The influence of socio-demographic and clinical factors on sick leave and return to work after open-heart surgery: a nationwide registry-based cohort study.

AIMS: To estimate sick leave (SL) duration after first-time elective open-heart surgery and identify factors contributing to increased SL. METHODS AND RESULTS: A retrospective nationwide cohort study combined data from the Norwegian Register for Cardiac Surgery and SL data from the Norwegian Labour and Welfare Administrations. All able-bodied adults who underwent first-time elective open-heart surgery in Norway between 2012 and 2021 were followed until one year after surgery. The impact of socio-demographic and clinical factors on SL after surgery was analysed using logistic regression and odds ratios. Of 5456 patients, 1643 (30.1%), 1798 (33.0%), 971 (17.8%), 1035 (18.9%), and 9 (0.2%) had SL of <3, 3-6, 6-9, and 9-12 months, and one year, respectively. SL > 6 months was associated with female gender, primary education only, and average annual income. Postoperative stroke, postoperative renal failure, New York Heart Association Functional Classification system (NYHA) score > 3, earlier myocardial infarction, and diabetes mellitus increased the odds of SL > 6 months. CONCLUSION: This study demonstrates that socio-demographic and clinical factors impact SL after first-time elective open-heart surgery. Patients who experience a stroke or develop renal failure after surgery have the highest odds of SL > 6 months. Females and patients with low education levels, earlier myocardial infarction, or NYHA scores III-IV have a twofold chance of SL > 6 months. The findings allow for future investigations of pre- and post-surgery interventions that can most effectively reduce SL and aid return to work.

Lack of collagen VIII reduces fibrosis and promotes early mortality and cardiac dilatation in pressure overload in mice.

AIMS: In pressure overload, left ventricular (LV) dilatation is a key step in transition to heart failure (HF). We recently found that collagen VIII (colVIII), a non-fibrillar collagen and extracellular matrix constituent, was reduced in hearts of mice with HF and correlated to degree of dilatation. A reduction in colVIII might be involved in LV dilatation, and we here examined the role of reduced colVIII in pressure overload-induced remodelling using colVIII knock-out (col8KO) mice. METHODS AND RESULTS: Col8KO mice exhibited increased mortality 3-9 days after aortic banding (AB) and increased LV dilatation from day one after AB, compared with wild type (WT). LV dilatation remained increased over 56 days. Forty-eight hours after AB, LV expression of main structural collagens (I and III) was three-fold increased in WT mice, but these collagens were unaltered in the LV of col8KO mice together with reduced expression of the pro-fibrotic cytokine TGF-ß, SMAD2 signalling, and the myofibroblast markers Pxn, α-SMA, and SM22. Six weeks after AB, LV collagen mRNA expression and protein were increased in col8KO mice, although less pronounced than in WT. In vitro, neonatal cardiac fibroblasts from col8KO mice showed lower expression of TGF-ß, Pxn, α-SMA, and SM22 and reduced migratory ability possibly due to increased RhoA activity and reduced MMP2 expression. Stimulation with recombinant colVIIIα1 increased TGF-ß expression and fibroblast migration. CONCLUSION: Lack of colVIII reduces myofibroblast differentiation and fibrosis and promotes early mortality and LV dilatation in response to pressure overload in mice.

Attenuated development of cardiac fibrosis in left ventricular pressure overload by SM16, an orally active inhibitor of ALK5.

Pressure overload-induced TGF-ß signaling activates cardiac fibroblasts (CFB) and leads to increased extracellular matrix (ECM) protein synthesis including fibrosis. Excessive ECM accumulation may in turn affect cardiac function contributing to development of heart failure. The aim of this study was to examine the effects of SM16, an orally active small molecular inhibitor of ALK5, on pressure overload-induced cardiac fibrosis. One week after aortic banding (AB), C57Bl/6J mice were randomized to standard chow or chow with SM16. Sham operated animals served as controls. Following 4 weeks AB, mice were characterized by echocardiography and cardiovascular magnetic resonance before sacrifice. SM16 abolished phosphorylation of SMAD2 induced by AB in vivo and by TGF-ß in CFB in vitro. Interestingly, Masson Trichrome and Picrosirius Red stained myocardial left ventricular tissue revealed reduced development of fibrosis and collagen cross-linking following AB in the SM16 treated group, which was confirmed by reduced hydroxyproline incorporation. Furthermore, treatment with SM16 attenuated mRNA expression following induction of AB in vivo and stimulation with TGF-ß in CFB in vitro of Col1a2, the cross-linking enzyme LOX, and the pro-fibrotic glycoproteins SPARC and osteopontin. Reduced ECM synthesis by CFB and a reduction in myocardial stiffness due to attenuated development of fibrosis and collagen cross-linking might have contributed to the improved diastolic function and cardiac output seen in vivo, in combination with reduced lung weight and ANP expression by treatment with SM16. Despite these beneficial effects on cardiac function and development of heart failure, mice treated with SM16 exhibited increased mortality, increased LV dilatation and inflammatory heart valve lesions that may limit the use of SM16 and possibly also other small molecular inhibitors of ALK5, as future therapeutic drugs.

