthetic Mitral Valve Thrombosis.

BACKGROUND: Prosthetic valve thrombosis (PVT) may impair pulmonary venous flow (PVF) and left atrial appendage (LAA) functions. An investigation was conducted to determine the association between left superior PVF and LAA functions and mitral PVT. METHODS: This observational case-control study included 100 consecutive patients (87 females, 13 males; mean age 59 years; range 35-71 years) with mechanical mitral PVT, and 50 age- and gender-matched otherwise healthy controls with normally functioning mitral prostheses. All patients were included after comprehensive transesophageal echocardiography (TEE) examinations for the presence and quantification of PVT, the left atrial diameter, and LAA length. Peak systolic velocity (PSV), velocity-time integral of systolic flow (VTI-s), peak diastolic velocity (PDV), velocity-time integral of diastolic flow (VTI-d), systolic fraction (SFr) of the left upper PVF and the flow of the LAA orifice were each recorded using color-guided pulsed-wave Doppler imaging during TEE. RESULTS: The PSV [30 cm/s (range: 13-77 cm/s) versus 44 cm/s (range: 16-71 cm/s)], respectively (p = 0.002), VTI-s [(2.85 cm (range: 0.5-10.7 cm) versus 5 cm (range: 1.3-12.7 cm)], respectively (p <0.001), VTI-d [(3 cm (range: 0.6-9.7 cm) versus 4.2 cm (range: 1.5-8.3 cm)], respectively (p <0.001), SFr (45.5% (range: 15.66-67.44%) versus 50 % (range: 21.11-82.61%)], respectively (p = 0.008), and LAA orifice velocity [(23 cm/s (range: 11-75 cm/s) versus 34 cm/s (range: 10-112 cm/s)], respectively (p = 0.011) were each significantly lower in patients with PVT compared to controls. The PDV was similar between groups. Patients with obstructive PVT (n = 21) had a lower PDV and a higher VTI-d compared to those with non-obstructive PVT. CONCLUSIONS: Mitral mechanical PVT is associated with decreased systolic PVF and LAA function. The presence of obstructive PVT is associated with further limitations of diastolic flow velocity, and a compensatory prolongation of diastolic flow of the left upper pulmonary vein.

A successful catheter ablation of a ventricular fibrillation.

Malignant ventricular arrhythmias are challenging to manage, requiring a multidisciplinary approach. The mechanism, which triggers ventricular fibrillation (VF) associated with ventricular extrasystoles has not been clarified yet, however, abolishing ventricular extrasystoles may stop ventricular fibrillation in these patients. By this case presentation, we aimed to present a successful treatment of an electrical storm (ES), which developed after an acute myocardial infarction, by catheter ablation.

Early Thrombosis of a Mitral Annuloplasty Ring in a Patient with MTHFR and Factor V Leiden Mutations.

Mitral annuloplasty ring thrombosis is an extremely infrequent pathology, for which no evidence-based antithrombotic management has yet been described. Herein is presented a case of heterozygous Factor V Leiden (FVL) and hyperhomocysteinemia with homozygous methylenetetrahydrofolate reductase (MTHFR) mutations that caused early thrombosis of the mitral annuloplasty ring. The clinical management and antithrombotic treatment of the patient, and the implications of hyperhomocysteinemia, are discussed. Video 1: Mobile 9-mm thrombus of mitral annuloplasty ring on two-dimensional (2D) transesophageal echocardiography. Video 2: Mitral annuloplasty ring thrombus on real time three-dimensional (RT-3D) transesophageal echocardiography. Video 3: 2D video showing the morphologic change of mitral annuloplasty ring thrombus after prolonged UFH infusion.

The Role of Protein Z and Protein Z-Dependent Protease Inhibitor Polymorphisms in the Development of Prosthetic Heart Valve Thrombosis.

