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Frontiers in Cardiovascular Medicine 2024This case report details the identification of a novel likely pathogenic splicing variant in the TTN gene, associated with dilated cardiomyopathy (DCM), in a 42-year-old...
This case report details the identification of a novel likely pathogenic splicing variant in the TTN gene, associated with dilated cardiomyopathy (DCM), in a 42-year-old male patient presenting with early-onset heart failure and reduced ejection fraction. DCM is a nonischemic heart condition characterized by left biventricular dilation and systolic dysfunction, with approximately one-third of cases being familial and often linked to genetic mutations. The TTN gene, encoding the largest human protein essential for muscle contraction and sarcomere structure, is implicated in about 25% of DCM cases through mutations, especially truncating variants. Our investigation revealed a previously unreported G > C mutation at the splice acceptor site in intron 356 of TTN, confirmed by Sanger sequencing and not found in population databases, suggesting a novel contribution to the understanding of DCM etiology. The case emphasizes the critical role of the TTN gene in cardiac function and the genetic complexity underlying DCM. A comprehensive literature review highlighted the prevalence and significance of splice variants in the TTN gene, particularly those affecting the titin A-band, which is known for its role in muscle contraction and stability. This variant's identification underscores the importance of genetic screening in patients with DCM, offering insights into the disease's familial transmission and potential therapeutic targets. Our findings contribute to the expanding knowledge of genetic factors in DCM, demonstrating the necessity of integrating genetic diagnostics in cardiovascular medicine. This case supports the growing evidence linking splicing mutations in specific regions of the TTN gene to DCM development and underscores the importance of genetic counseling and testing in managing heart disease.
PubMed: 38938651
DOI: 10.3389/fcvm.2024.1387063 -
JACC. Advances Oct 2023Clinical outcomes of bicuspid aortic valve (BAV) patients with ascending aortic diameters ≥50 mm who are under surveillance are poorly defined.
BACKGROUND
Clinical outcomes of bicuspid aortic valve (BAV) patients with ascending aortic diameters ≥50 mm who are under surveillance are poorly defined.
OBJECTIVES
The purpose of this study was to assess clinical outcomes in BAV patients with ascending aorta ≥50 mm.
METHODS
Multicenter retrospective cohort study of BAV adults with ascending aorta diameters ≥50 mm by transthoracic echocardiography (TTE). Patients were categorized into 50 to 54 mm and ≥55 mm groups. Clinical outcomes were aortic dissection (AoD), aorta surgery, surgical mortality, and all-cause death.
RESULTS
Of 875 consecutive BAV patients (age 60 ± 13 years, 86% men, aortic diameter 51 mm [interquartile range (IQR): 50-53 mm]), 328 (37%) underwent early surgery ≤3 months from index TTE. Of the remaining 547 patients under surveillance, 496 had diameters 50 to 54 mm and 51 had diameters ≥55 mm and were collectively followed for 7.51 (IQR: 3.98-12.20) years. Of 496 patients with diameters 50 to 54 mm under surveillance, 266 (54%) underwent surgery 2.0 (IQR: 0.77-4.16) years from index TTE. AoD occurred in 9/496 (1.8%) patients for an incidence of 0.4 cases per 100 person-years, surgical mortality was 5/266 (1.9%); and ≥moderate aortic stenosis (but not aorta size) was associated with all-cause death, hazard ratio: 2.05 (95% CI: 1.32-3.20), = 0.001. Conversely, in 547 total patients under surveillance (including 50-54 mm and ≥55 mm), both aorta size and ≥moderate aortic stenosis were associated with all-cause death (both ≤ 0.027). AoD rate in patients ≥55 mm under surveillance was 5.9%.
CONCLUSIONS
In BAV patients with ascending aorta 50 to 54 mm under surveillance, AoD incidence is low and the overall rates of AoD and surgical mortality are similar, suggesting clinical equivalence between surgical and surveillance strategies. Conversely, patients with aortas ≥55 mm should undergo surgery. Aortic stenosis is associated with all-cause death in these patients.
PubMed: 38938356
DOI: 10.1016/j.jacadv.2023.100626 -
Journal of Gynecology Obstetrics and... Jun 2024Prolonging the passive second stage of labor could increase vaginal birth rate, but the data concerning maternal and fetal morbidity are contradictory. The French...
OBJECTIVES
Prolonging the passive second stage of labor could increase vaginal birth rate, but the data concerning maternal and fetal morbidity are contradictory. The French guidelines did not specify a maximum duration of the passive second stage. Our objective was to assess if allowing a 4th hour after full dilatation before pushing increased maternal morbidity, compared to 3 h after full dilatation.