Lumican is increased in experimental and clinical heart failure, and its production by cardiac fibroblasts is induced by mechanical and proinflammatory stimuli.

During progression to heart failure (HF), myocardial extracellular matrix (ECM) alterations and tissue inflammation are central. Lumican is an ECM-localized proteoglycan associated with inflammatory conditions and known to bind collagens. We hypothesized that lumican plays a role in the dynamic alterations in cardiac ECM during development of HF. Thus, we examined left ventricular cardiac lumican in a mouse model of pressure overload and in HF patients, and investigated expression, regulation and effects of increased lumican in cardiac fibroblasts. After 4 weeks of aortic banding, mice were divided into groups of hypertrophy (AB) and HF (ABHF) based on lung weight and left atrial diameter. Sham-operated mice were used as controls. Accordingly, cardiac lumican mRNA and protein levels were increased in mice with ABHF. Similarly, cardiac biopsies from patients with end-stage HF revealed increased lumican mRNA and protein levels compared with control hearts. In vitro, mechanical stretch and the proinflammatory cytokine interleukin-1ß increased lumican mRNA as well as secreted lumican protein from cardiac fibroblasts. Stimulation with recombinant glycosylated lumican increased collagen type I alpha 2, lysyl oxidase and transforming growth factor-ß1 mRNA, which was attenuated by costimulation with an inhibitor of the proinflammatory transcription factor NFκB. Furthermore, lumican increased the levels of the dimeric form of collagen type I, decreased the activity of the collagen-degrading enzyme matrix metalloproteinase-9 and increased the phosphorylation of fibrosis-inducing SMAD3. In conclusion, cardiac lumican is increased in experimental and clinical HF. Inflammation and mechanical stimuli induce lumican production by cardiac fibroblasts and increased lumican altered molecules important for cardiac remodeling and fibrosis in cardiac fibroblasts, indicating a role in HF development.

Decorin, lumican, and their GAG chain-synthesizing enzymes are regulated in myocardial remodeling and reverse remodeling in the mouse.

On the basis of the role of small, leucine-rich proteoglycans (SLRPs) in fibrogenesis and inflammation, we hypothesized that they could be involved in cardiac remodeling and reverse remodeling as occurs during aortic stenosis and after aortic valve replacement. Thus, in a well-characterized aortic banding-debanding mouse model, we examined the SLRPs decorin and lumican and enzymes responsible for synthesis of their glycosaminoglycan (GAG) chains. Four weeks after banding of the ascending aorta, mice were subjected to a debanding operation (DB) and were subsequently followed for 3 or 14 days. Sham-operated mice served as controls. Western blotting revealed a 2.5-fold increase in the protein levels of glycosylated decorin in mice with left ventricular pressure overload after aortic banding (AB) with a gradual decrease after DB. Interestingly, protein levels of three key enzymes responsible for decorin GAG chain synthesis were also increased after AB, two of them gradually declining after DB. The inflammatory chemokine (C-X-C motif) ligand 16 (CXCL16) was increased after AB but was not significantly altered following DB. In cardiac fibroblasts CXCL16 increased the expression of the GAG-synthesizing enzyme chondroitin polymerizing factor (CHPF). The protein levels of lumican core protein with N-linked oligosaccharides increased by sevenfold after AB and decreased again 14 days after DB. Lumican with keratan sulfate chains was not regulated. In conclusion, this study shows alterations in glycosylated decorin and lumican core protein that might be implicated in myocardial remodeling and reverse remodeling, with a potential important role for CS/DS GAG chain-synthesizing enzymes.