BACKGROUND AND AIM OF THE STUDY: Protein Z (PZ) is a vitamin K-dependent factor that is synthesized mainly by the liver. It acts as an activator of serpin, the protein Z-dependent inhibitor (ZPI), which inhibits factor Xa. The potential role of alterations in protein Z and/or ZPI levels in the pathogenesis of thrombotic and/or hemorrhagic diseases has been previously investigated, but results have been conflicting. The study aim was to evaluate the role of PZ/ZPI polymorphisms in the development of prosthetic valve thrombosis (PVT). METHODS: This prospective, observational cross-sectional study included 50 consecutive patients with PVT [non-obstructive thrombosis (NOT) in 35 patients; obstructive thrombosis (OT) in 15] and 50 consecutive healthy subjects with normally functioning prostheses. gDNA was extracted from ca. 5 × 106 leukocytes, using the QIAamp DNA Mini Kit (Qiagen), according to the manufacturer's recommendations. For mutational analysis, a minisequencing method was employed. Results of the analyses were compared between the PVT and control groups, and also between the OT and NOT subgroups. RESULTS: The frequency of A allele (mutant type) of PZG79A was equal in all PVT patients and in controls. With regards to PZ-A13G polymorphisms, frequency of the mutant G allele was 22% in PVT patients and 19% in controls. Serpina-R67X polymorphism was observed in 8% of PVT patients and 6% of controls. Normal variant CC was present in 47 controls (94%), whereas a heterozygotic mutation (CT) was detected in four PVT patients (8%). Frequency of the ZPI-R67X mutation was significantly higher in patients with OT than in those with NOT (p = 0.041). CONCLUSIONS: The present study was the first to evaluate the potential impact of PZ (PZ-A13G, PZG79A) and ZPI (R-67X, W303X) polymorphisms in the development of PVT. Based on the results of this small observational case-control study, PZ/ZPI polymorphisms do not appear to play an active role in the development of PVT. Hence, further extensive studies are necessary.

A rare mechanism of aortic regurgitation in a young patient.

A 19-year-old male patient was admitted to our institute with dyspnea. His medical history had no rheumatic fever or infective endocarditis. Physical examination revealed a diastolic murmur over the aortic area, rales of bilateral lungs. Bedside transthoracic echocardiography (TTE) revealed a severe aortic regurgitation (AR) without aortic valve stenosis and a moderately dilated left ventricle accompanied by an ejection fraction of 55%. The aortic valve could not be clearly demonstrated as either bicuspid or tricuspid. Congenital AR typically occurs in conjunction with an additional cardiac abnormality or aortic valve stenosis. Furthermore, bicuspid aortic valves are observed in the majority of patients. The aortic valve is created from the truncus ridge of the truncus arteriosus while the embryological development.

Evaluation of the congenital supravalvular aortic stenosis by different imaging modalities.

A 36-year-old female was admitted to hospital exhibiting chest pain, dyspnea, and a heart murmur on the right upper sternal border, radiating to both carotid arteries. The blood pressure of the patient's right arm exceeded the pressure in the left by 25 mm Hg (Coanda effect). In spite of laboratory results that did not fall outside the expected range, the left ventricle was revealed to be hypertrophic following electrocardiography. Transthoracic echocardiography revealed a severe supravalvular aortic stenosis (SVAS) with a peak Doppler velocity of 6.04 cm/s and an estimated mean pressure gradient of 89 mm Hg, with moderate aortic and mitral regurgitation. Contrast-enhanced computed tomography (CCT) indicated a partial hourglass-shaped narrowing of the ascending aorta. Lesions associated with supravalvular stenosis of the pulmonary artery, patent ductus arteriosus, and aortic coarctation were ruled out by the CCT. Congenital SVAS is a rare heart condition, and three anatomically distinct forms have been described. The most common type is the "hourglass," which produces a marked thickening and disorganization of the aortic tissue, producing a constricting annular ridge at the superior margin of the sinuses of Valsalva.

A rare complication of mechanical aortic valve replacement: Separation in the region of the mitral-aortic intervalvular fibrosa.

