HTK vs. HTK-N for Coronary Endothelial Protection during Hypothermic, Oxygenated Perfusion of Hearts Donated after Circulatory Death.

Protection of the coronary arteries during donor heart maintenance is pivotal to improve results and prevent the development of coronary allograft vasculopathy. The effect of hypothermic, oxygenated perfusion (HOP) with the traditional HTK and the novel HTK-N solution on the coronary microvasculature of donation-after-circulatory-death (DCD) hearts is known. However, the effect on the coronary macrovasculature is unknown. Thus, we maintained porcine DCD hearts by HOP with HTK or HTK-N for 4 h, followed by transplantation-equivalent reperfusion with blood for 2 h. Then, we removed the left anterior descending coronary artery (LAD) and compared the endothelial-dependent and -independent vasomotor function of both groups using bradykinin and sodium-nitroprusside (SNP). We also determined the transcriptome of LAD samples using microarrays. The endothelial-dependent relaxation was significantly better after HOP with HTK-N. The endothelial-independent relaxation was comparable between both groups. In total, 257 genes were expressed higher, and 668 genes were expressed lower in the HTK-N group. Upregulated genes/pathways were involved in endothelial and vascular smooth muscle cell preservation and heart development. Downregulated genes were related to ischemia/reperfusion injury, oxidative stress, mitochondrion organization, and immune reaction. The novel HTK-N solution preserves the endothelial function of DCD heart coronary arteries more effectively than traditional HTK.

Improving Diastolic and Microvascular Function in Heart Transplantation with Donation after Circulatory Death.

The impact of the machine perfusion of donation after circulatory death (DCD) hearts with the novel Custodiol-N solution on diastolic and coronary microvascular dysfunction is unknown. Porcine DCD-hearts were maintained four hours by perfusion with normothermic blood (DCD-B), hypothermic Custodiol (DCD-C), or Custodiol-N (DCD-CN), followed by one hour of reperfusion with fresh blood, including microvascular and contractile evaluation. In another group (DCD group), one hour of reperfusion, including microvascular and contractile evaluation, was performed without a previous maintenance period (all groups N = 5). We measured diastolic function with a balloon catheter and microvascular perfusion by Laser-Doppler-Technology, resulting in Laser-Doppler-Perfusion (LDP). We performed immunohistochemical staining and gene expression analysis. The developed pressure was improved in DCD-C and DCD-CN. The diastolic pressure decrement (DCD-C: -1093 ± 97 mmHg/s; DCD-CN: -1703 ± 329 mmHg/s; DCD-B: -690 ± 97 mmHg/s; p < 0.05) and relative LDP (DCD-CN: 1.42 ± 0.12; DCD-C: 1.11 ± 0.13; DCD-B: 1.22 ± 0.27) were improved only in DCD-CN. In DCD-CN, the expression of eNOS increased, and ICAM and VCAM decreased. Only in DCD-B compared to DCD, the pathways involved in complement and coagulation cascades, focal adhesion, fluid shear stress, and the IL-6 and IL-17 pathways were upregulated. In conclusion, machine perfusion with Custodiol-N improves diastolic and microvascular function and preserves the microvascular endothelium of porcine DCD-hearts.

Role of left ventricle deformation analysis in stress echocardiography for significant coronary artery disease detection: A diagnostic study meta-analysis.

BACKGROUND: We compared the diagnostic accuracy of longitudinal strain (LS) imaging during stress echocardiography with visual assessment of wall motion (WM) for detecting significant coronary artery disease (CAD). METHODS: Our systematic search included studies reporting diagnostic measures for LS imaging and visual assessment of WM for detecting significant CAD during stress echocardiography. Summary diagnostic accuracy measures including area under the curve (AUC), sensitivity, specificity, diagnostic odds ratio (DOR), and likelihood ratios (LRs) were estimated. RESULTS: In thirteen studies with 978 patients, ten studies used invasive coronary angiography as the reference standard. Pooled AUC for diagnosing significant CAD was 0.92 (95% confidence interval [CI] 0.89-0.94) for LS imaging as compared to 0.83 (95% CI 0.80-0.86), P < 0.001 for visual assessment of WM. LS imaging had higher sensitivity (88% [95% CI 84-92] vs 74% [95% CI 68-80], P < 0.001) and comparable specificity to visual assessment of WM (80% [95% CI 72-87] vs 83% [95% CI 74-90], P = 0.592). The DOR for LS imaging and visual assessment of WM was 31 and 15, P = 0.254, respectively. The positive LR was 4.5 for both; negative LR was 0.14 and 0.31, P = 0.002 for LS imaging and visual assessment of WM, respectively. CONCLUSIONS: Longitudinal strain imaging during stress echocardiography has better diagnostic accuracy for detecting significant CAD as compared to visual assessment of WM. Studies using larger sample size and standardized techniques of strain measurement are required to further ascertain the added advantage of strain measurement over visual assessment alone.

The circadian rhythm: A key variable in aging?

The determination of age-related transcriptional changes may contribute to the understanding of health and life expectancy. The broad application of results from age cohorts may have limitations. Altering sample sizes per time point or sex, using a single mouse strain or tissue, a limited number of replicates, or omitting the middle of life can bias the surveys. To achieve higher general validity and to identify less distinctive players, bulk RNA sequencing of a mouse cohort, including seven organs of two strains from both sexes of 5 ages, was performed. Machine learning by bootstrapped variable importance and selection methodology (Boruta) was used to identify common aging features where the circadian rhythms (CiR) transcripts appear as promising age markers in an unsupervised analysis. Pathways of 11 numerically analyzed local network clusters were affected and classified into four major gene expression profiles, whereby CiR and proteostasis candidates were particularly conspicuous with partially opposing changes. In a data-based interaction association network, the CiR-proteostasis axis occupies an exposed central position, highlighting its relevance. The computation of 11,830 individual transcript associations provides potential superordinate contributors, such as hormones, to age-related changes, as in CiR. In hormone-sensitive LNCaP cells, short-term supraphysiologic levels of the sex hormones dihydrotestosterone or estradiol increase the expression of the CiR transcript Bhlhe40 and the associated senescence regulator Cdkn2b (p15). According to these findings, the bilateral dysregulation of CiR appears as a fundamental protagonist of aging, whose transcripts could serve as a biological marker and its restoration as a therapeutic opportunity.

