Klinische und prognostische Bedeutung von löslichem Angiotensin-Converting-Enzym 2 (sACE2) bei erwachsenen Patienten mit komplexen angeborenen Herzfehlern

Abstract

Im Rahmen der aktuellen COVID-19 Pandemie gelangte ACE2 wieder in den Fokus der Wissenschaft, da ACE2 als Rezeptor für SARS-CoV-2 identifiziert wurde. Daneben ist ACE2 als kardioprotektiver Gegenspieler im Renin-Angiotensin-Aldosteron-System bekannt, das bei verschiedenen kardiovaskulären Erkrankungen als auch beim Vorliegen einer Herzinsuffizienz aktiviert wird. Das Ziel unserer Untersuchung war, lösliches ACE2(sACE2) im Serum bei erwachsenen Patienten mit komplexen angeborenen Herzfehlern (AHF) zu bestimmen und Einflussfaktoren auf die sACE2-Konzentrationen zu eruieren. Zudem sollte der prognostische Stellenwert von sACE2 in unserem Patientenkollektiv untersucht werden. Es wurden daher Serumproben von 182 Patienten mit komplexen AHF bezüglich der sACE2-Konzentrationen analysiert und mit 63 alters- und geschlechtsgleichen gesunden Probanden verglichen. Erhöhte sACE2-Spiegel konnten bei allen Patienten mit unterschiedlichen komplexen AHF nachgewiesen werden. Die höchsten sACE2-Konzentrationen fanden sich bei Patienten mit Eisenmenger-Physiologie und Patienten mit einer höheren NYHA-Klasse ≥ III. Als unabhängiger Faktor für erhöhte sACE2-Spiegel konnte eine NYHA-Klasse ≥ III ausgemacht werden. Bezüglich des prognostischen Stellenwertes für die Gesamtmortalität und Herzinsuffizienz-bedingte Mortalität war sACE2 in der multivariablen Analyse den Standardbiomarkern NT-proBNP und hsTNT deutlich unterlegen. Zusammenfassend kann festgehalten werden, dass sich bei allen Patienten mit unterschiedlichen komplexen AHF erhöhte sACE2-Spiegel fanden. Da innerhalb dieses Patientenkollektivs bei Patienten mit Eisenmenger-Physiologie und Patienten mit einer höheren NYHA-Klasse ≥ III die höchsten sACE2-Konzentrationen gemessen werden konnten, weisen diese Subgruppen neben einer schlechteren Prognose möglicherweise auch eine erhöhte Vulnerabilität für COVID-19 auf. Im Gegensatz zu den etablierten Standard-Biomarkern NT-proBNP und hsTNT scheint sACE2 in diesem Patientenkollektiv kein robuster prognostischer Marker zu sein.

During the current COVID-19 pandemic, ACE2 has tremendously gained interest due to its dual role as the cell entry receptor for the novel coronavirus SARS-CoV-2 as well as the regulatory counterpart in the RAAS. ACE2 is a carboxymonopeptidase that predominantly occurs in a membrane-bound form (mACE2) whose ectodomain is released into the circulation by proteolytic shedding via a disintegrin and metalloproteinase (ADAM)-17 to form soluble ACE2 (sACE2). Previous studies have shown that sACE2 levels are elevated in patients with chronic left heart failure and increase according to NYHA class, BNP levels and reduced systolic left ventricular function [1]. Moreover, a prognostic value of sACE2 has been demonstrated in this cohort of patients that seems to be equivalent to that of natriuretic peptides [2]. Recently, elevated sACE2 levels have also been detected in patients with coronary heart disease [3] and confirmed in two large cohorts of patients with chronic left heart failure [4]. Furthermore, expression of mACE2 in myocardial tissue was found to be higher in patients with aortic valve stenosis than in controls or patients with mitral valve regurgitation [5]. The aim of our study therefore was to analyse sACE2 levels in adult patients with complex congenital heart disease in order to evaluate determinants of sACE2 and to assess its prognostic impact. For analysis, frozen serum samples of patients and controls having participated in previous studies were used. A total of 182 consecutive patients and 63 healthy controls were enrolled in the study showing no difference in sex distribution, age, body mass index or blood pressure. The recruitment period encompassed the time between January 2015 and December 2019 representing the pre-COVID-19 era. sACE2 concentrations were elevated in all subtypes of complex congenital heart disease with highest values found in patients with EIS (median 1418.4 pg/ml) or a higher NYHA class ≥ III (median 1856.2 pg/ml). Higher sACE2 levels were also detected in patients with a morphologically left ventricle as compared to patients with a morphologically right ventricle (median 841.7 pg/ml versus 633.9 pg/ml; p=0.026). Furthermore, higher sACE2 levels were found in patients with residual defects associated with ventricular pressure overload (median 1565.1 pg/ml). Linear regression analysis was used to figure out determinants of sACE2 concentrations. Univariable analysis revealed that a higher sACE2 level was associated with a higher NYHA class ≥ III, the presence of EIS, a higher creatinine concentration, a systemic morphological left ventricle and the use of MRA. In contrast, the use of ACEI/ARB was associated with lower sACE2 levels. In the multivariable analysis, a higher NYHA class ≥ III turned out to be the most significant and independent factor of elevated sACE2 levels (p=0.002) whereas the use of ACEI/ARB was the most significant factor of lower sACE2 concentrations (p=0.001). In order to evaluate the prognostic value of sACE2, ROC curves were plotted for all-cause mortality and heart failure related mortality comparing sACE2 with the well-established prognostic biomarkers hsTNT and NT-proBNP. Regarding all-cause mortality, AUC was significantly higher for NT-proBNP (AUC 0.941) and hsTNT (AUC 0.863) than for sACE2 (AUC 0.707) (p=0.004 and p=0.091, respectively). Regarding heart failure related mortality, AUCs were statistically not different for all biomarkers. However, adjusted cox regression analysis identified a higher NYHA class ≥ III and hsTNT as independent predictors of all-cause mortality and a higher NYHA class ≥ III and NT-proBNP as independent predictors of heart failure related mortality. Taken together, elevated sACE2 concentrations were detected in all subtypes of patients with complex congenital heart disease. Highest sACE2 levels were found in EIS patients or those with a higher NYHA class ≥ III reflecting a poorer prognosis and perhaps a potentially higher vulnerability to COVID-19 infection. In contrast to NT-proBNP or hsTNT, sACE2 doesn’t seem to be a robust prognostic marker in a cohort of patients with complex congenital heart disease.