The effect of
mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results.
This study aims to determine the impact ...of the
mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality).
MFS patients with a pathogenic
mutation followed at two specialised units were included.
mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients.
Two hundred and ninety patients with MFS were included: 113 (39%) with an HI-
mutation and 177 (61%) with a DN-
. At baseline, patients with HI-
had a larger aortic root diameter than patients with DN-
(HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI-
(HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI-
tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN-
(HR: 3.3, 95% CI 1.0 to 11.4, p=0.060).
Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.
To determine the efficacy of losartan vs. atenolol in aortic dilation progression in Marfan syndrome (MFS) patients.
A phase IIIb, randomized, parallel, double-blind study was conducted in 140 MFS ...patients, age range: 5-60 years, with maximum aortic diameter <45 mm who received losartan (n = 70) or atenolol (n = 70). Doses were raised to a maximum of 1.4 mg/kg/day or 100 mg/day. The primary end-point was the change in aortic root and ascending aorta maximum diameter indexed by body surface area on magnetic resonance imaging after 36 months of treatment. No serious drug-related adverse effects were observed. Five patients presented aortic events during a follow-up (one in the losartan and four in the atenolol groups, P = 0.366). After 3 years of follow-up, aortic root diameter increased significantly in both groups: 1.1 mm (95% CI 0.6-1.6) in the losartan and 1.4 mm (95% CI 0.9-1.9) in the atenolol group, with aortic dilatation progression being similar in both groups: absolute difference between losartan and atenolol -0.3 mm (95% CI -1.1 to 0.4, P = 0.382) and indexed by BSA -0.5 mm/m2 (95% CI -1.2 to 0.1, P = 0.092). Similarly, no significant differences were found in indexed ascending aorta diameter changes between the losartan and atenolol groups: -0.3 mm/m2 (95% CI -0.8 to 0.3, P = 0.326).
Among patients with MFS, the use of losartan compared with atenolol did not result in significant differences in the progression of aortic root and ascending aorta diameters over 3 years of follow-up.
Life expectancy in Marfan syndrome patients has improved thanks to the early detection of aortic dilation and prophylactic aortic root surgery. Current international clinical guidelines support the ...use of aortic root diameter as a predictor of complications. However, other imaging markers are needed to improve risk stratification. This study aim to ascertain whether proximal aorta longitudinal and circumferential strain and distensibility assessed by cardiac magnetic resonance (CMR) predict the aortic root dilation rate and aortic events in Marfan syndrome.
One hundred and seventeen Marfan patients with no previous aortic dissection, cardiac/aortic surgery, or moderate/severe aortic regurgitation were prospectively included in a multicentre protocol of clinical and imaging follow-up. At baseline, CMR was performed and proximal aorta longitudinal strain and ascending aorta circumferential strain and distensibility were obtained. During follow-up (85.7 75.0-93.2 months), the annual growth rate of aortic root diameter was 0.62 ± 0.65 mm/year. Fifteen patients underwent elective surgical aortic root replacement and four presented aortic dissection. Once corrected for baseline clinical and demographic characteristics and aortic root diameter, proximal aorta longitudinal strain, but not circumferential strain and distensibility, was an independent predictor of the aortic root diameter growth rate (P = 0.001, P = 0.823, and P = 0.997, respectively), z-score growth rate (P = 0.013, P = 0.672, and P = 0.680, respectively), and aortic events (P = 0.023, P = 0.096, and P = 0.237, respectively).
Proximal aorta longitudinal strain is independently related to the aortic root dilation rate and aortic events in addition to aortic root diameter, clinical risk factors, and demographic characteristics in Marfan syndrome patients.
Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that ...nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Abstract Objective Postoperative myocardial infarction remains a serious complication in cardiac surgery. The incidence and impact of this condition in acute type A aortic dissection are poorly ...understood. Methods A total of 1445 patients with acute type A aortic dissection who underwent surgery were enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2013. Individuals with preoperative myocardial infarction at hospital presentation and a history of myocardial infarction were excluded. Patients with postoperative myocardial infarction (n = 38, 2.6%) were compared with those without postoperative myocardial infarction (n = 1407, 97.4%). Results The postoperative myocardial infarction group was more often of white race (100% vs 90%, P = .043) with bicuspid aortic valve (15.6% vs 4.5%, P = .015). Imaging demonstrated more aortic root involvement (75.8% vs 49.5%, P = .003), pericardial effusion (65.5% vs 44.1%, P = .022), and coronary artery compromise (27.3% vs 10.2%, P = .022). Patients with postoperative myocardial infarction were more frequently hypotensive or in shock during surgery (42.9% vs 25.5%, P = .021). Patients with postoperative myocardial infarction were more likely to have undergone root replacement (54.5% vs 33.3%, P = .011), coronary artery bypass grafting (28.6% vs 7.4%, P < .001), or aortic valve replacement (40.0% vs 23.8%, P = .027), and less likely to have had complete arch replacement (2.8% vs 14.0%, P = .050). Median circulatory arrest time was higher in postoperative myocardial infarction (60 vs 38 minutes, P = .024). In-hospital mortality (57.9% vs 16.3%, P < .001) and Kaplan–Meier estimates of 5-year mortality ( P = .007) were distinctly higher in postoperative myocardial infarction. Conclusions Postoperative myocardial infarction is a devastating complication of type A aortic dissection repair. It is associated with bicuspid aortic valve, root involvement, pericardial effusion, and extent of surgical repair. Patients with postoperative myocardial infarction have higher serious postoperative complications, in-hospital mortality, and 5-year mortality rates than those without postoperative myocardial infarction.
Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the
(fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called ...fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms.
Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (
) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A;
mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration.
The main canonical pathways highlighted in the transcriptomic analysis in aortas from
mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young
mice. In vitro experiments in
-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in
mice.
Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.
Type-2 diabetes (T2DM) and arterial hypertension (HTN) are major risk factors for heart failure. Importantly, these pathologies could induce synergetic alterations in the heart, and the discovery of ...key common molecular signaling may suggest new targets for therapy. Intraoperative cardiac biopsies were obtained from patients with coronary heart disease and preserved systolic function, with or without HTN and/or T2DM, who underwent coronary artery bypass grafting (CABG). Control (
= 5), HTN (
= 7), and HTN + T2DM (
= 7) samples were analysed by proteomics and bioinformatics. Additionally, cultured rat cardiomyocytes were used for the analysis (protein level and activation, mRNA expression, and bioenergetic performance) of key molecular mediators under stimulation of main components of HTN and T2DM (high glucose and/or fatty acids and angiotensin-II). As results, in cardiac biopsies, we found significant alterations of 677 proteins and after filtering for non-cardiac factors, 529 and 41 were changed in HTN-T2DM and in HTN subjects, respectively, against the control. Interestingly, 81% of proteins in HTN-T2DM were distinct from HTN, while 95% from HTN were common with HTN-T2DM. In addition, 78 factors were differentially expressed in HTN-T2DM against HTN, predominantly downregulated proteins of mitochondrial respiration and lipid oxidation. Bioinformatic analyses suggested the implication of mTOR signaling and reduction of AMPK and PPARα activation, and regulation of PGC1α, fatty acid oxidation, and oxidative phosphorylation. In cultured cardiomyocytes, an excess of the palmitate activated mTORC1 complex and subsequent attenuation of PGC1α-PPARα transcription of β-oxidation and mitochondrial electron chain factors affect mitochondrial/glycolytic ATP synthesis. Silencing of PGC1α further reduced total ATP and both mitochondrial and glycolytic ATP. Thus, the coexistence of HTN and T2DM induced higher alterations in cardiac proteins than HTN. HTN-T2DM subjects exhibited a marked downregulation of mitochondrial respiration and lipid metabolism and the mTORC1-PGC1α-PPARα axis might account as a target for therapeutical strategies.
•This is the first reported case of Brevundimona aurantiaca infective endocarditis (IE) in humans.•This is the first report of IE acquired by water dispenser of a domestic refrigerator.•Complicated ...IE affecting the mitroaortic curtain, requiring a UFO procedure, is reported.
Infective endocarditis (IE) is a feared life-threatening complication that requires a multidisciplinary approach. Although a variety of microorganisms have caused IE, Brevundimonas aurantiaca human infection has never been reported previously. To our knowledge, this is the first reported case of endocarditis and human infection due to B. aurantiaca.
Surgery for intervalvular fibrous body reconstruction in aortic and mitral valve replacement is a complex operation, although mandatory in some circumstances. The long-term result of this operation ...remains unknown. The objective of this study was to analyze the outcomes of this technique.
A descriptive and retrospective study was carried out to analyze operative morbidity and mortality in fibrous body reconstruction with the "David technique" and to evaluate the midterm and long-term results regarding durability and survival.
A total of 40 consecutive patients underwent the David technique between 1997 and 2014. The mean age was 58 ± 15 years and 62.5% were male. The indications were active endocarditis with paravalvular and fibrous body abscesses in 26 patients (group A) and massive calcification of the intervalvular fibrous body in 14 patients (group B). Mean European system for cardiac operative risk evaluation I predicted risk of mortality was 36 ± 24 and 16 ± 15, respectively. The hospital mortality rate was 15.3% in group A and 7.1% in group B. Survival rate after 1, 5, and 10 years was 65.4%, 57.7%, and 50% for group A and 92.9%, 85.7%, and 78.6% for group B. Freedom from reoperation at 1, 5, and 10 years was 92.3%, 84.6%, and 76.9% for group A and 90.9%, 90.9%, and 90.9% for group B. Mean follow-up was 53 ± 8 months.
Although this complex operation is associated with high perioperative mortality, the long-term results are acceptable in patients where there are not suitable alternative procedures.
Left atrial appendage occlusion has become an alternative for long-term anticoagulation for patients with non-valvular atrial fibrillation. Although the procedure is safe, life-threatening ...complications such as embolization of the device or cardiac tamponade might occur. We present a case of a LAmbre device that migrated 4 days after being implanted and remained trapped in the mitral valve. Secondary massive mitral regurgitation with severe stenosis and haemodynamic instability required emergency surgery. The device was successfully removed, but severe damage in the anterior leaflet and chords forced a valve replacement.
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