The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12^−/−). SM-CXCL12^−/− mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12^−/− mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12^−/− mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.

Most episodes of acute heart failure (AHF) are characterized by increasing signs and symptoms of congestion, manifested by edema, pleura effusion and/or ascites. Immediately and repeatedly administered intravenous (IV) loop diuretics currently represent the mainstay of initial therapy aiming to achieve adequate diuresis/natriuresis and euvolemia. Despite these efforts, a significant proportion of patients have residual congestion at discharge, which is associated with a poor prognosis. Therefore, a standardized approach is needed. The door to diuretic time should not exceed 60 min. As a general rule, the starting IV dose is 20–40 mg furosemide equivalents in loop diuretic naïve patients or double the preexisting oral home dose to be administered via IV. Monitoring responses within the following first hours are key issues. (1) After 2 h, spot urinary sodium should be ≥50–70 mmol/L. (2) After 6 h, the urine output should be ≥100–150 mL/hour. If these target measures are not reached, the guidelines currently recommend a doubling of the original dose to a maximum of 400–600 mg furosemide per day and in patients with severely impaired kidney function up to 1000 mg per day. Continuous infusion of loop diuretics offers no benefit over intermittent boluses (DOSE trial). Emerging evidence by recent randomized trials (ADVOR, CLOROTIC) supports the concept of an early combination diuretic therapy, by adding either acetazolamide (500 mg IV once daily) or hydrochlorothiazide. Acetazolamide is particularly useful in the presence of a baseline bicarbonate level of ≥27 mmol/L and remains effective in the presence of preexisting/worsening renal dysfunction but should be used only in the first three days to prevent severe metabolic disturbances. Patients should not leave the hospital when they are still congested and/or before optimized long-term guideline-directed medical therapy has been initiated. Special attention should be paid to AHF patients during the vulnerable post-discharge period, with an early follow-up visit focusing on up-titrate treatments of recommended doses within 2 weeks (STRONG-HF).

Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy. Methods: We evaluated roxadustat’s impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI. Results: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling. Conclusions: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.

Lamins are important filaments forming the inner nuclear membrane. Lamin A is processed by zinc metalloproteinase (ZMPSTE24). Failure to cleave a truncated form of prelamin A—also called progerin—causes Hutchinson–Gilford progeria syndrome a well-known premature aging disease. Minor levels of progerin are readily expressed in the blood of healthy individuals due to alternative splicing. Previously, we found an association of increased progerin mRNA with overweight and chronic inflammation (hs-CRP). Here, we aimed to elucidate correlations of ZMPSTE24, lamin A/C and progerin with the inflammatory marker hs-CRP. In this retrospective, cross-sectional study we analyzed blood samples from 110 heart failure patients for quantitative mRNA expression of ZMPSTE24, lamin A/C, progerin and hs-CRP protein. Spearman correlations and linear regression analyses including adjustments for age, gender and ejection fraction showed a significant positive correlation of lnprogerin with lnZMPSTE24 (n = 110; r = 0.33; p = 0.0004) and lnlamin A/C (n = 110; r = 0.82, p < 0.0001), whereas no association was observed between lnlamin A/C and lnZMPSTE24 expression. Further analyses showed a significant positive correlation of lnhs-CRP with lnZMPSTE24 (n = 110; r = 0.21; p = 0.01) and lnlamin A/C (n = 110; r = 0.24; p = 0.03). We conclude that chronic inflammation is associated with increased expression of ZMPSTE24 and lamin A/C mRNA. Both markers also positively correlate with increased expression of the premature aging marker progerin which may be linked to cardiovascular aging.

Summary: Iron deficiency (ID) is a common comorbidity in heart failure (HF), affecting 55% of chronic and up to 80% of acute HF patients, regardless of ejection fraction (EF). An ID is associated with reduced quality of life, impaired exercise capacity (VO₂ peak), higher hospitalization rate and lower survival rate. It is also an independent predictor of HF outcomes. This consensus statement critically reviews the diagnostic criteria for ID in HF and provides recommendations for their use. The efficacy and safety of intravenous iron supplements, including ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), are analyzed highlighting the indications and potential adverse effects. Key clinical trials and guideline recommendations are summarized. In summary, the document addresses the diagnostics, treatment and monitoring of ID in HF.

Purpose: The relevance of repetitive [^99mTc]Tc-DPD scintigraphy in wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) remains unclear. We investigated the impact of tafamidis on cardiac [^99mTc]Tc-DPD uptake, clinical, and laboratory markers at 6 and 12 months, and correlated 12 months [^99mTc]Tc-DPD uptake regression with survival. Methods: This single-center study enrolled 39 ATTRwt-CM patients. Upon treatment initiation with tafamidis, patients underwent follow-up [^99mTc]Tc-DPD scintigraphy, and clinical and laboratory evaluations at 6 months (n = 6) and 12 months (n = 13), or both (n = 20). Results: Tafamidis resulted in a significant decline in Perugini score (6 months p = 0.008, 12 months p < 0.001), and (semi-)quantitative [^99mTc]Tc-DPD uptake (total cardiac uptake: baseline 816 [522–933] cps, vs. 6 months 634 [502–734] cps, p = 0.003, vs. 12 months 523 [108–754] cps, p = 0.001). Clinical and laboratory improvements were observed (NYHA: 6 months p = 0.007, 12 months p = 0.033; NT-proBNP: baseline 2586 [1271–5561] ng/L, vs. 6 months 2526 [1109–4786] ng/L, p = 0.016, vs. 12 months 2340 [1411–4749] ng/L, p = 0.012). In Kaplan–Meier analysis, a decrease in right ventricular [^99mTc]Tc-DPD tracer uptake equal to or greater than the median value at 12 months (-30%) was associated with improved survival (log-rank p = 0.021). Conclusions: Tafamidis in ATTRwt-CM resulted in significant reductions of cardiac [^99mTc]Tc-DPD uptake, NYHA class, and cardiac biomarkers at 6 and 12 months. Regression of right ventricular [^99mTc]Tc-DPD uptake at 12 months was associated with improved survival.