TY  - JOUR
AB  - AIMS: Myocardial inflammation and impaired mitochondrial oxidative capacity are hallmarks of heart failure (HF) pathophysiology. The extent of myocardial inflammation in patients suffering from ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and its association with mitochondrial energy metabolism are unknown. We aimed at establishing a relevant role of cardiac inflammation in the impairment of mitochondrial energy production in advanced ischaemic and non-ischaemic HF. METHODS: We included 81 patients with stage D HF (ICM, n = 44; DCM, n = 37) undergoing left ventricular assist device implantation (n = 59) or heart transplantation (n = 22) and obtained left ventricular tissue samples during open heart surgery. We quantified mitochondrial oxidative capacity, citrate synthase activity (CSA) and fibrosis and lymphocytic infiltration. We considered infiltration of >14 CD3+ cells/mm2 relevant inflammation. RESULTS: Patients with ICM or DCM did not differ regarding age (61.5 ± 5.7 vs. 56.5 ± 12.7 years, P = 0.164), sex (86% vs. 84% male, P = 0.725), type 2 diabetes mellitus (34% vs. 18%, P = 0.126) or chronic kidney disease (8% vs. 11%, P = 0.994). ICM exhibited oxidative capacity reduced by 23% compared to DCM (108.6 ± 41.4 vs. 141.9 ± 59.9 pmol/(s*mg), P = 0.006). Maximum production of reactive oxygen species was not significantly different between ICM and DCM (0.59 ± 0.28 vs. 0.69 ± 0.36 pmol/(s*ml), P = 0.196). Mitochondrial content, detected by CSA, was lower in ICM (359.6 ± 164.1 vs. 503.0 ± 198.5 nmol/min/mg protein, P = 0.002). Notably, relevant inflammation was more common in ICM (27% vs. 6%, P = 0.024), and the absolute number of infiltrating leucocytes correlated with lower oxidative capacity (r = -0.296, P = 0.019). Fibrosis was more prevalent in ICM (20.9 ± 21.2 vs. 7.2 ± 5.6% of area, P = 0.002), but not associated with oxidative capacity (r = -0.13, P = 0.327). CONCLUSIONS: More than every fourth ICM patient with advanced HF displays myocardial inflammation in the range of inflammatory cardiomyopathy associated with reduced mitochondrial oxidative capacity. Future studies may evaluate inflammation in ICM at earlier stages in standardised fashion to explore the therapeutic potential of immunosuppression to influence trajectories of HF in ICM.
AU  - Borger, J.G.*
AU  - Zweck, E.*
AU  - Moos, C.*
AU  - Horn, P.*
AU  - Voß, F.*
AU  - Schultheiss, H.P.*
AU  - Møller, J.E.*
AU  - Boeken, U.*
AU  - Aubin, H.*
AU  - Lichtenberg, A.*
AU  - Kelm, M.*
AU  - Roden, M.*
AU  - Polzin, A.*
AU  - Westenfeld, R.*
AU  - Szendroedi, J.
AU  - Scheiber, D.*
C1  - 72213
C2  - 56474
TI  - Myocardial inflammation is associated with impaired mitochondrial oxidative capacity in ischaemic cardiomyopathy.
JO  - ESC Heart Fail.
PY  - 2024
SN  - 2055-5822
ER  - 

TY  - JOUR
AB  - AIMS: Neprilysin (NEP), a zinc metallopeptidase, degrades a variety of bioactive peptides including natriuretic peptides terminating their biological action on arterial blood pressure and natriuresis. Pharmacological inhibition of NEP reduces mortality in patients with heart failure with reduced ejection fraction. Physiological interventions reducing NEP levels are unknown in humans. Because obesity leads to increased NEP levels and increases the risk for heart failure, we hypothesized that weight loss reduces NEP concentrations in plasma and tissue. METHODS AND RESULTS: We randomized overweight to obese human subjects to a low-fat or low-carbohydrate hypocaloric 6 month weight loss intervention. Soluble NEP was determined in plasma, and NEP mRNA was analysed from subcutaneous adipose tissue before and after diet. Low-fat diet-induced weight loss reduced soluble NEP levels from 0.83 ± 0.18 to 0.72 ± 0.18 μg/L (P = 0.038), while subcutaneous adipose tissue NEP mRNA expression was reduced by both dietary interventions [21% (P = 0.0057) by low-fat diet and 16% (P = 0.048) by low-carbohydrate diet]. We also analysed the polymorphisms of the gene coding for NEP, rs9827586 and rs701109, known to be associated with plasma NEP levels. For both single-nucleotide polymorphisms, minor allele carriers (A/A) had higher baseline plasma NEP levels (rs9827586: β = 0.53 ± 0.23, P < 0.0001; rs701109: β = 0.43 ± 0.22, P = 0.0016), and minor allele carriers of rs9827586 responded to weight loss with a larger NEP reduction (rs9827586: P = 0.0048). CONCLUSIONS: Our study identifies weight loss via a hypocaloric low-fat diet as the first physiological intervention in humans to reduce NEP in plasma and adipose tissue. Specific single-nucleotide polymorphisms further contribute to the decrease. Our findings may help to explain the beneficial effect of weight loss on cardiac function in patients with heart failure.