A 28-year-old man was admitted to our emergency service with a shortness of breath and palpitation. On admission, his blood pressure was high and he was in hypertensive pulmonary edema. His physical examination showed rales in both lungs and pansystolic murmur at mitral focus. His medical history included aortic valve replacement (AVR) because of native aortic valve infective endocarditis. Transthoracic echocardiography (TTE) showed normal functional aortic valve. Color flow imaging demonstrated severe mitral regurgitation with posterior eccentric jet. To examine in detail, transesophageal echocardiography (TEE) and three-dimensional (3D) echocardiography were performed. TEE disclosed a separation in the subaortic curtain leading to severe mitral regurgitation from the left ventricle to the left atrium. In addition to severe mitral regurgitation with posterior eccentric jet, 26-mm-long pouch was seen in mitral-aortic intervalvular fibrosa (MAIVF) at 120° TEE view. This pouch was separated from the mitral anterior leaflet junction releasing the mitral anterior leaflet and causing prolapse and chorda rupture in the A2 scallop of the mitral anterior leaflet. The MAIVF connects the anterior mitral leaflet to the posterior portion of the aortic annulus. The separation of the MAIVF represents a complication of the aortic valve replacement.

Evaluation of Aortic Paravalvular Leak: A Special Reference for Anatomical Localization.

BACKGROUND AND AIM OF THE STUDY: Paravalvular leakage (PVL) remains an unavoidable complication of heart valve surgery and in its severe forms may lead to heart failure and hemolysis. The study aim was to evaluate the echocardiographic, clinical, surgical and laboratory characteristics of patients with aortic PVL. METHODS: A total of 77 aortic PVL patients underwent transthoracic and transesophageal echocardiography examinations. Clinical, echocardiographical and surgical findings were also recorded. RESULTS: Among the 77 patients, 21 (27.3%) had mild, 33 (42.8%) had moderate and 23 (29.9%) had severe aortic PVL. Seventeen patients (22.1%) had moderate-to-severe hemolysis and had a higher incidence of multiple PVL compared to those with no or mild hemolysis. Moderate- to-severe PVL was more frequent between the non-coronary and the left coronary sinus annuli, especially adjacent to the left main coronary artery ostium. Percutaneous closure was performed in five patients. Eleven patients underwent surgical repair, and the localizations of PVL were in accordance with echocardiographic findings. CONCLUSIONS: Aortic PVL occurs more frequently between the non-coronary sinus and the left coronary sinus annuli, which may be associated with multiple factors. Difficulties in seating the prosthesis due to the steep angulation of the commissure and annulus, the avoidance of deep sutures, and focal annular calcification may make this region prone to injury and leakage.

Histopathological and Immunohistochemical Evaluation of Pannus Tissue in Patients with Prosthetic Valve Dysfunction.

BACKGROUND: Prosthetic valve dysfunction due to pannus formation is a rare but serious complication. Currently, limited data are available concerning the pathogenesis and immunohistochemical properties of pannus. The study aim was to investigate the morphological, histopathological and immunohistochemical characteristics of pannus formation in patients with prosthetic valve dysfunction. METHODS: A total of 35 patients (10 males, 25 females; mean age 44 ± 16 years) who had undergone re-do valve surgery due to prosthetic valve obstruction was enrolled in the study. Immunohistochemical studies were aimed at evaluating the expression of alphasmooth muscle actin (α-SMA) and desmin in myofibroblasts and smooth muscle cells; epithelial membrane antigen (EMA) in epithelial cells; and CD34, Factor VIII and vascular endothelial growth factor (VEGF) in endothelial cells. Matrix metalloproteinases (MMPs) -2 and -9, and transforming growth factor-beta (TGF-ß) were used to demonstrate cytokine release from macrophages, leukocytes, fibroblasts and myofibroblasts. RESULTS: Pannus appeared as a tough and thick tissue hyperplasia which began from outside the suture ring in the periannular region and extended to the inflow and outflow surfaces of the prosthetic valves. Histopathological analysis showed the pannus tissue to consist of chronic inflammatory cells (lymphocytes, plasma cells, macrophages and foreign body giant cells), spindle cells such as myofibroblasts, capillary blood vessels and endothelial cells laying down the lumens. Calcification was present in the pannus tissue of 19 explanted prostheses. Immunohistochemical studies revealed positive α-SMA expression in all patients, whereas 60.5% of patients were positive for desmin, 50% for EMA, 42.1% for VEGF, 39.5% for TBF-ß, 42.1% for MMP-2, 86.8% for CD34, and 97.4% for Factor VIII. MMP-9 was negative in all patients. CONCLUSIONS: Pannus tissue appears to be formed as the result of a neointimal response in periannular regions of prosthetic valves that consist of periannular tissue migration, myofibroblast and extracellular matrix proliferation with vascular components. It is a chronic active process in which mediators such as TGF-ß, VEGF and MMP-2 play roles in both matrix formation and degradation.

