Cardiovascular drugs attenuated myocardial resistance against ischaemia-induced and reperfusion-induced injury in a rat model of repetitive occlusion

We investigated the impact of cardioprotective drugs on ST-elevation, arrhythmias and infarct size in a rat model of repetitive coronary artery occlusion

Lipoprotein(a) as a risk factor for atherosclerotic cardiovascular disease in patients in non-metropolitan areas of Brandenburg, Germany

Background and aimsIn the non-metropolitan region of Brandenburg (Germany), which is characterized by high rates of cardiovascular diseases and underserved medical care, there is a lack of awareness regarding lipoprotein(a) [Lp(a)] as a risk factor. In addition, data from patients with atherosclerotic cardiovascular disease (ASCVD) in diverse regional backgrounds, including the understudied Brandenburg cohort, and various healthcare statuses remain insufficient.MethodsIn this WalkByLab study, Lp(a) levels were monitored in a non-metropolitan cohort (n = 850) in Brandenburg, Germany, comprising 533 patients at high cardiovascular risk and 317 healthy controls. Patients underwent a comprehensive angiological screening, which included blood serum analysis, assessment of medical and family history, cardiovascular risk, and disease status, and evaluation of lifestyle and quality of life. All parameters were evaluated with regard to two groups based on Lp(a) levels: low (<50 mg/dl) and high (≥50 mg/dl).ResultsBrandenburg patients with cardiovascular diseases showed higher Lp(a) levels than healthy controls (24.2% vs. 14.8%, p = 0.001). Logistic regression analysis with different characteristics revealed that Lp(a) was an independent risk factor significantly associated with ASCVD (OR 2.26, 95% CI 1.32–3.95, p = 0.003). The high-Lp(a) group showed a higher proportion of patients with coronary artery disease, peripheral artery disease, or cerebrovascular disease compared to the low-Lp(a) group (50% vs. 36.8%; 57.7% vs. 45.8%; 17.6% vs. 9.2%; p = 0.004); also, a higher percentage of patients in the high-Lp(a) group had heart failure (72.8% vs. 53.2%, p = 0.014) and myocardial infarction (24.7% vs. 13.9%, p = 0.001). The high-Lp(a) group exhibited higher rates of statins (63.1% vs. 50.4%, p = 0.003), ezetimibe (14.8% vs. 5.5.%, p = 0.001), and beta-blockers (55.7% vs. 40.7%, p = 0.001) use. Lp(a) levels were found to be independent of physical activity or smoking behavior and did not change over time (12 months).ConclusionsOur study highlights the significance of elevated Lp(a) levels in Brandenburg cardiovascular patients and identifies them as an independent risk factor for ASCVD, which has implications for addressing cardiovascular health of non-metropolitan populations

Leukocyte telomere length and mitochondrial DNA copy number associate with endothelial function in aging-related cardiovascular disease

BackgroundWe investigated the association between leukocyte telomere length, mitochondrial DNA copy number, and endothelial function in patients with aging-related cardiovascular disease (CVD).MethodsIn total 430 patients with CVD and healthy persons were enrolled in the current study. Peripheral blood was drawn by routine venipuncture procedure. Plasma and peripheral blood mononuclear cells (PBMCs) were collected. Cell-free genomic DNA (cfDNA) and leukocytic genomic DNA (leuDNA) were extracted from plasma and PBMCs, respectively. Relative telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) were analyzed using quantitative polymerase chain reaction. Endothelial function was evaluated by measuring flow-mediated dilation (FMD). The correlation between TL of cfDNA (cf-TL), mtDNA-CN of cfDNA (cf-mtDNA), TL of leuDNA (leu-TL), mtDNA-CN of leuDNA (leu-mtDNA), age, and FMD were analyzed based on Spearman's rank correlation. The association between cf-TL, cf-mtDNA, leu-TL, leu-mtDNA, age, gender, and FMD were explored using multiple linear regression analysis.Resultscf-TL positively correlated with cf-mtDNA (r = 0.1834, P = 0.0273), and leu-TL positively correlated with leu-mtDNA (r = 0.1244, P = 0.0109). In addition, both leu-TL (r = 0.1489, P = 0.0022) and leu-mtDNA (r = 0.1929, P < 0.0001) positively correlated with FMD. In a multiple linear regression analysis model, both leu-TL (β = 0.229, P = 0.002) and leu-mtDNA (β = 0.198, P = 0.008) were positively associated with FMD. In contrast, age was inversely associated with FMD (β = −0.426, P < 0.0001).ConclusionTL positively correlates mtDNA-CN in both cfDNA and leuDNA. leu-TL and leu-mtDNA can be regarded as novel biomarkers of endothelial dysfunction

