Sex-specific pathways in early cardiac response to pressure overload in mice

Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (α-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFβ2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF

Influence of estrogen receptor beta on the sex specific development of myocardial hypertrophy and left ventricular dysfunction in a mouse model

Hintergrund und Ziel – Frauen und Männer unterscheiden sich deutlich in Pathogenese und Verlauf der linksventrikulären Hypertrophie und Herzinsuffizienz. Diese Geschlechterunterschiede können zumindest partiell auf Sexualhormone, besonders Östrogene zurückgeführt werden. Östrogene wirken biologisch über zwei verschiedene Östrogenrezeptoren: ERα und ERβ. Viele Befunde weisen auf eine kardioprotektive Wirkung der Östrogene und speziell auf eine besondere Rolle des ERβ bei der Entwicklung der druckinduzierten Myokardhypertrophie und Dysfunktion hin. Das Ziel dieser Studie war es, die Rolle des ERβ für die geschlechtsspezifische Entwicklung der druckinduzierten Myokardhypertrophie und linksventrikulären Dysfunktion bei Mäusen zu untersuchen. Methoden – An männlichen und weiblichen Wildtypmäusen (WT) und Mäusen mit Deletion des ERβ (ERβ-/-) wurde die transverse Aortenkonstriktion (TAC) bzw. Scheinoperation (SHAM) durchgeführt. Jedes Tier wurde zwei, drei, vier, sechs und neun Wochen nach der Operation echokardiografisch untersucht. Dabei wurden der transstenotische Druckgradient, die linksventrikuläre Masse (LVM/TL), Auswurfsfraktion (EF) und relative diastolische Wanddicke bestimmt. Ergebnisse – Zwei Wochen nach TAC wurde die systolische Pumpfunktion aller Gruppen infolge signifikanter Myokardhypertrophie und konzentrischen Remodelings gleichmäßig aufrechterhalten. Geschlechterunterschiede in der Entwicklung der Linksherzhypertrophie wurden beobachtet: Männliche Wildtypmäuse entwickelten nach TAC eine signifikant stärkere linksventrikuläre Hypertrophie als altersgleiche, weibliche Wildtypmäuse (4.-9.Woche p<0,02). ERβ modulierte die Hypertrophieantwort geschlechtsspezifisch: Weibliche ERβ-/--Tiere zeigten nach TAC einen Trend zu einer stärkeren konzentrischen Linksherzhypertrophie mit ausgeprägter Septum und Hinterwanddicke als weibliche Wildtyptiere. ERβ hemmt somit das exzentrische Ventrikelwachstum bei weiblichen Wildtyptieren. Männliche Mäuse mit Deletion des ERβ entwickelten im neunwöchigen Verlauf eine niedrigere Linksherzhypertrophie als männliche Wildtyptiere. Beide Gruppen wiesen dabei eine Abnahme der relativen Hinterwanddicken und somit eine exzentrische Hypertrophie auf. Dies war bei ERβ-/--Mäusen etwas stärker ausgeprägt als bei WT-Tieren. Des Weiteren zeigten männliche ERβ-/--Mäuse gegenüber den weiblichen Vergleichstieren neun Wochen nach TAC einen signifikanten Abfall des transstenotischen Druckgradienten. Es bestanden Geschlechterunterschiede der kardialen Funktion bei Druckhypertrophie: Männliche Versuchsgruppen zeigten gegenüber weiblichen Mäusen eine im Trend schlechtere Ventrikelfunktion und neun Wochen nach TAC einen Verlust des konzentrischen Remodelings mit signifikanter Ventrikeldilatation (9.Woche p<0,05). ERβ hatte keinen signifikanten Einfluss auf die systolische Funktion. Schlussfolgerung – Das Geschlecht beeinflusst signifikant die Entwicklung der Linksherzhypertrophie und linksventrikulären Dysfunktion nach Druckbelastung. ERβ wirkt hierbei modulierend. Bisherige Studien zeigten vornehmlich einen protektiven Effekt des ERβ für das weibliche Herz. Diese Untersuchung zeigt darüber hinaus eine protektive Wirkung des ERβ auf die Hypertrophieantwort des männlichen Myokards. Weitere Studien sind nötig, um die Rolle des ERβ für die geschlechtsspezifische Entwicklung der Myokardhypertrophie und Herzinsuffizienz bei Frau und Mann zu untersuchen.Background – Woman and man show differences in the pathogenesis and characteristics of left ventricular hypertrophy and heart failure. These gender differences can be partially attributed to the role of sex hormones, in particular estrogens. Estrogens act biologically by two different estrogen receptors: ERα and ERβ. Many findings show a cardioprotective effect of estrogens and, in particular, a special role of ERβ in the development of pressure overload-induced myocardial hypertrophy and dysfunction. The aim of this study was to analyze the role of ERβ in the sex specific development of pressure overload-induced myocardial hypertrophy and left ventricular dysfunction in mice. Methods – We performed either transverse aortic constriction (TAC) or sham-operation (SHAM) in male and female wildtype-mice (WT) and mice with deletion of ERβ (ERβ-/-). Every animal was examined by echocardiography two, three, four, six and nine weeks after operation. We measured the gradient across the stenosis, left ventricular mass (LVM/TL), ejection fraction (EF) and relative wall-thickness. Results – Systolic pump function was maintained in all groups due to significant myocardial hypertrophy and concentric remodeling two weeks after operation. Gender differences in the development of left ventricular hypertrophy were observed: Male wildtype mice developed after TAC a significantly stronger left ventricular hypertrophy compared to age-matched female wildtype-mice (4th – 9th week p<0.02). ERβ modulated the hypertrophic response in a sex specific manner: Female ERβ-/- mice showed after TAC a stronger concentric left ventricular hypertrophy with distinct septal and posterior wall thickness compared to age-matched female wildtype mice. ERβ thus inhibits excentric ventricular growth in female wildtype mice. Male mice with deletion of ERβ developed a lower left ventricular hypertrophy compared to age-matched wildtype mice during the nine week follow-up. Both groups showed a decrease in relative wall thickness and thus an excentric hypertrophy. This effect was stronger pronounced in ERβ-/- mice compared to wildtype mice. Furthermore, male ERβ-/- mice showed a significant decrease in the gradient across the stenosis nine weeks after TAC compared to female age- and genotype-matched mice. We found gender differences in cardiac function after pressure overload- induced hypertrophy: Male groups showed a decreased ventricular function and nine weeks after TAC a loss in concentric remodeling with significant ventricular dilatation (9th week p<0.05). ERβ had no significant influence on systolic function. Conclusions – Gender influences significantly the development of pressure overload-induced left ventricular hypertrophy and dysfunction. ERβ plays a modulating role. Previous studies demonstrated mainly a protective effect of ERβ on the female heart. This study shows beyond a protective effect of ERβ on the hypertrophic response in male myocardium. Further studies are necessary to analyze the role of ERβ on the sex specific development of myocardial hypertrophy and heart failure in woman and man