Peripheral nerve repair is associated with augmented cross-tissue inflammation following vascularized composite allotransplantation.

Introduction: Vascularized composite allotransplantation (VCA), with nerve repair/coaptation (NR) and tacrolimus (TAC) immunosuppressive therapy, is used to repair devastating traumatic injuries but is often complicated by inflammation spanning multiple tissues. We identified the parallel upregulation of transcriptional pathways involving chemokine signaling, T-cell receptor signaling, Th17, Th1, and Th2 pathways in skin and nerve tissue in complete VCA rejection compared to baseline in 7 human hand transplants and defined increasing complexity of protein-level dynamic networks involving chemokine, Th1, and Th17 pathways as a function of rejection severity in 5 of these patients. We next hypothesized that neural mechanisms may regulate the complex spatiotemporal evolution of rejection-associated inflammation post-VCA. Methods: For mechanistic and ethical reasons, protein-level inflammatory mediators in tissues from Lewis rats (8 per group) receiving either syngeneic (Lewis) or allogeneic (Brown-Norway) orthotopic hind limb transplants in combination with TAC, with and without sciatic NR, were compared to human hand transplant samples using computational methods. Results: In cross-correlation analyses of these mediators, VCA tissues from human hand transplants (which included NR) were most similar to those from rats undergoing VCA + NR. Based on dynamic hypergraph analyses, NR following either syngeneic or allogeneic transplantation in rats was associated with greater trans-compartmental localization of early inflammatory mediators vs. no-NR, and impaired downregulation of mediators including IL-17A at later times. Discussion: Thus, NR, while considered necessary for restoring graft function, may also result in dysregulated and mis-compartmentalized inflammation post-VCA and therefore necessitate mitigation strategies. Our novel computational pipeline may also yield translational, spatiotemporal insights in other contexts.

Effect of immunomodulation on cardiac remodelling and outcomes in heart failure: a quantitative synthesis of the literature.

AIMS: Immunomodulation in heart failure (HF) has been studied in several randomized controlled trials (RCTs) with variable effects on cardiac structure, function, and outcomes. We sought to determine the effect of immunomodulation on left ventricular ejection fraction (LVEF), LV end-diastolic dimension (LVEDD), and all-cause mortality in patients with HF with reduced ejection fraction (HFrEF) through meta-analyses and trial sequential analyses (TSAs) of RCTs. METHODS AND RESULTS: PubMed, Embase®, Cochrane CENTRAL, and ClinicalTrials.gov were systematically reviewed to identify RCTs that studied the effects of immunomodulation in patients with HFrEF. The primary endpoint in this analysis was change in LVEF. Secondary outcomes were changes in LVEDD and all-cause mortality. TSA was used to quantify the statistical reliability of data in the cumulative meta-analyses. Nineteen RCTs with 1341 HFrEF subjects were eligible for analyses. The aetiology of HF, specific immunomodulation strategy, and treatment duration were variable across trials. Immunomodulation led to a greater improvement in LVEF [mean difference: +5.7% 95% confidence interval (CI): 3.0-8.5%, P < 0.001] and reduction in LVEDD (mean difference: -3.7 mm, 95% CI: -7.0 to -0.4 mm, P = 0.028) than no immunomodulation in meta-analyses and TSAs. We observed a non-significant decrease in all-cause mortality among those on immumomodulation (risk ratio: 0.7, 95% CI: 0.4-1.3, P = 0.234), but the Z-curve for cumulative treatment effect of immunomodulation in the TSA did not cross the boundary of futility. CONCLUSIONS: Immunomodulation led to improved cardiac structure and function in patients with HFrEF. While these benefits did not translate into a significant improvement in mortality, our analysis suggests that larger studies of targeted immunomodulation are needed to understand the true benefits.

Refractory versus resistant hypertension: Novel distinctive phenotypes.

Resistant hypertension (RHTN) is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients. It is defined as blood pressure (BP) >140/90 mmHg treated with ≥3 antihypertensive medications, including a diuretic, if tolerated. Refractory hypertension is a novel phenotype of severe antihypertensive treatment failure. The proposed definition for refractory hypertension, i.e. BP >140/90 mmHg with use of ≥5 different antihypertensive medications, including a diuretic and a mineralocorticoid receptor antagonist (MRA) has been applied inconsistently. In comparison to RHTN, refractory hypertension seems to be less prevalent than RHTN. This review focuses on current knowledge about this novel phenotype compared with RHTN including definition, prevalence, mechanisms, characteristics and comorbidities, including cardiovascular risk. In patients with RHTN excess fluid retention is thought to be a common mechanism for the development of RHTN. Recently, evidence has emerged suggesting that refractory hypertension may be more of neurogenic etiology due to increased sympathetic activity as opposed to excess fluid retention. Treatment recommendations for RHTN are generally based on use and intensification of diuretic therapy, especially with the combination of a long-acting thiazide-like diuretic and an MRA. Based on findings from available studies, such an approach does not seem to be a successful strategy to control BP in patients with refractory hypertension and effective sympathetic inhibition in such patients, either with medications and/or device based approaches may be needed.