Charakterisierung der frühen adaptiven zerebralen Arteriogenese

Arteriogenese bezeichnet das adaptive Wachstum von präexistenten kollateralen Arterien. Im Falle eines Arterienverschlusses ist Arteriogenese der endogen effizienteste Kompensationsmechanismus, um das Hypoperfusionsgebiet mit ausreichend Blut zu versorgen (Biologischer Bypasses). In dieser Arbeit wurde das frühe Wachstum von Kollateralgefäßen im Gehirn im ersten Modell für zerebrale Arteriogenese, dem 3-VO Modell (3-vessel occlusion), in der Ratte charakterisiert. (I) Die Untersuchung am nicht-ischämischen 3-VO Hypoperfusionsmodell zeigten, dass 7 Tage nach 3-VO die Arteria cerebri posterior (PCA) signifikant im Diameter anwächst. Histologische Untersuchungen konnten ein vermehrtes Zellwachstum in der PCA und das Einwandern von Makrophagen in den perivaskulären Bereich (24 Stunden und 3 Tage post 3-VO) darstellen und eine Aktivierung des Endothels 3 Tage nach 3-VO wurde mittels Rasterelektronenmikroskopie identifizieren. (II) Für eine genaue Anaylse des globalen Genexpressionsprofils der zerebralen Arteriogense wurde die wachsende PCA selektiv aus dem Gehirn entnommen und ein Genexpressionsprofil für die frühe zerebrale Arteriogenese erstellt (164 Gene dereguliert). Eine Unteruschung von biologischen und molekularen Prozessen zeigte, dass eine Vielzahl der deregulierten Gene in Zellproliferation und Inflammation involviert sind. Die Expression der Protease-Inhibitoren Kininogen und TIMP-1 wurde als “Marker” der frühen Arteriogenese in der PCA lokalisiert werden. Zusammenfassend zeigt diese Arbeit erstmals eine Übersicht der biologischen Prozesse in der zerebralen Arteriogenese und eröffnet neue Ideen für eine mögliche therapeutische Strategie.Arteriogenesis, the adaptive outward growth of pre-existing collateral arteries, is the most efficient endogenous rescue mechanisms in vertebrates against the occlusion of a major artery (biological bypass). Here, collateral growth was induced using the first model for cerebral arteriogenesis, the 3-vessel occlusion (3-VO) rat model. (I) 3-VO resulted in a significant diameter increase within 7 days in the posterior cerebral artery (PCA) and posterior communicating artery (Pcom), classifying the region of interest. Immunhistological staining demonstrated proliferative activation and macrophage invasion, already 24h post 3-VO within the PCA, confirming the arteriogenic phenotype. Furthermore, activation of the PCA endothelium was detected within 3 days post 3-VO by scanning electron microscopy. (II) For analysing the molecular mechanism of cerebral arteriogenesis, collateral tissue from the growing PCA was selectively isolated. Here, 24h post 3-VO 164 genes were detected to be significantly deregulated. Analysis of molecular annotations and networks associated with differentially expressed genes revealed that expression patterns contain gene transcripts predominantly involved in proliferation, inflammation, and migration. Early-phase cerebral arteriogenesis is characterized by protease inhibitor expression and showed that protease inhibitors TIMP-1 and kininogen are molecular markers of early-phase cerebral arteriogenesis. In summary, this work characterizes morphological features and genomic profiles of growing collaterals in the brain and develops novel ideas for a therapeutic stimulation of arteriogenesis