Outcomes and survival following thoracic endovascular repair in patients with aortic aneurysms limited to the descending thoracic aorta

Abstract Background Thoracic endovascular aortic repair (TEVAR) is a well-established therapy for descending aortic aneurysms (DTA). There is a paucity of large series reporting the mid- and long-term outcomes from this era. The main aim of this study was to evaluate the outcomes of TEVAR with regards to the effect of aortic morphology and procedure-related variables on survival, reintervention and freedom from endoleaks. Methods In this retrospective single center study, we evaluated the clinical outcomes among 158 consecutive patients with DTA than underwent TEVAR between 2006 and 2019 at our center. The cohort included 51% patients with device landing zones proximal to the subclavian artery and 25.9% patients undergoing an emergent or urgent TEVAR. The primary outcome was survival, and secondary outcomes were reintervention and occurrence of endoleaks. Results Median follow-up was 33 months [IQR 12 to 70] while 50 patients (30.6%) had longer than 5-year follow-up. With a median patient age of 74 years, post-operative Kaplan Meyer survival estimates were 94.3% (95%CI 90.8–98.0, SE 0.018%) at 30 days, 76.4% (95%CI 70.0–83.3, SE 0.034%) at one year and, 52.9% (95%CI 45.0–62.2, SE 0.043%) at five years. Freedom from reintervention at 30 days, one year, and five years was 92.9% (95%CI 89.0–97.1, SE 0.021%), 80.0% (95%CI 72.6–88.1, SE 0.039%), and 52.8% (95%CI 41.4–67.4, SE 0.065%), respectively. On cox regression analysis greater aneurysm diameter, and the use of device landing zones in aortic regions 0–1 were associated with an increased probability of all-cause mortality, and with reintervention during follow-up. Independent of aneurysm size undergoing urgent or emergent TEVAR was associated with higher mortality risk for the first three years post-operative but not on long-term follow-up. Conclusions Larger aneurysms and those requiring stent-graft landing in aortic zones 0 or 1, are associated with higher risk for mortality and reintervention. There remains a need to optimize clinical management and device design for larger proximal aneurysms

Effects of estrogen, an ERα agonist and raloxifene on pressure overload induced cardiac hypertrophy.

The aim of this study was to investigate the effects of 17β-estradiol (E2), the selective ERα agonist 16α-LE2, and the selective estrogen receptor modulator (SERM) raloxifene on remodeling processes during the development of myocardial hypertrophy (MH) in a mouse model of pressure overload. Myocardial hypertrophy in ovariectomized female C57Bl/6J mice was induced by transverse aortic constriction (TAC). Two weeks after TAC, placebo treated mice developed left ventricular hypertrophy and mild systolic dysfunction. Estrogen treatment, but not 16α-LE2 or raloxifene reduced TAC induced MH compared to placebo. E2, 16α-LE2 and raloxifene supported maintenance of cardiac function in comparison with placebo. Nine weeks after induction of pressure overload, MH was present in all TAC groups, most pronounced in the raloxifene treated group. Ejection fraction (EF) was decreased in all animals. However, 16α-LE2 treated animals showed a smaller reduction of EF than animals treated with placebo. E2 and 16α-LE2, but not raloxifene diminished the development of fibrosis and reduced the TGFβ and CTGF gene expression. Treatment with E2 or 16α-LE2 but not with raloxifene reduced survival rate after TAC significantly in comparison with placebo treatment. In conclusion, E2 and 16α-LE2 slowed down the progression of MH and reduced systolic dysfunction after nine weeks of pressure overload. Raloxifene did not reduce MH but improved cardiac function two weeks after TAC. However, raloxifene was not able to maintain EF in the long term period

