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Aims: Coronary artery disease (CAD) remains the leading cause of death worldwide. 'Stable' CAD is a chronic progressive condition, which recent European guidelines recommend referring to as 'chronic coronary syndrome' (CCS). Despite therapeutic advances, morbidity and mortality among patients with CCS remain high. Optimal secondary prevention in patients with CCS includes optimization of modifiable risk factors with behavioural changes and pharmacological therapy. The CHANGE study aims to provide evidence for optimization of secondary prevention in CCS patients by using a smartphone application (app)., Methods and Results: The CHANGE study is designed as a prospective, randomized, controlled trial with a 1:1 allocation ratio, which is currently performed in nine centres in Germany in a parallel group design. 210 patients with CCS will be randomly allocated either to the control group (standard-of-care) or to the intervention group, who will be provided the VantisTherapy* app in addition to standard-of-care to incorporate secondary prevention into their daily life. The study will be performed in an open design. Outcomes will be assessed using objective data from three in-person visits (0, 12, and 24 weeks). Primary outcomes will involve adherence to secondary prevention recommendations and quality of life (QoL). The recruitment process started in July 2022., Conclusion: The CHANGE study will investigate whether a smartphone-guided secondary prevention app, combined with a monitor function compared with standard-of-care, has beneficial effects on overall adherence to secondary prevention guidelines and QoL in patients with CCS., Trial Registration: The study is listed at the German study registry (DRKS) under the registered number DRKS00028081., Competing Interests: Conflict of interest: A.Z. received a lecture fee from Vantis GmbH on one occasion. The authors declare no conflicts of interest. The authors are not employees or beneficiaries of the Vantis GmbH., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Since kidney transplant recipients (KTRs) have a high cardiovascular disease burden, adequate risk prediction is of importance. Whether echocardiographic parameters and plasma biomarkers, natriuretic peptides [N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and troponin T provide complementary or overlapping prognostic information on cardiovascular events remains uncertain., Methods: The prospective Heterogeneity of Monocytes and Echocardiography Among Allograft Recipients in Nephrology (HOME ALONE) study followed 177 KTRs for 5.4 ± 1.7 years. Predefined endpoints were hospitalization for acute decompensated heart failure or all-cause death (HF/D) and major atherosclerotic cardiovascular events or all-cause death (MACE/D). At baseline, plasma NT-proBNP, plasma troponin T and echocardiographic parameters [left atrial volume index, left ventricular (LV) mass index, LV ejection fraction, and LV filling pressure] were assessed., Results: Among all echocardiographic and plasma biomarkers measured, only NT-proBNP was consistently associated with HF/D in univariate and multivariate {third versus first tertile: hazard ratio [HR] 4.20 [95% confidence interval (CI) 1.02-17.27]} analysis, and only troponin T was consistently associated with MACE/D in univariate and multivariate [third versus first tertile: HR 8.15 (95% CI 2.75-24.18)] analysis., Conclusion: Our data suggest that plasma biomarkers are robust and independent predictors of heart failure and atherosclerotic cardiovascular events after kidney transplantation, whereas standard echocardiographic follow-up does not add to risk prediction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Aims: Unicuspid aortic valve (UAV) is a rare congenital malformation associated with severe aortic stenosis or regurgitation. This study aimed to systematically determine echocardiographic criteria to identify UAV., Methods and Results: All patients underwent a preoperative baseline examination, including echocardiography. A total of 69 patients with intraoperatively confirmed UAV underwent an aortic valve repair procedure between August 2001 and May 2011. To compare the findings of UAV cases with those of other valve morphologies, we examined 99 consecutive patients with a bicuspid aortic valve (BAV) and 103 consecutive patients with a tricuspid aortic valve (TAV) undergoing isolated aortic valve surgery before May 2016. The mean age of the 271 patients was 44.2 ± 12.8 years; 85% were male, with a mean body mass index of 26.2 ± 4.0 kg/m2. Patients with UAV were younger and had fewer co-morbidities than patients with BAV or TAV, respectively. The major criteria for the echocardiographic diagnosis of UAV were defined based on our preoperative examination as follows: (i) single commissural attachment zone, (ii) rounded, leaflet-free edge on the opposite side of the commissural attachment zone, (iii) eccentric valvular orifice during systole, and (iv) patient age <20 years and mean transvalvular gradient >15 mmHg. The minor criteria were defined as an associated thoracic aortopathy and age <40 years. Three out of the four major criteria or two out of the four major criteria and one minor criterion were met in all patients with UAV and in none of the patients with BAV or TAV. Associated 95% confidence intervals were calculated for each estimate of sensitivity (94.7-100%) and specificity (98.1-100%), indicating that an adequate number of patients were included in each of the three groups., Conclusion: The proposed echocardiographic score appears to be a specific and sensitive method to distinguish UAV from BAV and TAV.