STUDY DESIGN
This single-center, retrospective, observational cohort study took place from January 1-December 31, 2020, in a tertiary maternity unit. All consecutive term nulliparous women who delivered under epidural anesthesia and without pathological fetal heart rate and reaching a second-stage passive phase of labor lasting at least 3 h were included. We compared 2 groups according to the duration of the passive second stage: "3-hour group" and "4-hour group". In the "3-hour group," featuring a second-stage passive phase of up to 3 h, pushing is initiated for favorable conditions, while a cesarean section is performed if conditions are deemed unfavorable. In the "4-hour group", obstetric conditions not justifying immediate pushing after three hours, and the obstetric team believed that an additional hour of expectant management could lead to a successful vaginal delivery. The principal endpoint was a composite criterion of maternal morbidity including obstetric anal sphincter injuries, postpartum hemorrhage, transfusion and intrauterine infection.
RESULTS
We included 111 patients in the "4-hour group" and 349 in the "3-hour group". Composite maternal morbidity did not increase in the "4-hour group" compared to the "3-hour group" (21 (18.9 %) versus 61 (17.5 %); p = 0.73). Neonatal morbidity was similar between the two groups. In the "4-hour group, 91 (82 %) patients had vaginal deliveries", 62 (55,9 %) by spontaneous vaginal delivery and 29 (26,1 %) with instrumental assistance.
CONCLUSION
For selected patients, waiting for 4 h at full dilation can be beneficial due to the high rate of vaginal delivery and low incidence of maternal and fetal complications.
PubMed: 38936801
DOI: 10.1016/j.jogoh.2024.102818 -
American Journal of Obstetrics &... Jun 2024Induction of labor (IOL) is recommended following prelabor rupture of membranes (PROM). The optimal method for IOL and need for cervical ripening in those with PROM and...
BACKGROUND
Induction of labor (IOL) is recommended following prelabor rupture of membranes (PROM). The optimal method for IOL and need for cervical ripening in those with PROM and an unfavorable cervical examination is unclear.
OBJECTIVE
To determine if oxytocin or oral misoprostol results in a shorter time to delivery among nulliparous patients with an unfavorable cervical examination and PROM diagnosis and to evaluate patient satisfaction with both methods.
STUDY DESIGN
This is a randomized clinical trial conducted at an urban tertiary care center from 2019-2023. Subjects were nulliparas ≥ 36 weeks with an unfavorable starting cervical exam (≤ 2 cm and Bishop < 8). The primary outcome was time from IOL to delivery in hours compared between oxytocin versus oral misoprostol. Secondary outcomes included suspected intraamniotic infection, cesarean delivery, composite maternal and neonatal morbidity, and patient satisfaction (assessed by Birth Satisfaction Scale-Revised (BSS-R)). Sub-group analyses for those with BMI ≥ 30kg/m and cervical dilation ≥ 1cm were performed. We required 148 subjects to have 80% power to detect a 2-hour difference in time to delivery. The study was stopped early by the DSMB due to feasibility concerns in recruiting desired sample size Results: 108 subjects were randomized: 56 oxytocin; 52 oral miso. The median gestational age at induction was 39.5 weeks; the mean starting cervical dilation was 1.1 cm. There was no statistical difference in time to delivery between groups overall: 14.9 hours oxytocin v. 18.1 hours oral misoprostol (p=0.06). In sub-group analyses, there was a 5h shorter time to delivery with oxytocin for those with a BMI ≥ 30kg/m (16.6 hours oxytocin v. 21.8 hours oral misoprostol, p 0.04) and 4.5h shorter time to delivery with oxytocin for those with cervix ≥ 1cm (12.9 hours oxytocin v. 17.3 hours oral misoprostol, p 0.04). There were no differences in intraamniotic infection, cesarean delivery, maternal or neonatal morbidity between the groups. Patient satisfaction was higher for those receiving oxytocin compared to misoprostol (29.0 vs. 26.3, p=0.03).
CONCLUSIONS
Among nulliparas with PROM and an unfavorable cervix, there was no difference in overall time to delivery between oxytocin and oral misoprostol. This result should be interpreted with caution given early study discontinuation and inadequate power. However, a shorter time to delivery with oxytocin was noted in obese patients and those with cervical dilation of at least 1 cm. Furthermore, patient satisfaction was higher in the oxytocin group, and there was no increased risk of neonatal or maternal morbidity with oxytocin.
PubMed: 38936618
DOI: 10.1016/j.ajogmf.2024.101414 -
Journal of Applied Physiology... Jun 2024In a 77-year-old former world-record holding male marathoner (2:08:33.6) this study sought to investigate the impact of lifelong intensive endurance exercise on cardiac...
