Nanoscale Structural Comparison of Fibrillin-1 Microfibrils Isolated from Marfan and Non-Marfan Syndrome Human Aorta.

Fibrillin-1 microfibrils are essential elements of the extracellular matrix serving as a scaffold for the deposition of elastin and endowing connective tissues with tensile strength and elasticity. Mutations in the fibrillin-1 gene (FBN1) are linked to Marfan syndrome (MFS), a systemic connective tissue disorder that, besides other heterogeneous symptoms, usually manifests in life-threatening aortic complications. The aortic involvement may be explained by a dysregulation of microfibrillar function and, conceivably, alterations in the microfibrils' supramolecular structure. Here, we present a nanoscale structural characterization of fibrillin-1 microfibrils isolated from two human aortic samples with different FBN1 gene mutations by using atomic force microscopy, and their comparison with microfibrillar assemblies purified from four non-MFS human aortic samples. Fibrillin-1 microfibrils displayed a characteristic "beads-on-a-string" appearance. The microfibrillar assemblies were investigated for bead geometry (height, length, and width), interbead region height, and periodicity. MFS fibrillin-1 microfibrils had a slightly higher mean bead height, but the bead length and width, as well as the interbead height, were significantly smaller in the MFS group. The mean periodicity varied around 50-52 nm among samples. The data suggest an overall thinner and presumably more frail structure for the MFS fibrillin-1 microfibrils, which may play a role in the development of MFS-related aortic symptomatology.

Zinc-aspirin preconditioning reduces endothelial damage of arterial grafts in a rodent model of revascularization.

Introduction: Coronary artery bypass grafting (CABG) is the most common cardiac surgical procedure. The prognosis of revascularization via CABG is determined by the patency of the used grafts, for which an intact endothelium is essential. The degree of ischemia-reperfusion injury (IRI), which occurs during the harvest and implantation of the grafts, is an important determinant of graft patency. Preconditioning with aspirin, a nonsteroidal anti-inflammatory drug has been shown to reduce the functional and molecular damage of arterial grafts in a rodent model. Studies have found that the zinc-aspirin complex may be able to exert an even better protective effect in pathological cardiovascular conditions. Thus, our aim was to characterize the protective effect of zinc-aspirin complex on free arterial grafts in a rodent model of revascularization. Methods: Donor Lewis rats were treated with either zinc-aspirin, aspirin, or placebo (n = 8) for 5 days, then the aortic arches were harvested and stored in cold preservation solution and implanted heterotopically in the abdominal cavity of the recipient rats, followed by 2 h of reperfusion. There was also a non-ischemia-reperfusion control group (n = 8). Functional measurements using organ bath and histomorphological changes using immunohistochemistry were analyzed. Results: The endothelium dependent maximal vasorelaxation was improved (non-transplanted control group: 82% ± 3%, transplanted control group: 14% ± 2%, aspirin group: 31% ± 4%, zinc-aspirin group: 52% ± 4%), the nitro-oxidative stress and cell apoptosis decreased, and significant endothelial protection was shown in the groups preconditioned with aspirin or zinc-aspirin. However, zinc-aspirin proved to be more effective in the reduction of IRI, than aspirin alone. Discussion: Preconditioning with zinc-aspirin could be a promising way to protect the function and structural integrity of free arterial grafts, thus improving the outcomes of CABG.

Long-Term Outcomes Stratified by Age in Patients with a Mechanical versus Biological Mitral Valve Replacement.

Objectives: Balancing anticoagulation and reoperation risks determines prostheses choice (mechanical/biological) for mitral valve replacement. We aimed to re-evaluate the outcomes after biological versus mechanical mitral valve replacement. Methods: We compared long-term benefits and risks of mechanical and biological prostheses in 2056 patients (52% men, 48% women; 65.4 ± 12.1 years) who underwent mitral valve replacements between 1993−2017, in a retrospective single-centre study. Data sources included prospective institutional database, social registry, general practitioner data and follow-up questionnaire. Patients were stratified by age: < = 39 y (n = 82), 40−49 y (n = 164), 50−59 y (n = 335), 60−69 y (n = 593), 70−79 y (n = 743) and > = 80 y (n = 139). Long-term outcomes (mortality, reoperations, bleeding) were analysed. Results: Altogether, 1308 mechanical (53% men, 47% women; 61.5 ± 11.7 years) and 748 biological (50% men, 50% women; 72.3 ± 9.6 years) valves were implanted. The reason for valve replacement was stenosis in 162, insufficiency in 823 and combined in 323 cases for mechanical, while it was 46, 567 and 135 for biological valves, respectively. Overall cumulative survival was higher with mechanical prosthesis (mean: 139 ± 4 vs. 102 ± 5 months, 10 y: 55% vs. 33%, p < 0.0001). Subgroup analysis revealed higher survival among patients receiving mechanical prosthesis up to 60 years (< = 39 y p = 0.047, 40−49 y p < 0.0001, 50−59 y p = 0.001). In patients 60−69 years, overall survival did not differ; however, in survivors beyond 8 years, mechanical prosthesis showed improved survival (p = 0.014). While between 70−79 years survival was nearly identical, for above 80 years, patients had a higher survival with biological prosthesis (p = 0.014). Conclusion: The present data demonstrated a higher survival of mechanical prosthesis in a wide range of patients after mitral valve replacement.