AU  - Henke, C.
AU  - Haufe, S.*
AU  - Ziehl, D.*
AU  - Bornstein, S.R.
AU  - Schulz-Menger, J.*
AU  - Heni, M.
AU  - Engeli, S.*
AU  - Jordan, J.*
AU  - Birkenfeld, A.L.
C1  - 61468
C2  - 50275
CY  - One Montgomery St, Suite 1200, San Francisco, Ca 94104 Usa
SP  - 938-942
TI  - Low-fat hypocaloric diet reduces neprilysin in overweight and obese human subjects.
JO  - ESC Heart Fail.
VL  - 8
IS  - 2
PB  - Wiley Periodicals, Inc
PY  - 2021
SN  - 2055-5822
ER  - 

TY  - JOUR
AB  - Aims: Chronic heart failure with reduced ejection fraction remains a major health issue. To date, no reliable biomarker is available to predict reduced left ventricular ejection fraction (LV-EF). We aimed to identify novel circulating biomarkers for reduced left ventricular function using untargeted serum metabolomics in two independent patient cohorts. Methods and results: Echocardiography and non-targeted serum metabolomics were conducted in two patient cohorts with varying left ventricular function: (1) 25 patients with type 2 diabetes with established cardiovascular disease or high cardiovascular risk (LV-EF range 20–66%) (discovery cohort) and (2) 37 patients hospitalized for myocardial infarction (LV-EF range 25–60%) (validation cohort). In the discovery cohort, untargeted metabolomics revealed seven metabolites performing better than N-terminal pro-B-type natriuretic peptide in the prediction of impaired left ventricular function shown by LV-EF. For only one of the metabolites, acisoga, the predictive value for LV-EF could be confirmed in the validation cohort (r = −0.37, P = 0.02). In the discovery cohort, acisoga did not only correlate with LV-EF (r = −60, P = 0.0016), but also with global circumferential strain (r = 0.67, P = 0.0003) and global longitudinal strain (r = 0.68, P = 0.0002). Similar results could be detected in the discovery cohort in a 6 month follow-up proofing stability of these results over time. With an area under the curve of 0.86 in the receiver operating characteristic analysis, acisoga discriminated between patients with normal EF and LV-EF < 40%. Multivariate analysis exposed acisoga as independent marker for impairment of LV-EF (Beta = −0.71, P = 0.004). Conclusions: We found the polyamine metabolite acisoga to be elevated in patients with impaired LV-EF in two independent cohorts. Our analyses suggest that acisoga may be a valuable biomarker to detect patients with heart failure with reduced ejection fraction.
AU  - Puetz, A.*
AU  - Artati, A.
AU  - Adamski, J.
AU  - Schuett, K.*
AU  - Romeo, F.*
AU  - Stoehr, R.*
AU  - Marx, N.*
AU  - Federici, M.*
AU  - Lehrke, M.*
AU  - Kappel, B.A.*
C1  - 63610
C2  - 51456
CY  - One Montgomery St, Suite 1200, San Francisco, Ca 94104 Usa
TI  - Non-targeted metabolomics identify polyamine metabolite acisoga as novel biomarker for reduced left ventricular function.
JO  - ESC Heart Fail.
PB  - Wiley Periodicals, Inc
PY  - 2021
SN  - 2055-5822
ER  - 

TY  - JOUR
AB  - AIMS: Acute cellular rejection (ACR) following heart transplantation (HTX) is associated with long-term graft loss and increased mortality. Disturbed mitochondrial bioenergetics have been identified as pathophysiological drivers in heart failure, but their role in ACR remains unclear. We aimed to prove functional disturbances of myocardial bioenergetics in human heart transplant recipients with mild ACR by assessing myocardial mitochondrial respiration using high-resolution respirometry, digital image analysis of myocardial inflammatory cell infiltration, and clinical assessment of HTX patients. We hypothesized that (i) mild ACR is associated with impaired myocardial mitochondrial respiration and (ii) myocardial inflammation, systemic oxidative stress, and myocardial oedema relate to impaired mitochondrial respiration and myocardial dysfunction. METHODS AND RESULTS: We classified 35 HTX recipients undergoing endomyocardial biopsy according International Society for Heart and Lung Transplantation criteria to have no (0R) or mild (1R) ACR. Additionally, we quantified immune cell infiltration by immunohistochemistry and digital image analysis. We analysed mitochondrial substrate utilization in myocardial fibres by high-resolution respirometry and performed cardiovascular magnetic resonance (CMR). ACR (1R) was diagnosed in 12 patients (34%), while the remaining 23 patients revealed no signs of ACR (0R). Underlying cardiomyopathies (dilated cardiomyopathy 50% vs. 65%; P = 0.77), comorbidities (type 2 diabetes mellitus: 50% vs. 35%, P = 0.57; chronic kidney disease stage 5: 8% vs. 9%, P > 0.99; arterial hypertension: 59% vs. 30%, P = 0.35), medications (tacrolimus: 100% vs. 91%, P = 0.54; mycophenolate mofetil: 92% vs. 91%, P > 0.99; prednisolone: 92% vs. 96%, P > 0.99) and time post-transplantation (21.5 ± 26.0 months vs. 29.4 ± 26.4 months, P = 0.40) were similar between groups. Mitochondrial respiration was reduced by 40% in ACR (1R) compared with ACR (0R) (77.8 ± 23.0 vs. 128.0 ± 33.0; P < 0.0001). Quantitative assessment of myocardial CD3+ -lymphocyte infiltration identified ACR (1R) with a cut-off of >14 CD3+ -lymphocytes/mm2 (100% sensitivity, 82% specificity; P < 0.0001). Myocardial CD3+ infiltration (r = -0.41, P < 0.05), systemic oxidative stress (thiobarbituric acid reactive substances; r = -0.42, P < 0.01) and myocardial oedema depicted by global CMR derived T2 time (r = -0.62, P < 0.01) correlated with lower oxidative capacity and overt cardiac dysfunction (global longitudinal strain; r = -0.63, P < 0.01). CONCLUSIONS: Mild ACR with inflammatory cell infiltration associates with impaired mitochondrial bioenergetics in cardiomyocytes. Our findings may help to identify novel checkpoints in cardiac immune metabolism as potential therapeutic targets in post-transplant care.