In a 77-year-old former world-record holding male marathoner (2:08:33.6) this study sought to investigate the impact of lifelong intensive endurance exercise on cardiac structure, function and the trajectory of functional capacity (determined by maximal oxygen consumption, V̇Omax) throughout the adult lifespan. As a competitive runner, our athlete (DC) reported performing up to 150-300 miles/wk of moderate-to-vigorous exercise, and sustained 10-15 hours/wk of endurance exercise after retirement from competition. DC underwent maximal cardiopulmonary exercise testing in 1970 (aged 27yrs), 1991 (aged 49yrs) and 2020 (aged 77yrs) to determine V̇Omax. At his evaluation in 2020, DC also underwent comprehensive cardiac assessments including resting echocardiography, and resting and exercise cardiac magnetic resonance to quantify cardiac structure and function at rest and during peak supine exercise. DC's V̇Omax showed minimal change from 27yrs (69.7mL/kg/min) to 49yrs (68.1mL/kg/min), although it eventually declined by 36% by the age of 77yrs (43.6mL/kg/min). DC's V̇Omax at 77yrs, was equivalent to the 50 percentile for healthy 20-29 year-old males and 2.4 times the requirement for maintaining functional independence. This was partly due to marked ventricular dilatation (left-ventricular end-diastolic volume: 273mLs), which facilitates a large peak supine exercise stroke volume (200mLs) and cardiac output (22.2L/min). However, at the age of 78 years, DC developed palpitations and fatigue, and was found to be in atrial fibrillation requiring ablation procedures to revert his heart to sinus rhythm. Overall, this life study of a world champion marathon runner exemplifies the substantial benefits and potential side effects of many decades of intense endurance exercise.
PubMed: 38935800
DOI: 10.1152/japplphysiol.00070.2024 -
Advanced Science (Weinheim,... Jun 2024Anthracyclines are chemotherapeutic drugs used to treat solid and hematologic malignancies. However, life-threatening cardiotoxicity, with cardiac dilation and heart...
Anthracyclines are chemotherapeutic drugs used to treat solid and hematologic malignancies. However, life-threatening cardiotoxicity, with cardiac dilation and heart failure, is a drawback. A combination of in vivo for single cell/nucleus RNA sequencing and in vitro approaches is used to elucidate the underlying mechanism. Genetic depletion and pharmacological blocking peptides on phosphatidylinositol binding clathrin assembly (PICALM) are used to evaluate the role of PICALM in doxorubicin-induced cardiotoxicity in vivo. Human heart tissue samples are used for verification. Patients with end-stage heart failure and chemotherapy-induced cardiotoxicity have thinner cell membranes compared to healthy controls do. Using the doxorubicin-induced cardiotoxicity mice model, it is possible to replicate the corresponding phenotype in patients. Cellular changes in doxorubicin-induced cardiotoxicity in mice, especially in cardiomyocytes, are identified using single cell/nucleus RNA sequencing. Picalm expression is upregulated only in cardiomyocytes with doxorubicin-induced cardiotoxicity. Amyloid β-peptide production is also increased after doxorubicin treatment, which leads to a greater increase in the membrane permeability of cardiomyocytes. Genetic depletion and pharmacological blocking peptides on Picalm reduce the generation of amyloid β-peptide. This alleviates the doxorubicin-induced cardiotoxicity in vitro and in vivo. In human heart tissue samples of patients with chemotherapy-induced cardiotoxicity, PICALM, and amyloid β-peptide are elevated as well.
PubMed: 38935046
DOI: 10.1002/advs.202401945 -
Voprosy Kurortologii, Fizioterapii, I... 2024Arterial hypertension is a major risk factor for cardiovascular disease, affecting a large proportion of the population worldwide. The study of the listed literature... (Review)
Review
Arterial hypertension is a major risk factor for cardiovascular disease, affecting a large proportion of the population worldwide. The study of the listed literature made it possible to assess the effectiveness and necessity of physical exercise in the treatment of hypertension syndrome, including various types of exercise, intensity, duration, and frequency, since drug treatment is not enough for successful therapy. To prevent and treat hypertension, a comprehensive approach is required, including aerobic exercise, which will lower blood pressure by dilating blood vessels.
Topics: Humans; Hypertension; Exercise Therapy; Exercise
PubMed: 38934957
DOI: 10.17116/kurort202410103141 -
Hepatology Communications Jul 2024The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown.
BACKGROUND
The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown.
METHODS
Here, we established an animal model of gallbladder dysfunction and assessed the role of a diseased gallbladder in cholestasis-induced hepatic fibrosis (CIHF).