Preventive Impella® Support in High-Risk Patients Undergoing Cardiac Surgery.

BACKGROUND: Patients with severely reduced LV-EF ≤ 30% undergoing CABG have a high risk for postoperative cardiogenic shock. The optimal timing of an adequate hemodynamic support has an impact on short- and midterm mortality after CABG. This study aimed to assess the prophylactic use of the Impella pump in high-risk patients undergoing elective cardiac surgery. METHODS: In this single-center retrospective study, 14 patients with LV-EF (≤30%) undergoing cardiac surgery received a prophylactic, perioperative Impella (5.0, 5.5) support between 2020 and 2022. RESULTS: The mean age at surgery was 64.2 ± 2.6 years, the mean preoperative LV-EF was 20.7% ± 1.56%. The duration of Impella support was 4 (3-7.8) days and the 30-day survival rate was 92.85%. Acute renal failure occurred in four patients who were dialyzed on average for 1.2 ± 0.7 days. Mechanical ventilation was needed for 1.75 (0.9-2.7) days. Time to inotrope/vasopressor independence was 2 (0.97-7.25) days with a highest lactate level (24 h postoperatively) of 3.8 ± 0.6 mmol/l. Postoperative LV-EF showed a significant improvement when compared to preoperative LV-EF (29.1% ± 2.6% vs. 20.7% ± 1.56% (p = 0.022)). CONCLUSION: The prophylactic Impella application seems to be a safe approach to improve the outcomes of this patient population.

Aspirin Reduces Ischemia-Reperfusion Injury Induced Endothelial Cell Damage of Arterial Grafts in a Rodent Model.

Long-term graft patency determines the prognosis of revascularization after coronary artery bypass grafting (CABG). Ischemia-reperfusion (I/R) injury of the graft suffered during harvesting and after implantation might influence graft patency. Aspirin, a nonsteroidal anti-inflammatory drug improves the long-term patency of vein grafts. Whether aspirin has the same effect on arterial grafts is questionable. We aimed to characterize the beneficial effects of aspirin on arterial bypass grafts in a rodent revascularization model. We gave Lewis rats oral pretreatment of either aspirin (n = 8) or saline (n = 8) for 5 days, then aortic arches were explanted and stored in cold preservation solution. The third group (n = 8) was a non-ischemia-reperfusion control. Afterwards the aortic arches were implanted into the abdominal aorta of recipient rats followed by 2 h of reperfusion. Endothelium-dependent vasorelaxation was examined with organ bath experiments. Immunohistochemical staining were carried out. Endothelium-dependent maximal vasorelaxation improved, nitro-oxidative stress and cell apoptosis decreased, and significant endothelial protection was shown in the aspirin preconditioned group, compared to the transplanted control group. Significantly improved endothelial function and reduced I/R injury induced structural damage were observed in free arterial grafts after oral administration of aspirin. Aspirin preconditioning before elective CABG might be beneficial on free arterial graft patency.

Case Report: Morphological Characterization and Long-Term Observation of Bilateral Sequential Internal Mammary Artery Aneurysms in a Patient With Confirmed FBN1 Mutation.