Case Report: Successful endovascular treatment of acute type A aortic dissection

Introduction: Open surgical repair remains the current gold standard for the treatment of acute type A aortic dissection. However, especially elderly patients with relevant comorbidities who are deemed unfit for open surgery may benefit from a minimally invasive endovascular approach. Methods: We report a case of an 80-year-old male with retrograde acute type A aortic dissection and peripheral malperfusion after receiving thoracic endovascular aortic repair due to thoracic aortic aneurysm. Our individualized endovascular approach consisted of left carotid-subclavian bypass, proximal extension of thoracic endovascular aortic repair using a covered stent graft and a single covered stent graft for the ascending aorta in combination with an uncovered stent for the aortic arch. Results: Postoperative computed tomographic angiography demonstrated excellent outcome with no signs of endoleak or patent false lumen. Follow-up after 3.5 years showed a stable result with no signs of stent failure or dissection progress. No aortic re-interventions were needed in the further course. Discussion: An individualized endovascular approach may be justified for acute type A aortic dissection in elderly patients with high surgical risk if performed in specialized aortic centers. Additional short-length stent graft devices are needed to address the anatomical challenges of the ascending aorta. For enhanced remodeling of the dissected aorta, the use of an additional uncovered stent may be advisable.ISSN:2297-055

Aortic remodelling and late outcomes following thoracic endovascular repair with a bare-metal stent distal extension among patients with complicated type-B aortic dissection

OBJECTIVES: The goal of this study was to describe the factors affecting mid and late aortic remodelling following thoracic endovascular aortic repair with the PETTICOAT (Provisional Extension To Induce Complete Attachment) technique among patients with complicated acute or subacute type B aortic dissection. METHODS: A retrospective single-centre study that evaluates clinical and morphological outcomes among 65 consecutive patients. The area and diameter of the true and false lumen, overall aortic diameter and false lumen perfusion were evaluated. RESULTS: Concomitant direct visceral artery stenting was successfully conducted in 32 (49%) patients. There was one (1.5%) postoperative stroke; three (4.6%) patients developed spinal cord ischaemia; two (3%) patients suffered retrograde type A dissection; and two (3%) patients had mesenteric ischaemia, despite successful reperfusion, that required a bowel resection. Median postoperative follow-up was 63.1 (interquartile range, 32.1- 91.8) months. The probability of survival was 96.9% [95% confidence interval (CI) 88.3%-99.2%] at 30 days, 93.9% (95% CI 84.4%-97.6%) at 1 year, 78.0 (95% CI 64.2%-87.0%) at 5 years and 72.8% (95% CI at 57.9%-83.2%) at 10 years postoperatively. There was a statistically significant postoperative increase in true-lumen area, diameter and true-lumen index in all five aortic levels measured. Complete false lumen (FL) thrombosis at the coeliac trunk, renal arteries and aortic bifurcation levels was observed in 47%, 15% and 24% of patients at midterm (6-15 months) and in 29%, 21% and 29% on late (later than 21 months) computed tomography angiograms (CTA). Persistent false lumen (FL) perfusion at the coeliac level on midterm CTA was associated with a larger extent of late aortic growth (P = 0.042) and was, in the majority of cases, caused by iliac re-entries either alone (28.57) or in combination with visceral and lumbar (28.57%) or distal aortic (10.71%) re-entries. A larger abdominal aortic diameter at midterm was associated with an increased probability of distal aortic reinterventions (hazard ratio 7.26, 95% CI 2.41-21.9, P < 0.001). CONCLUSIONS: Persistent FL perfusion of the distal aorta at midterm following TEVAR with the PETTICOAT technique among patients with acute and subacute type B dissection is caused mainly by iliac, visceral, lumber and distal aorta re-entries. Patients with persistent FL perfusion have an increased risk of aortic aneurysmal growth at late follow-up.ISSN:1569-9293ISSN:1569-928

Echocardiographic parameter for all measured time points.

*<p>p<0,05 vs. Placebo;</p>†<p>p<0,05 vs. E2;</p>‡<p>p<0,05 vs. ERα agonist</p

Chronic pressure overload induced mortality.

<p>Highest survival rate was observed in placebo treated animals after TAC (92.3%; 1 out of 13). Treatment with E2 or 16α-LE2 led to a significant lower survival rate compared to placebo groups (both groups: 58.3%; 5 out of 13). Log rank Test; p<0.05.</p

LV hypertrophy and function 2 and 9 weeks after sham or TAC surgery.

<p>T-test;</p>#<p>p<0.05 vs. ShamOVX+ShamTAC.</p>*<p>p<0.05 vs. OVX+ShamTAC.</p