Histomorphologische Charakterisierung dilatierter und nicht-dilatierter Aortenwand bei unikuspider Aortenklappenmorphologie im Vergleich zur Aorta bei trikuspider Aortenklappe

1 Zusammenfassung 1.1 Deutschsprachige Zusammenfassung 1.1.1 Hintergründe Fehlbildungen der Aortenklappe sind mit einem erhöhten Risiko für das Auftreten von Aneurysmen der Aorta ascendens assoziiert. Ein Großteil der dazu verfügbaren Daten stammt aus der Analyse von Aorten von Individuen mit bikuspider Aortenklappe. Dies ist dadurch begründet, dass es sich bei der bikuspiden Aortenklappe um die häufigste angeborene Fehlbildung des Herzens handelt. Deutlich seltener ist eine sogenannte unikuspide Aortenklappe. Weniger Daten zu Aorta ascendens Aneurysmen bei unikuspider Aortenklappe sind verfügbar. Basierend auf alten Studien gilt die Degeneration der Aorta ascendens in Assoziation mit der unikuspiden Aortenklappe als ein relevanter Risikofaktor für Aortendissektionen. 1.1.2 Fragestellung Folgende Fragestellung wurde bearbeitet: (1) Unterscheiden sich Aorten bei unikuspider und trikuspider Aortenklappe hinsichtlich der VV unter Berücksichtigung des Dilatationsstatus? (2) Unterscheidet sich die Verteilung der endothelialen Stickoxidsynthase in Aorten von Individuen mit unikuspider und trikuspider Aortenklappe unter Berücksichtigung des Dilatationsstatus? (3) Gibt es Unterschiede im Auftreten von Apoptose in der Aorta von Individuen mit unikuspider und trikuspider Aortenklappe? (4) Bestehen Unterschiede zwischen Aorten bei unikuspider und trikuspider Aortenklappe unter Berücksichtigung des Dilatationsstatus hinsichtlich des Kernverlustes glatter Muskelzellen? (5) Gibt es Unterschiede hinsichtlich der mukoiden extrazellulären Matrixakkumulation in der Aortenwand von Individuen mit unikuspider und trikuspider Aortenklappe unter Berücksichtigung des Dilatationsstatus? 1.1.3 Material und Methoden Nach Zustimmung der lokalen Ethikkommission, Aufklärung und schriftlicher Einwilligung erfolgte im Rahmen kardiochirurgischer Eingriffe an der Aortenklappe und / oder der Aorta ascendens die Entnahme von Gewebeproben aus der Aorta ascendens. Insgesamt wurden 74 Individuen in die vorliegende Studie eingeschlossen. Davon hatten 25 Individuen eine unikuspide Aortenklappe. Es dienten 49 Aorten, von Individuen mit trikuspider Aortenklappe als Vergleich. Es erfolgte eine feingewebliche Untersuchung des Aortengewebes mit Standardfärbungen und Immunhistochemien. 1.1.4 Ergebnisse Im Zusammenhang mit Dilatation der Aorta ascendens beobachtete man ein tieferes Einwachsen der Vasa vasorum in die Aortenwand. Die relative Anzahl von Zellen mit dem Nachweis der endothelialen Stickoxidsynthase in der Tunica intima und den Vasa vasorum war vergleichbar. Außerdem lag bei aneurysmatischen Aorten weiter verbreiteter Kernverlust glatter Muskelzellen vor. Hinsichtlich der mukoiden extrazellulären Matrixakkumulation zeigten dilatierte Aorten signifikant schwerere und ausgedehntere Befunde. Betrachtet man die Aortenklappenmorphologie, so beobachtete man bei unikuspider Aortenklappe signifikant mehr apoptotische Zellen pro mm². Interessanterweise zeigten Individuen mit trikuspider Aortenklappe eine schwerwiegendere Degeneration der Aorta ascendens als Individuen mit unikuspider Aortenklappe. 1.1.5 Schlussfolgerung Die Ergebnisse dieser Studie suggerieren, dass das Einwachsen der Vasa vasorum in die Aortenwand Teil der Kompensationsmechanismen bei Degeneration der Gefäßwand ist. Ferner implizieren die Befunde, dass die Vasa vasorum die Hauptlokalisation der endothelialen Stickoxidsynthase in der Aortenwand sind. Außerdem wurde die Apoptose als möglicherweise relevanter Prozess in der Pathophysiologie der Degeneration der Aorta ascendens bei unikuspider Anlage der Aortenklappe identifiziert. Weiter zeigten nicht Aorten von Individuen mit unikuspider Aortenklappe, sondern Aorten von Individuen mit trikuspider Aortenklappe histologische Merkmale einer aggressiven und schwerwiegenden Degeneration. Somit scheint die Degeneration der Aorta ascendens in Assoziation mit einer unikuspiden Aortenklappe weniger aggressiv als bisher angenommen.1.2 Englischsprachige Zusammenfassung 1.2.1 Background Malformation of the aortic valve is associated with ascending aortic aneurysm formation. A large amount of data on this topic was generated by analyzing individuals with bicuspid aortic valve with the bicuspid aortic valve being the most frequent cardiac malformation. Compared to the bicuspid aortic valve the unicuspid aortic valve is a rare cardiac malformation. Thus, little is known on ascending aortic degeneration and associated aneurysm formation in this entity. Based on older trials ascending aortic degeneration in association with a unicuspid aortic valve is believed to be a relevant risk factor for aortic dissections. 1.2.2 Objectives Following objectives were analyzed: (1) Differ aortas in presence of unicuspid and tricuspid aortic valve regarding the vasa vasorum under consideration of the dilatation status? (2) Are there differences in the distribution of the endothelial nitric oxide synthase within the aortic wall of individuals with unicuspid and tricuspid aortic valve with regard of the dilatation status? (3) Differ aortas from individuals with unicuspid and tricuspid aortic valve regarding the abundance of apoptosis? (4) Do aortas with unicuspid and tricuspid aortic valve morphology differ regarding smooth muscle cell nuclei loss considering the dilatation status? (5) Does mucoid extracellular matrix accumulation differ in aortas of individuals with unicuspid and tricuspid aortic valve under consideration of the aortic width? 1.2.3 Material and methods After approval by the local ethics committee and written informed consent of the patients ascending aortic tissue during surgery of the ascending aorta and/or the aortic valve was obtained. Overall 74 individuals were included in this analysis. Of these, 25 individuals had unicuspid aortic valve morphology. The tissue of 49 individuals with a tricuspid aortic valve served as control. Histological analysis were performed using standard stains and immunohistochemistry. 1.2.4 Results Deeper ingrowth of the vasa vasorum was observed in association with aortic dilatation. Regarding the distribution of the endothelial nitric oxide synthase the relative number of cells expressing the endothelial nitric oxide synthase was comparable between the tunica intima and the vasa vasorum. Dilated aortas presented with significantly more smooth muscle cell nuclei loss. In addition, dilated aortas had significantly more widespread and more severe mucoid extracellular matrix accumulation. Regarding aortic valve morphology, aortas from individuals with unicuspid aortic valve morphology had significantly more apoptotic cells per mm². Interestingly, aortas from individuals with a tricuspid aortic valve showed significantly more severe aortic degeneration than aortas from individuals with a unicuspid aortic valve. 1.2.5 Conclusion The data presented suggest ingrowth of the vasa vasorum to be part of compensatory mechanisms in the degeneration of the aortic wall. Further, it is implicated that the vasa vasorum seems to be the main localization of the endothelial nitric oxide synthase within the aortic wall. In addition, apoptosis seems to be relevant in the aortic wall degeneration in association with unicuspid aortic valve morphology. Interestingly aortas from individuals with a tricuspid aortic valve instead of aortas from individuals with a unicuspid aortic valve showed signs of severe aortic degeneration. Thus, aortic wall changes in association with unicuspid aortic valve morphology seem to be more benign than generally assumed.