Marfan syndrome (MFS) is a genetically determined connective tissue disorder that leads to ocular, skeletal, and severe cardiovascular involvement. High mortality of MFS is associated with aortic dissection and aneurysm characteristic to the syndrome. In MFS, only a few cases of peripheral arterial involvement have been reported so far, mostly without a genetically confirmed diagnosis. We report a 41-year-old MFS patient with a saccular pearl-string-like aneurysm on the right internal mammary artery (RIMA) and a single aneurysm on the left internal mammary artery (LIMA). To our knowledge this is the first reported case on internal mammary artery aneurysms with this special morphology and with follow-up and blood pressure control as primary therapeutic approach in a patient with genetically confirmed MFS. The aneurysms with the above described morphology first appeared as small aneurysms on a CT scan 6 years after a cardiac operation. Due to the lack of guidelines, based on the asymptomatic state of the patient, the increased tortuosity of the affected vessels and the history of prior cardiac surgery, we decided to closely monitor these aneurysms with blood pressure control and without carrying out any interventions. On the CT scans done 3, 11, 12, 17, and 32 months after identifying the aneurysms, no progression of these structures was detected. Our findings confirm the possibility of the occurrence of internal mammary artery aneurysms in patients with FBN1 mutation and we believe that monitoring these aneurysms with blood pressure management can be a suitable option in selected cases.

Potential predictors of severe cardiovascular involvement in Marfan syndrome: the emphasized role of genotype-phenotype correlations in improving risk stratification-a literature review.

BACKGROUND: Marfan syndrome (MFS) is a genetically determined systemic connective tissue disorder, caused by a mutation in the FBN1 gene. In MFS mainly the cardiovascular, musculoskeletal and ocular systems are affected. The most dangerous manifestation of MFS is aortic dissection, which needs to be prevented by a prophylactic aortic root replacement. MAIN BODY: The indication criteria for the prophylactic procedure is currently based on aortic diameter, however aortic dissections below the threshold defined in the guidelines have been reported, highlighting the need for a more accurate risk stratification system to predict the occurrence of aortic complications. The aim of this review is to present the current knowledge on the possible predictors of severe cardiovascular manifestations in MFS patients, demonstrating the wide range of molecular and radiological differences between people with MFS and healthy individuals, and more importantly between MFS patients with and without advanced aortic manifestations. These differences originating from the underlying common molecular pathological processes can be assessed by laboratory (e.g. genetic testing) and imaging techniques to serve as biomarkers of severe aortic involvement. In this review we paid special attention to the rapidly expanding field of genotype-phenotype correlations for aortic features as by collecting and presenting the ever growing number of correlations, future perspectives for risk stratification can be outlined. CONCLUSIONS: Data on promising biomarkers of severe aortic complications of MFS have been accumulating steadily. However, more unifying studies are required to further evaluate the applicability of the discussed predictors with the aim of improving the risk stratification and therefore the life expectancy and quality of life of MFS patients.

Changing strategies in aortic root reconstruction in Marfan syndrome / Stratégiai szemléletváltás a Marfan-szindrómás betegeken végzett aortagyök-rekonstrukciókban.