RESULTS
Mice with smooth muscle-specific deletion of Mypt1, the gene encoding the main regulatory subunit of myosin light chain phosphatase (myosin phosphatase target subunit 1 [MYPT1]), had apparent dysfunction of gallbladder motility. This dysfunction was evidenced by abnormal contractile responses, namely, inhibited cholecystokinin 8-mediated contraction and nitric oxide-resistant relaxation. As a consequence, the gallbladder displayed impaired bile filling and biliary tract dilation comparable to the alterations in CIHF. Interestingly, the mutant animals also displayed CIHF features, including necrotic loci by the age of 1 month and subsequently exhibited progressive fibrosis and hyperplastic/dilated bile ducts. This pathological progression was similar to the phenotypes of the animal model with bile duct ligation and patients with CIHF. The characteristic biomarker of CIHF, serum alkaline phosphatase activity, was also elevated in the mice. Moreover, we observed that the myosin phosphatase target subunit 1 protein level was able to be regulated by several reagents, including lipopolysaccharide, exemplifying the risk factors for gallbladder dysfunction and hence CIHF.
CONCLUSIONS
We propose that gallbladder dysfunction caused by myosin phosphatase target subunit 1 ablation is sufficient to induce CIHF in mice, resulting in impairment of the bile transport system.
Topics: Animals; Myosin-Light-Chain Phosphatase; Mice; Disease Models, Animal; Liver Cirrhosis; Cholestasis; Gallbladder Diseases; Gallbladder; Male; Mice, Knockout
PubMed: 38934703
DOI: 10.1097/HC9.0000000000000473 -
Fetal Diagnosis and Therapy Jun 2024Congenital microgastria (CM) is a rare condition due to early interruption of stomach development between the 4th and 8th week of gestation, leading to a small midline...
INTRODUCTION
Congenital microgastria (CM) is a rare condition due to early interruption of stomach development between the 4th and 8th week of gestation, leading to a small midline tubular stomach. Prenatal diagnosis of CM is a challenge with important implications. This study explores the value of biochemical amniotic fluid (AF) analysis and fetal magnetic resonance imaging (MRI) for the prenatal diagnosis of CM in case of non visible stomach on fetal ultrasound.
CASE PRESENTATION
Four cases of CM were retrospectively investigated in terms of fetal ultrasound, MRI findings and biochemical AF analyses. The patients were referred to the Prenatal Diagnosis Unit of the Hôpital Femme Mère Enfant (Lyon, France) at a mean age of 21 weeks of gestation for absent or small fetal stomach on ultrasound with a suspected diagnosis of esophageal atresia. Ultrasound examination confirmed that the stomach was absent in two of the four fetuses and small in the other two. This feature was associated with a congenital heart defect in two cases and a terminal transverse limb defect in one case. Standard genetic workup (CGH array) results were normal. Biochemical AF analysis, including the esophageal atresia (EA) index were not suggestive of EA. Fetal MRI showed a small midline tubular stomach, associated with a dilated esophagus, highly suggestive of CM.
CONCLUSION
If the fetal stomach is absent on ultrasound, CM should be considered if the AF volume is normal, especially during the third trimester, and if the EA index is not suggestive of gastrointestinal obstruction. In these cases, the diagnosis can be confirmed by fetal MRI, through observation of a small midline tubular stomach associated with a dilated esophagus.
PubMed: 38934150
DOI: 10.1159/000539888 -
Fetal Diagnosis and Therapy Jun 2024Immune checkpoint inhibitors (ICIs) are extensively used in present-day clinical practice for treating many types of cancers at different stages. To date, there is...
INTRODUCTION
Immune checkpoint inhibitors (ICIs) are extensively used in present-day clinical practice for treating many types of cancers at different stages. To date, there is scarce data on the use of immunotherapy in pregnancy. Immune-related adverse events (irAE) are a typical consequence of this therapy miming autoimmune diseases.
CASE PRESENTATION
A 35-year-old woman (G1P0) diagnosed with gastric carcinoma underwent neoadjuvant chemotherapy followed by surgery. During follow-up, axillary metastasis was discovered, radiotherapy failed, consequently immunotherapy was started. Concurrently, pregnancy was ensued. Despite potential risks, the patient opted to continue immunotherapy and the pregnancy. At 31 weeks, fetal bowel dilation was noted. Subsequently, the fetus also developed fetal growth restriction (FGR). A Cesarean Section (CS) was performed at 35 weeks. The newborn required repeated bowel resections for necrotizing enterocolitis (NEC), necessitating extensive medical intervention. The mother continues pembrolizumab treatment with positive response.
CONCLUSION
To the best of our knowledge this might constitute a possible case of fetal immune-related adverse event after immunotherapy in utero exposure.
PubMed: 38934141
DOI: 10.1159/000540000