Background: Obstructive sleep apnea (OSA) is associated with hypertension and the progression of chronic kidney disease (CKD). Renal sympathetic innervation contributes to either condition., Methods: We investigated the effect of renal sympathetic denervation (RDN) on blood pressure (BP), renal perfusion, and neurohumoral responses during and after repetitive obstructive apneas in a pig model for OSA. BP, femoral artery, and renal artery flow were measured in 29 spontaneously breathing urethane-chloralose-anesthetized pigs. The effect of RDN (n = 14) and irbesartan (n = 3) was investigated. Repetitive tracheal occlusions for 2 minutes with applied negative tracheal pressure at -80 mbar were performed over 4 hours., Results: Spontaneous breathing attempts during tracheal occlusion caused an intra-apneic breathing synchronous oscillating pattern of renal flow. Renal flow oscillations were > 2-fold higher compared with femoral flow that almost showed changes proportional to the BP alterations (2.9%/mm Hg vs. 1.3%/mm Hg; P < 0.0001). A marked postapneic BP rise from 102 ± 3 to 172 ± 8 mm Hg (P < 0.00001) was associated with renal hypoperfusion (from 190 ± 24 to 70 ± 20 ml/min; P < 0.00001) occurring after application of obstructive respiratory events. RDN, but not irbesartan, inhibited postapneic BP rises and renal hypoperfusion and attenuated increased plasma renin activity and aldosterone concentration induced by repetitive tracheal occlusions. Additionally, increased urinary protein/creatinine ratio was significantly reduced by RDN, whereas intra-apneic hemodynamic changes or blood gases were not modified by RDN., Conclusions: Repetitive obstructive respiratory events result in postapneic BP rises and renal hypoperfusion, as well as neurohumoral responses and increased protein/creatinine ratio. These changes are mainly sympathetically driven because they could be attenuated by RDN., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: Peripartum cardiomyopathy (PPCM) is associated with high mortality and morbidity. Endothelial damage involving cathepsin-D to form a 16 kDa prolactin (PRL) peptide is pathogenetically relevant. Inhibiting PRL peptide with bromocriptine has yielded promising results. We investigated whether microparticles (MPs) can be quantified in serum as markers for diagnosis and treatment effects in PPCM., Methods and Results: Patients with PPCM were compared with age-matched healthy post-partum women (PPCTR), healthy pregnant women (PCTR), healthy non-pregnant women (NPCTR), patients with ischaemic cardiomyopathy (ICM), patients with stable coronary artery disease (CAD) and healthy controls (HCTR). Peripartum cardiomyopathy treated with bromocriptine (PPCM-BR) and with PPCM without bromocriptine-treatment as control (PPCM-BRCTR) were compared. Microparticles were determined by flow cytometry. Endothelial MPs (EMPs) were elevated in PPCM compared with PPCTR, PCTR, and NPCTR, each P< 0.001. They were significantly elevated compared with ICM, CAD, and HCTR (P< 0.001). Pregnancy (PCTR) exhibited only slight increases vs. ICM, CAD, NPCTR, and HCTR. The increase in PPCM was due to an increase of activated but not apoptotic EMPs. Platelet-derived microparticles were highly increased in PPCM compared with ICM (P< 0.001) but 9.3 ± 4.4-fold compared with CAD (P< 0.001). In NPCTR (P< 0.001) compared with NPCTR, the increase was 5.9 ± 1.7-fold (P< 0.001). Microparticles generated from monocytes (MMPs) were increased 2.4 ± 1.8-fold in PPCM compared with PCTR (P< 0.001) and 4.8 ± 3.6-fold compared with CAD (P< 0.001), whereas leucocyte MPs (LMPs) were not significantly elevated. Endothelial microparticles were significantly reduced in PPCM treated additionally with bromocriptine compared with PPCM treated only with heart failure therapy (P< 0.001)., Conclusion: Microparticle profiles may in long-term distinguish PPCM from normal pregnancy, heart failure, and vascular diseases and might be a diagnostic marker related to the pathomechanism of PPCM.

Aims: In patients with obstructive coronary artery disease (CAD), the growth of collateral arteries, i.e. arteriogenesis, can preserve myocardial tissue perfusion and function. Monocytes modulate this process, supplying locally the necessary growth factors and degrading enzymes. Knowledge on factors involved in human arteriogenesis is scarce. Thus, the aim of the present study is to identify targets in monocytes that are critical for arteriogenesis in patients with CAD., Methods and Results: A total of 50 patients with a chronic total coronary occlusion were dichotomized according to their collateral flow index. From each patient, RNA was isolated from unstimulated peripheral blood monocytes, monocytes stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, and from macrophages. Increased mRNA expression of galectin-2 was found in three out of four monocytic cell types of patients with a low capacity of the collateral circulation (P= 0.03 for unstimulated monocytes; P= 0.02 for LPS-stimulated monocytes; P= 0.20 for IL-4-stimulated monocytes; P= 0.02 for macrophages). Additionally, galectin-2 mRNA expression was significantly associated with the rs7291467 polymorphism in LGALS2 encoding galectin-2 in all four monocytic cell types. Patient with the rs7291467 CC genotype displayed highest galectin-2 expression, and also tended to have a lower arteriogenic response. To evaluate the effect of galectin-2 on arteriogenesis in vivo, we used a murine hindlimb model. Treatment with galectin-2 markedly impaired the perfusion restoration at Day 7., Conclusion: Collectively, these results identify galectin-2 as a novel inhibitor of arteriogenesis. Modulation of galectin-2 may constitute a new therapeutic strategy for the stimulation of arteriogenesis in patients with CAD.

Aims: Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth., Methods and Results: The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 ± 15.8-60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L-arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments., Conclusion: Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.