Összefoglaló. Bevezetés: A Marfan-szindróma autoszomális domináns módon öröklodo, szisztémás kötoszöveti betegség. A hosszú távú túlélés szempontjából fontos a nagyérkatasztrófák megelozése. Szívsebészeti szempontból a legfontosabb elváltozás az aortagyök tágulata. Aortagyök-rekonstrukciós beavatkozásaink Bentall-DeBono-, David I. és módosított Yacoub-mutétek, melyek mind preventív jelleggel, mind dissectio esetén jó eredménnyel végezhetok. Célkituzés: A marfanos betegeknél eltéro technikával végzett aortagyök-rekonstrukciós mutéteink összehasonlítása. Módszer: A Semmelweis Egyetem Városmajori Szív- és Érgyógyászati Klinikáján 1993 és 2020 között Marfan-szindrómásoknál elvégzett Bentall-DeBono-, David I. és módosított Yacoub-féle aortagyök-rekonstrukciókat elemeztük. A mutét szerinti csoportok életkora a beavatkozás idején 29,69 (21,98-41,25) év, 29,15 ± 11,99 év és 35,29 ± 14,14 év volt, a fenti sorrendben. Az adatok forrásául a Magyar Marfan Regiszter és az Aortagyök-rekonstrukciós Regiszter szolgált. Eredmények: Az utánkövetési ido 132 ± 81,04 hónap volt a Bentall-, 76 ± 27,77 hónap a David-, valamint 4,5 (0,75-11,75) hónap a Yacoub-mutét esetén. A David- és a Yacoub-beavatkozások gyakrabban voltak profilaktikusak, mint a Bentall-operációk (p = 0,0153; p = 0,0085). A Bentall-mutéteknél ritkább volt a primer mutét esetleges késobbi elégtelenségébol fakadó reoperáció, mint a David-operációknál (p<0,001). David-beavatkozásnál a Bentall-mutéthez képest hosszabb volt a cardiopulmonaris bypass (p = 0,0013) és az aortalefogás ideje (p = 0,0048), valamint David- és Yacoub-mutét esetén gyakrabban lépett fel korai posztoperatív szövodmény, mint Bentall-operációnál (p = 0,0005; p = 0,0037). A késoi szövodmények és a túlélés tekintetében a csoportok nem különböztek. Következtetés: Marfan-szindrómában a leggyakrabban halált okozó szövodmény az akut aortaruptura, illetve akut aortadissectio. Eredményeink alapján mindhárom profilaktikus aortagyök-rekonstrukciós mutéti típus jól reprodukálható és jó eredménnyel végezheto Marfan-szindrómában. Orv Hetil. 2021; 162(18): 696-704. INTRODUCTION: Marfan syndrome is an autosomal dominant, systemic connective tissue disorder. Preventing vascular complications is essential for long-term survival. Aortic dilation is the main cardiac surgical manifestation. Bentall-DeBono, David I and modified Yacoub aortic root reconstructions treat and prevent aortic dissections with great outcomes. OBJECTIVE: Comparing results of aortic root reconstructions in Marfan syndrome. METHOD: We analysed the data of Bentall-DeBono, David I and modified Yacoub operations performed in Marfan syndrome at the Heart and Vascular Center, Semmelweis University between 1993 and 2020. Ages of surgical groups at the time of operation were 29.69 (21.98-41.25) years, 29.15 ± 11.99 years and 35.29 ± 14.14 years, respectively. Data were obtained from the Hungarian Marfan Register and the Aortic Root Reconstruction Register. RESULTS: Follow-up time was 132 ± 81.04 months for Bentall, 76 ± 27.77 months for David and 4.5 (0.75-11.75) months for Yacoub groups. David and Yacoub operations were prophylactic more frequently than Bentall ones (p = 0.0153; p = 0.0085). Freedom from reoperation after primary surgery insufficiency was more common for Bentall than for David procedure (p<0.001). Compared to Bentall, David surgeries required longer cardiopulmonary bypass (p = 0.0013) and aortic cross clamp time (p = 0.0048), more early postoperative complications occurred after David and Yacoub, than after Bentall operations (p = 0.0005; p = 0.0037). Late complications and survival did not differ among the groups. CONCLUSION: In Marfan syndrome, acute aortic rupture and dissection are the main contributors to mortality. Based on our results, the prophylactic aortic root reconstructions are reproducible and can be performed with great outcomes. Orv Hetil. 2021; 162(18): 696-704.

Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement.

BACKGROUND: Marfan syndrome (MFS) is a systemic connective tissue disorder with life-threatening manifestations affecting the ascending aorta. MFS is caused by dominant negative (DN) and haploinsufficient (HI) mutations of the FBN1 gene. Our aim was to identify mutations of MFS patients with high detection rate and to investigate the use of a gene panel for patients with Marfanoid habitus. We also aimed to examine correlations between genotype and cardiovascular manifestations to predict "malignant" mutations. METHODS: 136 individuals were enrolled. In the first phase, next-generation sequencing (NGS) and Sanger sequencing were performed for 57 patients to screen the FBN1 gene, followed by multiplex ligation-dependent probe amplification (MLPA) in negative cases. For repeated negative results, NGS gene panel involving 9 genes was used. In the second phase, 79 patients were tested primarily with the same gene panel, negative samples were tested by MLPA. RESULTS: 84 pathogenic mutations were detected, out of which 78 affected FBN1, 6 non-FBN1 mutations (2 TGFB2, 1 TGFBR2, 2 TGFBR1, 1 SMAD3) are associated with Loeys-Dietz syndrome (LDS). LDS patients had lower systemic score and they were younger, but their aortic involvement did not differ. MLPA detected 4 multi-exon deletions of FBN1 gene, which could not be identified by our first-step screening method. Aortic involvement (aortic dissection and/or dilation) did not differ significantly among HI and DN mutations (p = 0.061). Combined group of HI and DN mutations eliminating a disulphide-bonding cysteine (DN Cys) had significantly higher aortic involvement rate than DN mutations not eliminating a disulphide-bonding cysteine (DN non-Cys) (p < 0.001). Patients with DN Cys required significantly more aortic surgeries than HI and DN non-Cys mutations (p = 0.042 and p = 0.015, respectively). CONCLUSIONS: Due to the relevant number of mutations affecting genes other than FBN1, preferred approach for testing individuals with Marfanoid habitus is using a gene panel rather than single-gene analysis, followed by MLPA for negative samples. DN Cys and HI mutations should be considered as risk factors for aortic involvement. Genetic testing for patients with Marfanoid features and a systemic score under 7 is recommended, as LDS patients may have lower scores, but they may have severe cardiovascular manifestations.