Differential regulation of extracellular matrix constituents in myocardial remodeling with and without heart failure following pressure overload.

Patients with aortic stenosis develop various degrees of myocardial hypertrophy and heart failure (HF) despite comparable transvalvular gradients. An important element in the transition from compensated hypertrophy to HF is dilatation of the left ventricle (LV). The molecular pathology associated with LV dilatation and development of HF is not known. Thus, we examined potential differences in the regulation of myocardial extracellular matrix (ECM) constituents in mice with hypertrophy only (ABnonHF) and with HF (ABHF) as response to comparable pressure overload. The ascending aorta was banded, or left loose in sham-operated mice. Increased lung weight and left atrial diameter indicating pulmonary congestion were used to identify ABHF mice. Cardiac function and geometry were evaluated by echocardiography. Despite comparable pressure gradients and cardiac output, ABHF had reduced fractional shortening (23%), reduced systolic (28%) and diastolic (32%) tissue velocity and increased LV internal dimension in diastole (10%) and systole (17%) (LVIDd/s) compared to ABnonHF (p≤0.05). Microarray analyses identified 120 differently regulated genes related to ECM in ABHF compared to ABnonHF (p≤0.05). Interestingly, in ABHF, we found a 24% (p≤0.05) reduction of the LV collagen VIII protein levels despite increased levels of LV total collagen by 23% (p≤0.05). LV collagen VIII correlated negatively with LVIDd (R=0.55, p=0.03) and LVIDs (R=0.72, p=0.002). As this protein may function as a "sealant" binding collagen fibrils together, reduction of collagen VIII could potentially contribute to LV dilatation and development of HF.

Endothelin-1 in the human myocardium and circulating plasma: evaluation before, during and after correction of aortic stenosis with aortic valve replacement.

OBJECTIVES: Due to the pathological effects of endothelin-1 (ET-1) on cardiomyocytes and the extracellular matrix, ET-1 levels may impact on the prognosis of aortic stenosis (AS) patients operated with aortic valve replacement (AVR). We examined ET-1 levels in AS patients throughout the whole AVR process, thus exposing potential therapeutic windows of opportunity. METHODS: Plasma ET-1 levels were measured before and 2 days, 6 and 12 months after AVR in 22 patients with AS. Myocardial ET-1 was measured in biopsies from 7 patients undergoing AVR. Peroperatively, plasma ET-1 was analyzed in the coronary sinus and radial artery before aortic cross-clamp and at 5 and 20 min of reperfusion, in a second group of 30 patients. RESULTS: Circulating ET-1 levels were transiently increased 2.6-fold 2 days following AVR. Myocardial ET-1 protein was 2.1-fold higher in patients with AS compared to controls. Plasma levels of ET-1 correlated to echocardiographic markers of diastolic dysfunction postoperatively. There was no increase in plasma ET-1 during early reperfusion, but veno-arterial differences indicated potential cardiac ET-1 extraction. CONCLUSIONS: Plasma ET-1 increases 2 days following AVR and myocardial ET-1 protein levels are increased in patients with AS before AVR. Peroperatively, no plasma ET-1 augmentation or release from the heart was observed in AS patients.

GDF-15 is increased during early reperfusion following aortic valve replacement.

OBJECTIVES: To examine the circulating levels of Growth differentiation factor 15 (GDF-15) and Interleukin 18 (IL-18) in relation to ischemia and early reperfusion, and cardioplegia type during isolated aortic valve replacement (AVR). DESIGN: Thirty consecutive patients operated for aortic stenosis with AVR at Oslo University Hospital, Ullevål, were included in the study. The patients were randomized into two groups, receiving either cold blood or crystalloid cardioplegia. Samples from both the radial artery and coronary sinus were analyzed before cardiac ischemia, and after 5 and 20 minutes of reperfusion. RESULTS: Radial artery and coronary sinus plasma GDF-15 were significantly elevated after 5 and 20 minutes of reperfusion in both cardioplegia groups. In the total group of thirty patients, this represented an increase of 31% and 55% in the radial artery and an increase of 27% and 40% in the coronary sinus after 5 and 20 minutes of reperfusion respectively. IL-18 increased after 20 minutes of reperfusion in the crystalloid cardioplegia group only. No veno-arterial differences were detected during reperfusion. CONCLUSIONS: Plasma levels of GDF-15 were significantly elevated after 5 and 20 minutes of myocardial reperfusion during AVR. Plasma levels of IL-18 were elevated after 20 minutes, but only when using crystalloid cardioplegia.

