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Background Mitochondrial dysfunction is a driving factor in the development of heart failure (HF) and relates to poor cardiac function. Through elevated oxidative stress it is linked to myocardial inflammation. Both mechanisms promote the development of cardiac fibrosis, a key contributor to adverse outcomes in ischaemic and non-ischaemic HF. Differences in myocardial mitochondrial function and inflammation between patients with ischaemic and non-ischaemic HF have been indicated. While immunosuppression in non-ischaemic HF with myocardial inflammation has improved long-term results, little is known about possible benefits in ischaemic HF. Purpose We hypothesised that: 1. Myocardial lymphocytic inflammation and fibrosis differ in patients with HF due to ischaemic cardiomyopathy (ICM) compared to patients with dilated cardiomyopathy (DCM). 2. Inflammation and fibrosis are associated with markers of mitochondrial dysfunction. Methods Myocardial tissue specimens were obtained from the left ventricular (LV) apex of 65 patients (n[ICM] = 33, n[DCM] = 32) with HF requiring an LV assist device or heart transplantation. We assessed oxidative phosphorylation capacity (OXPHOS) via high resolution respirometry in saponine-permeabilised myocardial fibres (OROBOROS Oxygraph-2k). Reactive oxygen species (ROS) production was measured fluoroscopically via the Amplex Red method. Immunohistochemistry staining for CD3 was performed on snap-frozen tissue and digitally analysed. Azan staining was used for quantification of fibrotic area. Statistical analysis was conducted with GraphPad Prism v9.0 and IBM SPSS v27.0. Results ICM and DCM patients did not differ significantly regarding age (60.9±5.4 vs. 55.8±12.4 years, p=0.11), sex (91% vs. 90% male, p=0.93), BMI (27.6±5.1 vs. 26.5±6.0 kg/m2, p=0.82), or diabetic status (31% vs. 20% Type 2 Diabetes mellitus, p=0.31). Tissue specimens of ICM patients displayed about three times larger fibrotic areas compared to DCM (20.9±21.2 vs. 7.2±5.6%, p=0.001). Cellular inflammation (>14 CD3+ cells/mm2) was significantly more common in ICM than DCM patients. (27 vs. 6%, p=0.024). Inflammation and fibrosis did not correlate significantly (r=0.09, p=0.46). Fibrosis was not associated with OXPHOS capacity (r=−0.129, p=0.33). In patients with inflammation, OXPHOS capacity was lower compared to patients without inflammation (92.3±40.1 vs. 131.6±55.6 pmol/(s*mg), p=0.031) and inflammation was associated with lower OXPHOS capacity (r=−0.296, p=0.019). There was a trend towards lower electron transfer capacity in patients with inflammation (98.6±43.1 vs. 129.7±48.3 pmol/(s*mg), p=0.053). ROS production was not significantly different between tissue specimens with or without inflammation (0.51±0.21 vs. 0.67±0.33 pmol/(s*ml), p=0.17). Conclusions Myocardial cellular inflammation is prominent in ICM patients and relates to impaired mitochondria. Future studies may evaluate possible benefits from immunosuppression in ICM patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Research Foundation (DFG)

Background/Introduction Bioprosthetic valve degeneration is a growing clinical challenge in our aging society. Especially type 2 diabetes mellitus represents a risk factor for bioprosthetic valve deterioration with likewise worldwide rising prevalence. The proteoglycan biglycan has been shown to be associated with degenerative changes of the valve in diabetic patients even though underlying mechanisms are yet unknown. Purpose The impact of hyperglycaemia on bioprosthetic valve tissue was analysed in an established mouse model of ectopic calcification. Thereby, the role of biglycan in bioprosthetic valve degeneration was assessed in biglycan-deficient mice (Bgn-/0) in comparison to wild type littermates (WT). Methods Hyperglycaemia was induced in six weeks old mice by intraperitoneal injection of streptozotocin (STZ; 55 mg/kg body weight) on five consecutive days. Blood glucose concentration was verified two weeks after treatment and bioprosthetic valve material was implanted subcutaneously. After eight weeks, phenotype of invading cells and extracellular matrix remodelling of implants were analysed with histochemical and immunohistological staining. Furthermore, gene expression of invading cells, circulating cytokines in blood plasma and calcium accumulation in the tissue were quantified. Results STZ treatment significantly increased blood glucose levels in both genotype groups (WT-STZ: 156 mg/dl; WT+STZ: 353 mg/dl; Bgn-/0-STZ: 142 mg/dl; Bgn-/0+STZ: 396 mg/dl). Immunohistological staining identified most of cells invading the bioprosthetic tissue and the surrounded capsule as Mac2-positive and partly positive for vimentin, whereas alpha smooth muscle actin and von Willebrand factor were only detectable sporadically. Movat pentachrome staining exhibited an altered extracellular matrix composition of collagen and proteoglycans due to hyperglycaemia, while the elastin amount remained stable. Gene expression analysis showed an increased expression of the proteoglycan decorin in hyperglycaemic mice (WT-STZ: 0.55; WT+STZ: 1.13; Bgn-/0-STZ: 0.51; Bgn-/0+STZ: 1.70). Circulating cytokines (IL-1β, IL-2, IL-5, IL-10, INF-γ, TNF-α, GM-CSF) were influenced neither by hyperglycaemia nor by the genotype of the mice. Alizarin and von Kossa staining exhibited small to moderate calcium deposits in the bioprosthetic valve tissue. A colorimetric assay showed a significantly increased calcium accumulation in WT with hyperglycaemia versus normoglycemic WT (WT-STZ: 8.96 μg/mg; WT+STZ: 18.54 μg/mg), an observation that was lost in Bgn-/0 (Bgn-/0-STZ: 9.84 μg/mg; Bgn-/0+STZ: 12.97 μg/mg). Conclusion Hyperglycaemia significantly promotes destructive remodelling in bioprosthetic valve material. Biglycan-deficiency limits degenerative processes associated with diabetes, suggesting that biglycan as a component of the extracellular matrix has an adverse effect in diabetes-associated bioprosthetic valve deterioration. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dr. Rusche grant of the German Heart Foundation and the German Society for Thoracic and Cardiovascular Surgery