Ultraslow thrombolytic therapy: A novel strategy in the management of PROsthetic MEchanical valve Thrombosis and the prEdictors of outcomE: The Ultra-slow PROMETEE trial.

BACKGROUND: Low-dose (25mg), slow infusion (6hours) of tissue-type plasminogen activator (t-PA) with repetition as needed has been shown to provide effective and safer thrombolysis in patients with prosthetic valve thrombosis (PVT). Further prolonging the infusion time may be rational with regard to reducing complication rates without reducing success rates. We aimed to investigate the efficacy and safety of ultraslow (25hours) infusion of low-dose (25mg) alteplase (t-PA) for PVT. METHODS AND RESULTS: Transesophageal echocardiography-guided thrombolytic therapy (TT) was administered to 114 patients with PVT in 120 different episodes between 2009 and 2013 in a single center. Prosthetic valve thrombosis was obstructive in 77 (64.2%) and nonobstructive in 43 (35.8%) episodes. Ultraslow infusion (25hours) of low-dose (25mg) t-PA, as the TT regimen, was used in all patients admitted with PVT. The end points were thrombolytic success, mortality, and complication rates. The overall success rate of TT was 90% (95% CI 0.85-0.95). The univariate predictors of an unsuccessful result were higher New York Heart Association (NYHA) class, thrombus cross-sectional area, duration of suboptimal anticoagulation, lower baseline valve area, and presence of atrial fibrillation. The NYHA class was the only independent predictor of TT failure by multiple variable analysis. The overall complication rate was 6.7% (3.3% nonfatal major, 2.5% minor, and 0.8% death). The predictors of complications were presence of atrial fibrillation, higher NYHA class, and thrombus area. CONCLUSION: Ultraslow (25hours) infusion of low-dose (25mg) t-PA without bolus appears to be associated with quite low nonfatal complications and mortality for PVT patients without loss of effectiveness, except for those with NYHA class IV.

Evaluation of p53 Polymorphism in Patients with Pannus-Derived Prosthetic Dysfunction.

BACKGROUND AND AIM OF THE STUDY: Prosthetic valve dysfunction (PVD) due to pannus formation is considered to occur due to a bioreaction to prosthetic material. The p53 gene plays a critical role in apoptosis and cell proliferation. p53 Arg72Pro polymorphism has been found to be associated with coronary stent restenosis, but has not yet been studied in prosthetic heart valve dysfunction. The study aim was to evaluate the association between pannus-derived PVD and p53 G72C(Arg72Pro) polymorphism. METHODS: This single-center, prospective study included 25 patients (20 females, five males; mean age 45.6 +/- 12.5 years; group 1) who underwent redo valve surgery due to PVD, and 49 age- and gender-matched control patients (44 females, five males; mean age 47.3 +/- 12.2 years; group 2) with normofunctional prostheses. The prostheses were examined using transthoracic and transesophageal echocardiography. Analyses of p53 G72C(Arg72Pro) polymorphism were performed using Roche LightCyler 2.0 Real-time polymerase chain reaction. RESULTS: The most common location of replaced valves was the mitral position in both groups (88% and 89.8%, respectively). In group 1, normal alleles (GG) were observed in 12 patients (48%), while one patient (4%) showed a homozygous mutation (GC) and 12 patients (48%) showed a heterozygous mutation (CC). In group 2, 21 patients (42.9%) had normal alleles (GG), while four (8.2%) had a homozygous mutation (CC) and 24 (48.9%) had a heterozygous mutation (GC). No significant difference was observed between the groups with regards to p53 Arg72Pro polymorphism (p = 0.769). CONCLUSION: In patients with prosthetic valves, the underlying mechanism behind pannus formation is unrelated to p53 Arg72Pro polymorphism.