Exercise and cardiovascular diseases

Exercise is a physiologic stressor that has multiple beneficial effects on cardiovascular system. Currently exercise training is a class I intervention as part of a multifactorial long-term process that includes: clinical assistance, assessment of global cardiovascular risk, identification of specific objective for each cardiovascular risk factor, formulation of an individual treatment plan with multiple intervention aimed at reduction of the risk, educational programs, planning of long term follow-up. This paper reviews the evidences of benefit of exercise in the most common heart diseases and describes the role of exercise training in the cardiac rehabilitation programs

Effect of ACEI and ARB treatment on nitric oxide-dependentendothelial function

<jats:p>Summary: Background: Angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are widely used as a first-line therapy for the treatment of cardiovascular disease. Here, ACEI modulate the bradykinin receptor (BDKRB1 and BDKRB2) system and NO-dependent endothelial function, thus determining cardiovascular health and regenerative arteriogenesis. The current study aims at evaluating nitric oxide-dependent endothelial function, and gene expression of bradykinin receptors in peripheral blood mononuclear cells (PBMC) from patients with ACEI or ARB treatment. Patients and methods: The WalkByLab has been established to screen cardiovascular patients for peripheral artery disease and coronary artery disease. In total 177 patients from WalkByLab with heterogenous disease and risk status were randomly selected, divided according to their medication history into the following groups: 1. ACEI group, 2. ARB group or 3. non-ACE/ARB group. Total plasma nitrite/nitrate (NO) levels were measured, endothelial function was evaluated by assessing flow meditated dilation (FMD). PBMC were isolated from peripheral whole blood, and gene expression (qRT-PCR) of bradykinin receptors and angiotensin converting enzyme were assessed. Results: Plasma total NO concentration in the ACEI group (24.66±16.28, µmol/l) was increased as compared to the ARB group (18.57±11.58, µmol/l, P=0.0046) and non-ACE/ARB group (16.83±8.64, µmol/l, P=0.0127) in patients between 40 to 90 years of age. However, FMD values (%) in the ACEI group (7.07±2.40, %) were similar as compared to the ARB (6.35±2.13, %) and non-ACE/ARB group (6.51±2.15, %), but significantly negatively correlated with age. Interestingly, BDKRB1 mRNA level was significantly higher and BDKRB2 mRNA level lower in the ACEI group (BDKRB1 3.88-fold±1.05, BDKRB2 0.22-fold±0.04) as compared to the non-ACE/ARB group (BDKRB1 1.00-fold±0.39, P<0.0001, BDKRB2 1.00-fold±0.45, P=0.0136). Conclusions: ACEI treatment enhances total nitrite/nitrate concentration, furthermore, upregulates BDKRB1 in PBMC, but downregulates BDKRB2 mRNA expression. FMD is a strong determinant of vascular aging and is sensitive to underlying heterogenous cardiovascular diseases.</jats:p&gt

Nitroglycerin application and coronary arteriogenesis.

BACKGROUND:In the presence of a coronary occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (biological bypasses) that have the potential to allow a certain level of perfusion distal to the blockage. Termed arteriogenesis, this phenomenon proceeds via a complex combination of events, with nitric oxide (NO) playing an essential role. The aim of this study was to investigate the effects of supplemental administration of NO donors, i.e., short-acting nitroglycerin (NTG) or slow-release pelleted isosorbide dinitrate (ISDN), on collateral development in a repetitive coronary artery occlusion model in rats. METHODS:Coronary collateral growth was induced via a repetitive occlusion protocol (ROP) of the left anterior descending coronary artery (LAD) in rats. The primary endpoints were the histological evaluation of rat heart infarct size and ST-segment elevation (ECG-analysis) upon final permanent occlusion of the LAD (experimentally induced myocardial infarction). The effects of NTG or ISDN were also evaluated by administration during 5 days of ROP. We additionally investigated whether concomitant application of NTG can compensate for the anti-arteriogenic effect of acetylsalicylic acid (ASA). RESULTS:After 5 days of ROP, the mean infarct size and degree of ST-elevation were only slightly lower than those of the SHAM group; however, after 10 days of the protocol, the ROP group displayed significantly less severe infarct damage, indicating enhanced arteriogenesis. Intermittent NTG application greatly decreased the ST-elevation and infarct size. The ISDN also had a positive effect on arteriogenesis, but not to the same extent as the NTG. Administration of ASA increased the infarct severity; however, concomitant dosing with NTG somewhat attenuated this effect. CONCLUSION:Intermittent treatment with the short-acting NTG decreased the size of an experimentally induced myocardial infarct by promoting coronary collateral development. These new insights are of great relevance for future clinical strategies for the treatment of occlusive vascular diseases