Background Bicycle exercise is the exercise modality of choice to unmask the dynamic nature of mitral regurgitation (MR). Handgrip exercise may serve as alternative exercise intervention, as it can be performed physically accomplished by the majority of patients. Until now, there are only scarce data on the prevalence and magnitude of dynamic MR during handgrip exercise. Purpose To assess extent and predictors of exercise-induced dynamic MR during handgrip exercise in patients with primary MR. Methods We prospectively included patients with primary MR and at least mild severity that underwent echocardiography at rest and during three minutes of handgrip exercise according to a standardized protocol. Results The final patient cohort included 166 patients. Mean age was 72±12 years, 57% were female and 53% had atrial fibrillation. At rest, MR severity was graded as mild in 57% of patients, moderate MR in 27% and severe in 16%. Handgrip exercise led to an increase in at least one grade in MR severity in 31 patients (19%), while 15 patients (9%) experienced a decrease of MR severity (Fig. 1B). Twenty patients (14%) of those with non-severe MR at rest, developed severe MR during handgrip exercise (Fig. 1B). According to a pre-defined cutoff of increase in effective orifice regurgitant area (EROA) >10 mm2 during exercise, 19% of patients revealed a marked exercise-induced increase in MR, irrespective of the severity of MR at rest. Patients with marked exercise-induced increases in MR severity (EROA >10 mm2) had elevated left- (53±22ml/m2 vs. 44±19ml/m2; p=0.036), and right atrial volumes (43±19ml/m2 vs. 34±18ml/m2; p=0.014), more often pathology of the anterior mitral leaflet (e.g. prolapse; flail leaflet) (65% vs. 33%; p Conclusion(s) In patients with primary MR, handgrip echocardiography unmasks marked exercise-induced increases of MR severity in every fifth patient independent of the severity at rest. A relevant number of patients with non-severe MR at rest developed severe MR during exercise. Dynamic MR is associated with bi-atrial dilatation, increased mitral annulus diameter, and pathology of the anterior mitral valve leaflet. Moreover, changes in MR severity during handgrip exercise correlate with changes in pulmonary pressures. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf Maximilian Spieker for a Clinician Scientist Track.

Objective Donor hypernatremia has been associated with primary graft dysfunction in heart transplantation and is known to be associated with impaired outcome following liver and renal transplantation. However, controversial data exist regarding the impact of sodium deregulation in patient survival after heart transplantation (HTx). This study aims to investigate the impact of donor sodium levels on early morbidity and short- and midterm survival following HTx. Methods Between September 2010 and June 2021, a total of n=218 patients underwent HTx in our centre. From those, 214 could be included retrospectively in our study. For each donor, sodium levels were collected and different cut-off levels from 145 to 159 mmol/l were investigated by Kaplan-Meier-analysis. Then, recipients were divided in three groups regarding donor sodium: Normonatremia (133–145 mmol/l, n=73), mild hypernatremia (146–156 mmol/l, n=105) and severe hypernatremia (>156 mmol/l, n=35). Recipient and donor variables were reviewed and compared, including peri- and postoperative characteristics and recipient survival after up to 5 years after transplantation. Results All patients were comparable regarding baseline characteristics and perioperative parameters. Regarding early mortality, 90-day survival was significantly reduced only in patients with severe donor hypernatremia in comparison to normonatremia (see table 1 and fifgure 1, 90% vs. 71%, p=0.02), but not in mild normonatremia (89%, p=0.89). 1-year survival was comparable in all groups (p>0.28). Conclusion Donor hypernatremia was associated with reduced short-term survival, while correlation weakens >1 year after HTx. Future prospective studies are needed to confirm the possible cut-off value of 156 mmol/l for donor-acceptancy. Funding Acknowledgement Type of funding sources: None.