Psychological factors affecting Marfan syndrome patients with or without cardiac surgery.

BACKGROUND: Marfan syndrome (MFS) is a systemic connective tissue disorder belonging to a group of rare diseases. Several psychologically distressing factors can challenge life for MFS patients. The aim of the present study was, therefore, to assess the psychological and psychosocial aspects of MFS with the goal of identifying a means of improving disease management for patients. METHODS: A total of 66 adult patients with MFS were enrolled into the study prospectively and were divided into operated (OP) and non-operated (NOP) subgroups. Multiple questionnaire tests were used to determine the mental and physical state of our patients. Demographic and surgical data were collected. The results of the tests were also compared to the Hungarostudy (HS) population (representing the average Hungarian population) by using a propensity-matched control. RESULTS: OP group scores yielded more alcohol consumption (P<0.001), while NOP group showed more sleep disturbances. Scores on the MMSE, BECK, STAI and STAI-T tests showed no significant difference comparing the OP and NOP groups. MFS patients appear to have moderate pain-related disability and mild depressive symptoms and sleep disturbances (P<0.05) compared to the HS group. On 10-point scale, MFS patients were more satisfied with their lives (P<0.001) and considered themselves happier (P<0.001) than the HS population; however, they also spent more days on sick leave and in hospital over the past year. The HS group yielded a higher overall percentage of current smokers and pack-per-year consumption than the MFS patients overall (P=0.003 and P<0.001 respectively). CONCLUSIONS: Marfan patients' psychosocial life differs in many ways (including sleep disturbances, healthier lifestyle, pain-related suffering) from the average Hungarian population. Therefore, as part of a multidisciplinary approach during treatment, modern management of MFS should include psychosocial exploration and psychological support in addition to traditional medical options.

Increased visceral arterial tortuosity in Marfan syndrome.

BACKGROUND: Clinical evidence suggests that the currently recommended approach to estimate the risk of aortic dissection in Marfan syndrome (MFS) is not reliable enough. Therefore, we investigated the possible role of visceral arterial tortuosity in the risk stratification. METHODS AND RESULTS: Splenic and renal arteries of 37 MFS patients and 74 age and gender matched control subjects were segmented using CT angiography imaging. To measure tortuosity, distance metric (DM), sum of angles metric (SOAM), inflection count metric (ICM), and the ratio of ICM and SOAM (ICM/SOAM) were calculated. DM of the splenic, right and left renal artery was significantly higher in MFS patients than in controls (2.44 [1.92-2.80] vs. 1.75 [1.57-2.18] p < 0.001; 1.16 [1.10-1.28] vs. 1.11 [1.07-1.15] p = 0.011; 1.40 [1.29-1.70] vs. 1.13 [1.09-1.23] p < 0.001, respectively). A similar tendency for ICM and an opposite tendency for SOAM were observed. ICM/SOAM was significantly higher in the MFS group compared to controls in case of all three arteries (73.35 [62.26-93.63] vs. 50.91 [43.19-65.62] p < 0.001; 26.52 [20.69-30.24] vs. 19.95 [16.47-22.95] p < 0.001; 22.81 [18.64-30.96] vs. 18.38 [15.29-21.46] p < 0.001, respectively). MFS patients who underwent aortic root replacement had increased right and left renal DM and ICM/SOAM compared to MFS patients without surgery. CONCLUSION: To our knowledge this is the first demonstration of increased arterial tortuosity in MFS on visceral arteries. Visceral arterial tortuosity, dominated by curves of lower frequency but higher amplitude according to the observed opposite tendency between the DM and SOAM metrics, could be a possible new predictor of serious manifestations of MFS.

Hungarian Marfan family with large FBN1 deletion calls attention to copy number variation detection in the current NGS era.

Copy number variations (CNVs) comprise about 10% of reported disease-causing mutations in Mendelian disorders. Nevertheless, pathogenic CNVs may have been under-detected due to the lack or insufficient use of appropriate detection methods. In this report, on the example of the diagnostic odyssey of a patient with Marfan syndrome (MFS) harboring a hitherto unreported 32-kb FBN1 deletion, we highlight the need for and the feasibility of testing for CNVs (>1 kb) in Mendelian disorders in the current next-generation sequencing (NGS) era.