AU  - Scheiber, D.*
AU  - Zweck, E.*
AU  - Albermann, S.*
AU  - Jelenik, T.*
AU  - Spieker, M.*
AU  - Bönner, F.*
AU  - Horn, P.*
AU  - Schultheiss, H.P.*
AU  - Aleshcheva, G.*
AU  - Escher, F.*
AU  - Boeken, U.*
AU  - Akhyari, P.*
AU  - Roden, M.*
AU  - Kelm, M.*
AU  - Szendroedi, J.
AU  - Westenfeld, R.
C1  - 62948
C2  - 51198
CY  - One Montgomery St, Suite 1200, San Francisco, Ca 94104 Usa
TI  - Human myocardial mitochondrial oxidative capacity is impaired in mild acute heart transplant rejection.
JO  - ESC Heart Fail.
PB  - Wiley Periodicals, Inc
PY  - 2021
SN  - 2055-5822
ER  - 

TY  - JOUR
AB  - AIMS: Although absolute (AID) and functional iron deficiency (FID) are known risk factors for patients with cardiovascular (CV) disease, their relevance for the general population is unknown. The aim was to assess the association between AID/FID with incident CV disease and mortality in the general population. METHODS AND RESULTS: In 12 164 individuals from three European population-based cohorts, AID was defined as ferritin < 100 μg/L or as ferritin < 30 μg/L (severe AID), and FID was defined as ferritin < 100 μg/L or ferritin 100-299 μg/L and transferrin saturation < 20%. The association between iron deficiency and incident coronary heart disease (CHD), CV mortality, and all-cause mortality was evaluated by Cox regression models. Population attributable fraction (PAF) was estimated. Median age was 59 (45-68) years; 45.2% were male. AID, severe AID, and FID were prevalent in 60.0%, 16.4%, and 64.3% of individuals. AID was associated with CHD [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04-1.39, P = 0.01], but not with mortality. Severe AID was associated with all-cause mortality (HR 1.28, 95% CI 1.12-1.46, P < 0.01), but not with CV mortality/CHD. FID was associated with CHD (HR 1.24, 95% CI 1.07-1.43, P < 0.01), CV mortality (HR 1.26, 95% CI 1.03-1.54, P = 0.03), and all-cause mortality (HR 1.12, 95% CI 1.01-1.24, P = 0.03). Overall, 5.4% of all deaths, 11.7% of all CV deaths, and 10.7% of CHD were attributable to FID. CONCLUSIONS: In the general population, FID was highly prevalent, was associated with incident CHD, CV death, and all-cause death, and had the highest PAF for these events, whereas AID was only associated with CHD and severe AID only with all-cause mortality. This indicates that FID is a relevant risk factor for CV diseases in the general population.
AU  - Schrage, B.*
AU  - Rübsamen, N.*
AU  - Ojeda, F.M.*
AU  - Thorand, B.
AU  - Peters, A.
AU  - Koenig, W.*
AU  - Söderberg, S.*
AU  - Söderberg, M.*
AU  - Mathiesen, E.B.*
AU  - Njølstad, I.*
AU  - Kee, F.*
AU  - Linneberg, A.*
AU  - Kuulasmaa, K.*
AU  - Tarja, P.*
AU  - Salomaa, V.*
AU  - Blankenberg, S.*
AU  - Zeller, T.*
AU  - Karakas, M.*
C1  - 63168
C2  - 51363
CY  - One Montgomery St, Suite 1200, San Francisco, Ca 94104 Usa
SP  - 4584–4592
TI  - Association of iron deficiency with incident cardiovascular diseases and mortality in the general population.
JO  - ESC Heart Fail.
VL  - 8
PB  - Wiley Periodicals, Inc
PY  - 2021
SN  - 2055-5822
ER  -