Background Mitral regurgitation (MR) is frequent in patients with ischemic heart disease and carries a dismal prognosis. Recent studies suggest that ischemic MR is a dynamic condition influenced by global and regional left ventricular (LV) remodeling as well as mitral valvular deformation. Handgrip exercise may serve as alternative exercise intervention to bicycle exercise. Purpose To assess degree and determinants of exercise-induced changes in ischemic MR during handgrip exercise. Methods We prospectively enrolled 205 patients with at least mild ischemic MR that underwent echocardiography at rest and during three minutes of handgrip exercise according to a standardized protocol. Results Mean age in our patient cohort was 75±10 years, 30% were female, and 58% suffer from atrial fibrillation. Median NT-proBNP was 2657 (1331–6599) ng/l. Mean left ventricular ejection fraction was 44±14%. At rest, MR severity was graded as mild in 57% of patients, moderate MR in 34% and severe in 9%. Mean effective regurgitant orifice area (EROA) at rest was 15±6 mm2 and regurgitation volume was 25±11 ml. During handgrip exercise, 58 patients (28%) showed an increase in MR severity in at least one grade; 30 patients (15%) with non-severe MR at rest, developed severe MR during handgrip exercise. The EROA decreased (>5 mm2) in 5% of patients, remained unchanged in 50% (between −5 mm2 and +5 mm2), and increased (>5 mm2) in 45% of patients (Fig. 1B). A small increase (5–10 mm2) was observed in 30%, while 15% of patients revealed a marked increase in EROA (>10 mm2) (Fig. 1B). The degree of MR at rest was not associated with exercise-induced increases in EROA (r=−0.03; p=0.641)(Fig. 1C). However, echocardiographic parameters of local (e.g. tenting height) and global (e.g. LVESVi) LV remodeling, as well as mitral valvular deformation correlated with exercise-induced changes in EROA (Table 1). Conclusion In patients with secondary MR due to ischemic heart disease, handgrip echocardiography unmasks exercise-induced increases of MR severity in a significant proportion of patients. Dynamic MR during handgrip exercise is associated with parameters of global and local LV remodeling as well with parameters of mitral valvular deformation. Future studies need to address the prognostic importance of exercise-induced changes in MR severity in patients with ischemic cardiomyopathy. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf to Maximilian Spieker for a Clinician Scientist Track.

Background Pulmonary hypertension (PH) is an established prognosticator in patients with mitral regurgitation (MR). However, a substantial proportion of patients with MR presents without PH at rest but may develop PH during exercise. Previous studies already demonstrated the prevalence and prognostic impact of PH during bicycle exercise. Until now, there are no data on exercise PH assessed by handgrip exercise. Purpose To assess prevalence and predictors of exercise-induced PH during handgrip exercise in patients with MR. Methods We prospectively included patients with MR and at least mild severity that underwent echocardiography at rest and during three minutes of handgrip exercise according to a standardized protocol. PH was defined by systolic pulmonary artery pressure (SPAP) >50 mmHg. Results The final patient cohort included 371 patients with primary and secondary MR. Mean age was 74±11 years, 48% were female and 59% had atrial fibrillation. Median NT-proBNP was 2017 (845–4976) ng/l. Thirty-eight percent of patients had primary MR, while 62% presented with secondary MR. At rest, MR severity was graded as mild in 56% of patients, moderate in 32% and severe in 12%. Mean SPAP at rest was 40±12 mmHg, and 63 patients (17%) revealed PH at rest (SPAP >50 mmHg). Handgrip exercise leads to an increase in SPAP by 7±12 mmHg. Thus, during exercise 137 patients (37%) exhibited SPAP >50 mmHg. Together, 110 patients (32%) of those patients without PH at rest, showed PH during handgrip exercise. Left- (OR 1.021 (1.010 to 1.033); p Conclusion(s) In patients with primary and secondary MR, handgrip echocardiography unmasks exercise PH in every third patient without PH at rest. Bi-atrial dilatation, right ventricular function, tricuspid regurgitation and SPAP at rest were predictors of exercise PH, while changes in MR severity during handgrip exercise correlate with changes in pulmonary pressures. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf to Maximilian Spieker for a Clinician Scientist Track.