Association of endothelial function and lower extremity perfusion inperipheral artery disease

<jats:p> Summary: Background: The current study aims to investigate the association between endothelial function and lower extremity perfusion in patients with peripheral artery disease (PAD). Patients and methods: In total 229 patients with PAD (Rutherford stage 0–3) were enrolled in the current study. Endothelial function was assessed by measuring flow-mediated dilation (FMD) and endothelial cell proliferation capacity (ECPC). Lower extremity perfusion was assessed by measuring oscillometry-based ankle brachial index (oABI) and pulse wave index (PWI). In addition, carotid intima-media-thickness (cIMT) was also measured as a surrogate marker for atherosclerosis. Correlations between FMD, ECPC, oABI, PWI, and cIMT were analysed using Pearson correlation coefficient. The relationship between the above variables and the severity of PAD was investigated using ordinal logistic regression analysis. Results: Correlation analysis showed that FMD negatively associated with PWI (r = –0.183, p = 0.005), ECPC positively associated with oABI (r = 0.162, p = 0.014), and oABI negatively associated with PWI (r = –0.264, p < 0.001). Ordinal logistic regression analysis showed that ECPC ( β = –0.009, p = 0.048), oABI ( β = -5.290, p < 0.001), and age ( β = −0.058, p = 0.002) negatively associated with the PAD Rutherford stages. In addition, PWI ( β = 0.006, p < 0.001), cIMT ( β = 18.363, p = 0.043) positively associated with the PAD Rutherford stages. Conclusions: Endothelial function significantly associates with lower extremity perfusion in patients with PAD, and both are related to the severity of PAD. </jats:p&gt

Knockout of Density-Enhanced Phosphatase-1 Impairs Cerebrovascular Reserve Capacity in an Arteriogenesis Model in Mice

Collateral growth, arteriogenesis, represents a proliferative mechanism involving endothelial cells, smooth muscle cells, and monocytes/macrophages. Here we investigated the role of Density-Enhanced Phosphatase-1 (DEP-1) in arteriogenesis in vivo, a protein-tyrosine-phosphatase that has controversially been discussed with regard to vascular cell biology. Wild-type C57BL/6 mice subjected to permanent left common carotid artery occlusion (CCAO) developed a significant diameter increase in distinct arteries of the circle of Willis, especially in the anterior cerebral artery. Analyzing the impact of loss of DEP-1 function, induction of collateralization was quantified after CCAO and hindlimb femoral artery ligation comparing wild-type and DEP-1−/− mice. Both cerebral collateralization assessed by latex perfusion and peripheral vessel growth in the femoral artery determined by microsphere perfusion and micro-CT analysis were not altered in DEP-1−/− compared to wild-type mice. Cerebrovascular reserve capacity, however, was significantly impaired in DEP-1−/− mice. Cerebrovascular transcriptional analysis of proarteriogenic growth factors and receptors showed specifically reduced transcripts of PDGF-B. SiRNA knockdown of DEP-1 in endothelial cells in vitro also resulted in significant PDGF-B downregulation, providing further evidence for DEP-1 in PDGF-B gene regulation. In summary, our data support the notion of DEP-1 as positive functional regulator in vascular cerebral arteriogenesis, involving differential PDGF-B gene expression