Inhibition of SMAD2 phosphorylation preserves cardiac function during pressure overload.

AIMS: Left ventricular (LV) pressure overload leads to myocardial remodelling and reduced cardiac function. Both cardioprotective and deleterious effects have been attributed to SMAD2/3 (SMAD, small mothers against decapentaplegic) signalling, but the role of these important molecules in pressure overload remains unclear. The aim of this study was to examine the effects of SMAD2 inhibition on cardiac function and remodelling in mice subjected to aortic banding (AB), using a small molecule inhibitor (SM16) of SMAD2 signalling. METHODS AND RESULTS: C57BL/6 mice were subjected to 1 week of AB, which led to a three-fold increased phosphorylation of SMAD2 that was reduced by SM16 (P≤ 0.05), as measured by western blotting. Cardiac function was evaluated by echocardiography and was preserved by SM16, as fractional shortening was increased by 38% (P≤ 0.05) and mitral flow deceleration reduced by 28% compared with AB mice not receiving SM16 (P≤ 0.05). In accordance with this, SM16 abolished the 21% increase in lung weight in AB mice (P≤ 0.05). Cardiomyocyte hypertrophy and foetal gene expression, as measured by qPCR, were also reduced. Myocardial collagen protein was unaltered 1 week after AB. LV sarcoplasmic reticulum Ca(2+)ATPase (SERCA2) reduction in AB mice and in transforming growth factor-ß1-stimulated rat cardiomyocytes was diminished by SM16. Ca(2+) transient decay kinetics were improved in cardiomyocytes isolated from AB mice receiving SM16. CONCLUSION: In pressure overload, pharmacological inhibition of SMAD2 signalling attenuated cardiomyocyte hypertrophy and preserved cardiac function. SM16 prevented SMAD2-mediated downregulation of SERCA2 in vivo and in cardiomyocytes, suggesting improved cardiomyocyte Ca(2+) handling as a possible cardioprotective mechanism.

Coronary artery dissection and acute myocardial infarction following blunt chest trauma.

Blunt chest trauma might lead to cardiac injury ranging from simple arrhythmias to lethal conditions such as cardiac rupture. We experienced a case of initially overlooked traumatic coronary artery dissection which resulted in acute myocardial infarction (AMI). A high degree of suspicion is needed to diagnose this condition. Based on our case, we will give an overview of relevant literature on this topic. ECG, echocardiography, coronary angiography and cardiac enzymes are valuable tools in diagnosing this rare condition. The time span from coronary artery occlusion to revascularisation must be short if AMI is to be avoided.

Alterations in circulating activin A, GDF-15, TGF-beta3 and MMP-2, -3, and -9 during one year of left ventricular reverse remodelling in patients operated for severe aortic stenosis.

BACKGROUND: Patients with aortic stenosis (AS) develop left ventricular remodelling with cardiomyocyte hypertrophy and increased fibrosis. Following aortic valve replacement (AVR) reverse remodelling usually takes place. AIMS: To examine circulating levels of members of the transforming growth factor (TGF) beta superfamily and matrix metalloproteinases (MMP), known to have important effects on hypertrophy and extracellular matrix, in patients operated for AS. METHODS: Circulating levels of activin A, GDF-15, TGF-beta3, MMP-2, -3, and -9 were measured in twenty-two patients undergoing AVR preoperatively, and 2 days, six months and 12 months postoperatively. Echocardiography and a six minute walking test evaluated reverse remodelling and physical performance. RESULTS: Activin A increased at six (1081.00+/-98.05 pg/ml, p<0.05) and twelve months (1263.09+/-141.43 pg/ml, p<0.05) compared to the preoperative value (855.00+/-76.30 pg/ml) and correlated negatively to physical performance. The preoperative value was also increased compared to controls (639.54+/-63.05 pg/ml, p<0.05). GDF-15, MMP-3 and -9 were all increased at two days postoperatively (p<0.05). MMP-3 correlated with left ventricular end diastolic dimension (p<0.05). MMP-2 did not change during the study period. TGF-beta3 was only slightly reduced at six months postoperatively. CONCLUSION: The observed alteration in circulating levels of members of the TGF-beta superfamily and MMPs might play a role in the reverse remodelling process following AVR for AS.