Elderly with Varying Extents of Cardiac Disease Show Interindividual Fluctuating Myocardial TRPC6-Immunoreactivity

Both particular myocardial locations in the human heart and the canonical transient receptor potential 6 (TRPC6) cation channel have been linked with cardiac pathophysiologies. Thus, the present study mapped TRPC6-protein distribution in select anatomic locations associated with cardiac disease in the context of an orienting pathological assessment. Specimens were obtained from 5 body donors (4 formalin fixation, 1 nitrite pickling salt-ethanol-polyethylene glycol (NEP) fixation; median age 81 years; 2 females) and procured for basic histological stains and TRPC6- immunohistochemistry. The latter was analyzed descriptively regarding distribution and intensity of positive signals. The percentage of positively labelled myocardium was also determined (optical threshold method). Exclusively exploratory statistical analyses were performed. TRPC6-protein was distributed widespread and homogenously within each analyzed sample. TRPC6-immunoreactive myocardial area was comparable regarding the different anatomic regions and sex. A significantly larger area of TRPC6-immunoreactive myocardium was found in the NEP-fixed donor compared to the formalin fixed donors. Two donors with more severe heart disease showed smaller areas of myocardial TRPC6-immunoreactivity overall compared to the other 3 donors. In summary, in the elderly, TRPC6-protein is widely and homogenously distributed, and severe cardiac disease might be associated with less TRPC6-immunoreactive myocardial area. The tissue fixation method represents a potential confounder

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Two Cases of Quadricuspid Aortic Valve: Aortic Regurgitation and Degeneration

Background Quadricuspid aortic valve is rare and occasionally associated with aortic regurgitation and ascending aortic dilatation. Recent studies suggest an association of aortic regurgitation with ascending aortic medial degeneration. Case Description Histologic evaluation of ascending aortic tissue of two individuals with regurgitant quadricuspid aortic valve, one dilated, one non-dilated, yielded comparable degeneration in the Media. Conclusion Regurgitation of quadricuspid aortic valve may lead to the degeneration of Tunica media of the ascending aorta

Elderly with Varying Extents of Cardiac Disease Show Interindividual Fluctuating Myocardial TRPC6-Immunoreactivity

Both particular myocardial locations in the human heart and the canonical transient receptor potential 6 (TRPC6) cation channel have been linked with cardiac pathophysiologies. Thus, the present study mapped TRPC6-protein distribution in select anatomic locations associated with cardiac disease in the context of an orienting pathological assessment. Specimens were obtained from 5 body donors (4 formalin fixation, 1 nitrite pickling salt-ethanol-polyethylene glycol (NEP) fixation; median age 81 years; 2 females) and procured for basic histological stains and TRPC6-immunohistochemistry. The latter was analyzed descriptively regarding distribution and intensity of positive signals. The percentage of positively labelled myocardium was also determined (optical threshold method). Exclusively exploratory statistical analyses were performed. TRPC6-protein was distributed widespread and homogenously within each analyzed sample. TRPC6-immunoreactive myocardial area was comparable regarding the different anatomic regions and sex. A significantly larger area of TRPC6-immunoreactive myocardium was found in the NEP-fixed donor compared to the formalin fixed donors. Two donors with more severe heart disease showed smaller areas of myocardial TRPC6-immunoreactivity overall compared to the other 3 donors. In summary, in the elderly, TRPC6-protein is widely and homogenously distributed, and severe cardiac disease might be associated with less TRPC6-immunoreactive myocardial area. The tissue fixation method represents a potential confounder

Initial sequencing and analysis of the human genome

International audienc

Nat Genet

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings