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Mechanical injury during transradial coronary angiography (TCA) results in the induction of vascular injury. The intake of cocoa flavanols seven days prior to and after elective TCA mitigated long-term functional decline and hyperplasia.

BackgroundEndothelial function and cardioprotection through remote ischemic preconditioning (rIPC) are severely impaired in type 2 diabetes mellitus (T2DM). Proline-rich tyrosine kinase 2 (Pyk2), a downstream target of the insulin receptor, reduces endothelial nitric oxide synthase (eNOS) activity. Therapeutic options to rescue cardioprotection in T2DM and improve outcomes after acute myocardial infarction (AMI) are lacking. We hypothesized that vascular endothelium contributes to rIPC, and that inhibition of Pyk2 restores cardioprotection in T2DM through modulation of eNOS, thus limiting infarct size.MethodsNew Zealand Obese (NZO) mice were used as a polygenic model of T2DM. Effects of Pyk2-inhibition on endothelial function, remote ischemic preconditioning (rIPC), and infarct size (IS) after ischemia/reperfusion (I/R) were compared in NZO, eNOS KO, and C57Bl/6 (Bl6) mice. Plasma derived from mice and individuals with or without T2DM at baseline and after rIPC was transferred to isolated hearts and aortic rings to assess the effects of Pyk2-inhibition on remote tissue protection.ResultsTransfer experiments with plasma drawn from non-diabetic humans and mice exposed to rIPC demonstrate that endothelium-dependent signals for remote tissue protection are conveyed by plasma. Key features reflecting the glucometabolic spectrum in T2DM were detected in NZO mice, including hyperinsulinemia, insulin resistance, obesity, and impaired glucose tolerance. Similar to T2DM patients, these mice also revealed endothelial dysfunction with decreased flow-mediated dilation (FMD), reduced circulating nitrite levels, elevated arterial blood pressure, and larger infarct size after I/R. Pyk2 increased the phosphorylation of eNOS on its inhibitory site (Tyr656). Cardioprotective effects by rIPC were lost in NZO mice. Inhibition of Pyk2 restored endothelial function and rescued endothelium-dependent cardioprotection after rIPC displayed by lower IS and improved LV function post I/R.ConclusionEndothelial function contributing to remote tissue protection is severely impaired in diabetes mellitus. Proline-rich tyrosine kinase 2 is a novel target to rescue cardioprotection through endothelium-dependent remote ischemic preconditioning, advocating its role in limiting infarct size in diabetes mellitus.Clinical perspective What is new?Vascular endothelium contributes to remote tissue protection in ischemic preconditioning, which is severely impaired in diabetesProline-rich tyrosine kinase 2 reduces eNOS-activity, causes endothelial dysfunction, and impairs cardioprotection through ischemic preconditioningInhibition of proline-rich tyrosine kinase 2 restores eNOS activity, endothelial function, and cardioprotective effects of remote ischemic preconditioning limiting infarct size in an experimental model of diabetes.What are the clinical implications?Proper endothelial function is cirtical to maintain cardiovascular health. Endothelial dysfunction contributes to impaired remote tissue protection in diabetes.These data demonstrate for the first time that endothelium-dependent cardioprotection in myocardial ischemia/reperfusion through remote ischemic preconditioning can be restored in diabetes.Proline-rich tyrosine kinase 2 is a novel target to restore endothelium-dependent remote cardioprotection to improve the outcome of diabetic patients with acute myocardial infarction.

BackgroundLoss of functional capacity is one of the hallmarks in cardiovascular aging. Cocoa flavanols (CF) exert favorable effects on endothelial function, blood pressure, and inflammation. These cardiovascular health markers worsen with increasing age and limit functional exercise capacity.AimTo investigate the effect of CF on cardiorespiratory-fitness in healthy elderly.MethodsIn a randomized, double-masked, placebo-controlled, parallel-group dietary intervention trial, 68 healthy elderly (55-79 years, 28 female) received either 500 mg of CF or a nutrient-matched control capsule twice a day for 30 days. Primary endpoint was defined as peak oxygen consumption (VO2) in a cardiopulmonary exercise test (CPET). Secondary endpoints were oxygen pulse (VO2/heart rate (HR)), resting blood pressure (BP), and resting vascular function.ResultsAfter 30 days of CF intake peakVO2increased by 190 ml/min (95% CI 1-371 ml/min) and peakVO2/kg by 2.5 ml/(min*kg) (95% CI 0.30-4.2 ml/(min*kg)). O2-pulse increased by 1.7 ml (95% CI 0.29-3.2 ml) and max exercise capacity by 9.6 W (95% CI 2.1-17.7 W). CF decreased resting systolic and diastolic BP by 5.4 mmHg (95% CI -10.7 - -0.1 mmHg) and 2.9 mmHg (95% CI (-) 5.5-(-) 0.4 mmHg), respectively. Flow-mediated vasodilation (FMD) increased by an absolute 1.3% (95% CI 0.76-1.79 %) in the CF group. Indexes of pulmonary function were not affected. No changes for primary and secondary endpoints were detected in control.ConclusionCF substantially improve markers of cardiorespiratory fitness in healthy elderly humans highlighting their potential to preserve cardiovascular health with increasing age.

Structured AbstractBackgroundAssessment of left ventricular (LV) function and volume after ST-segment elevation myocardial infarction (STEMI) is recommended to guide clinical decision within and after hospitalization. Early after STEMI, initial LV reshaping and hypokinesia may affect analysis of LV function. A comparative evaluation of left ventricular ejection fraction (LVEF) and stroke volume (SV) by different imaging modalities to assess LV function early after STEMI has not been performed so far.MethodsLV function was assessed by LVEF and SV using serial imaging within 24h and 5 days after STEMI with cineventriculography (CVG), 2-dimensional echocardiography (2DE), 2D and 3D cardiovascular magnetic resonance (2D/3D) in 82 patients. Respective parameters were compared between modalities and to 3D gold standard CMR.Results2D analyses of LVEF using CVG and 2DE as well as 2D CMR yielded uniform results within 24h and 5 days of STEMI. SV assessment between CVG and 2DE at day 1 after STEMI was comparable, whereas values for SV were higher using 2D CMR on all occasions (pConclusionsEarly after STEMI, 2D analysis of LVEF yielded robust results across all imaging techniques implying that CVG, 2DE, and 2D CMR can be used interchangeably in this setting. SV measurements to assess cardiac function differed substantially between imaging techniques due to higher intermodality-differences of absolute volumetric measurements.

RationaleThe impact of aortic valve stenosis (AS) on systemic endothelial function independent of standard modifiable risk factors (SMuRFs) is unknown.ObjectiveWe hypothesized that AS induces subclinical hemoglobin release from red blood cells (RBCs) following transvalvular passage due to post-stenotic aberrant blood flow and that cell-free hemoglobin (fHb) may limit endothelial NO bioavailability, affecting vascular function.Methods and ResultsAS induces swirling blood flow in the ascending aorta which impairs RBC integrity with consecutive release of fHb. Indeed, swirl flow magnitude assessed by 4D flow cardiac magnetic resonance correlates with fHb levels. Elevated systemic fHb reduces NO bioavailability and thus impairs endothelial cell function as evidenced by impaired flow mediated dilation (FMD). In addition, we here demonstrate impaired FMD in an experimental model of AS utilising C57BL/6 mice with preserved left ventricular function and without cardiovascular risk factors. In this model, endothelial dysfunction is accompanied by significantly increased fHb, exaggerated NO consumption and increased plasma levels of nitroso species and the final NO oxidation product, nitrate. Scavenging of fHb by infusion of haptoglobin reversed these deleterious effects. There observations were verified by transfer experiments with human plasma (sampled from patients with AS sheduled for TAVR) using a murine aortic ring bioassay system where the plasma from AS patients induced endothelial dysfunction when compared to plasma from control individuals without AS. Importantly, these deleterious effects were reversed by successful aortic valve replacement via TAVR independent of SMuRFs.ConclusionsIn aortic valve stenosis, increases in post-valvular swirl blood flow in the ascending aorta induces subclinical hemolysis that impairs NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement limits NO scavenging by realigning of postvalvular blood flow to normal physiological patterns.

Aortic valve stenosis (AS) is the most frequent valve disease with relevant prognostic impact. Experimental model systems for AS are scarce and comprehensive imaging techniques to simultaneously quantify function and morphology in disease progression are lacking. Therefore, we refined an acute murine AS model to closely mimic human disease characteristics and developed a high-resolution magnetic resonance imaging (MRI) approach for simultaneous in-depth analysis of valvular, myocardial as well as aortic morphology/pathophysiology to identify early changes in tissue texture and critical transition points in the adaptive process to AS. AS was induced by wire injury of the aortic valve. Four weeks after surgery, cine loops, velocity, and relaxometry maps were acquired at 9.4 T to monitor structural/functional alterations in valve, aorta, and left ventricle (LV). In vivo MRI data were subsequently validated by histology and compared to echocardiography. AS mice exhibited impaired valve opening accompanied by significant valve thickening due to fibrotic remodelling. While control mice showed bell-shaped flow profiles, AS resulted not only in higher peak flow velocities, but also in fragmented turbulent flow patterns associated with enhanced circumferential strain and an increase in wall thickness of the aortic root. AS mice presented with a mild hypertrophy but unaffected global LV function. Cardiac MR relaxometry revealed reduced values for both T1 and T2 in AS reflecting subtle myocardial tissue remodelling with early alterations in mitochondrial function in response to the enhanced afterload. Concomitantly, incipient impairments of coronary flow reserve and myocardial tissue integrity get apparent accompanied by early troponin release. With this, we identified a premature transition point with still compensated cardiac function but beginning textural changes. This will allow interventional studies to explore early disease pathophysiology and novel therapeutic targets.

Intact endothelial function plays a fundamental role for the maintenance of cardiovascular (CV) health. The endothelium is also involved in remote signaling pathway-mediated protection against ischemia/reperfusion (I/R) injury. However, the transfer of these protective signals into clinical practice has been hampered by the complex metabolic alterations frequently observed in the cardiometabolic continuum, which affect redox balance and inflammatory pathways. Despite recent advances in determining the distinct roles of hyperglycemia, insulin resistance (InR), hyperinsulinemia, and ultimately diabetes mellitus (DM), which define the cardiometabolic continuum, our understanding of how these conditions modulate endothelial signaling remains challenging. It is widely accepted that endothelial cells (ECs) undergo functional changes within the cardiometabolic continuum. Beyond vascular tone and platelet-endothelium interaction, endothelial dysfunction may have profound negative effects on outcome during I/R. In this review, we summarize the current knowledge of the influence of hyperglycemia, InR, hyperinsulinemia, and DM on endothelial function and redox balance, their influence on remote protective signaling pathways, and their impact on potential therapeutic strategies to optimize protective heterocellular signaling.

The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch that controls the expression of antioxidant and cytoprotective enzymes, including enzymes catalyzing glutathione de novo synthesis. In this study, we aimed to analyze whether Nrf2 deficiency influences antioxidative capacity, redox state, NO metabolites, and outcome of myocardial ischemia reperfusion (I/R) injury. In Nrf2 knockout (Nrf2 KO) mice, we found elevated eNOS expression and preserved NO metabolite concentrations in the aorta and heart as compared to wild types (WT). Unexpectedly, Nrf2 KO mice have a smaller infarct size following myocardial ischemia/reperfusion injury than WT mice and show fully preserved left ventricular systolic function. Inhibition of NO synthesis at onset of ischemia and during early reperfusion increased myocardial damage and systolic dysfunction in Nrf2 KO mice, but not in WT mice. Consistent with this, infarct size and diastolic function were unaffected in eNOS knockout (eNOS KO) mice after ischemia/reperfusion. Taken together, these data suggest that eNOS upregulation under conditions of decreased antioxidant capacity might play an important role in cardioprotection against I/R. Due to the redundancy in cytoprotective mechanisms, this fundamental antioxidant property of eNOS is not evident upon acute NOS inhibition in WT mice or in eNOS KO mice until Nrf2-related signaling is abrogated.

Background Recently, we established an experimental model of moderate aortic valve stenosis (AS) aiming to mimic human disease progression closely. Functional and structural MRI of a mouse model in experimental aortic valve stenosis has not been accomplished so far. Purpose Here, we aimed at developing comprehensive MRI approach for simultaneous assessment of changes in valvular, left ventricular and aortic morphology and function. Methods Male 12-week-old wildtype mice (C57Bl/6) were subjected to wire injury of the aortic valve to induce aortic valve stenosis. High resolution MRI at 9.4T was used to monitor subsequent functional and structural changes in the aortic valve, the ascending aorta, the left ventricle and aortic flow patterns. Results MRI permits accurate planimetry of the orifice and the thickness of the aortic valve, allows a reliable three-dimensional mapping of transvalvular aortic flow, simultaneously depicts aortic regurgitation in 3D fashion and permits assessment of left ventricular changes due to AS. In our model we observed a reduced valve orifice and an increase in valve thickness. Homogenous flow pattern under control converted to heterogenous and turbulent flow with progression of AS associated with increased aortic strain, aortic wall and left ventricular wall thickness. Conclusions In a murine model of aortic valve stenosis MRI is capable to reliably display a three-dimensional transvalvular aortic flow profile with concomitant quantification of structural and functional changes in aortic valve, left ventricle, and ascending aorta. This comprehensive functional imaging at high resolution and distinct reproducibility offers for the first time serial assessment of disease progression in an experimental model of aortic valve stenosis.

Introduction: Body temperature (BT) abnormalities are frequently observed in critically ill patients. We aimed to assess admission BT in a heterogeneous critically ill patient population admitted to an intensive care unit (ICU) as a prognostic parameter for intra-ICU and long-term mortality. Methods: A total of 6,514 medical patients (64 ± 15 years) admitted to a German ICU between 2004 and 2009 were included. A follow-up of patients was performed retrospectively. The association of admission BT with both intra-ICU and long-term mortality was investigated by logistic regression. Results: Patients with hypothermia (p < 0.001), and a 4-fold increase for the risk of hypothermia (mortality 24%; OR 4.05, 95% CI 3.38–4.85; p < 0.001) with respect to intra-ICU and long-term mortality. Moreover, hypothermia was even more harmful than hyperthermia, and both were strongly associated with intra-ICU mortality, especially in patients admitted with acute coronary syndrome (hypothermia: hazard ratio 6.12, 95% CI 4.12–9.11; p < 0.001; hyperthermia: OR 2.70, 95% CI 1.52–4.79; p< 0.001). Conclusion: Admission BT is an independent risk predictor for both overall intra-ICU and long-term mortality in critically ill patients admitted to an ICU. Therefore, BT at admission might not only serve as a parameter for individual risk stratification but can also influence individual therapeutic decision-making.

The use of contrast media (CM) in diagnostic and interventional cardiology is increasing worldwide, while treated patients become older and suffer from more comorbidities. CM is associated with multiple adverse effects (AE) - ranging from clinically insignificant to life-threatening [1]. Guidelines recommend reducing the amount of administered CM as low as reasonably possible [2]. However, following this recommendation in daily practice remains difficult and CM volumes vary greatly [3]. Great efforts have been undertaken to develop contrast-sparing devices [4]: One of the first was the manual stopcock-manifold and hand-held syringe arrangement, which has been used as the standard technique for CM administration for decades. Later, automated contrast injection systems have been developed to optimize workflow efficiency and reduce both CM volume delivery and fluoroscopy time under controlled injection settings [5]. Parallel, the DyeVert system was introduced [6,7]. In brief, this system works as a fluid pathway resistance modulator to reduce CM over-injection via a dedicated diversion valve. The valve is connected to a secondary fluid pathway and works dependent on the injection pressure. In consequence, it diverts some of the CM into the reservoir chamber within the module. The saved overflow would otherwise be injected to the patient as aortic reflux without any positive effects on angiographic image quality. So far, the DyeVert™ Plus was incompatible with power injection systems and was thus restricted to use with the conventional stopcock-manifold-syringe system. However, the DyeVert™ Power XT Contrast Reduction System (DyeVert Power XT System; Osprey Medical, Minnetonka, MN, USA) has now been specifically designed to work in combination with ACIST CVi Contrast Delivery System (ACIST, ACIST Medical Systems, Eden Prairie, MN, USA). This short report summarizes our first experience combining the DyeVert Power XT System with ACIST in a consecutive patient population undergoing diagnostic or interventional ICA at our institution.

Cardiac functionality is dependent on a balanced protein turnover. Accordingly, regulated protein decay is critical to maintain cardiac function. Here we demonstrate that deficiency of SPRED2, an intracellular repressor of ERK-MAPK signaling markedly expressed in human heart, resulted in impaired autophagy, heart failure, and shortened lifespan. SPRED2-/- mice showed cardiomyocyte hypertrophy, cardiac fibrosis, impaired electrical excitability, and severe arrhythmias. Mechanistically, cardiomyocyte dysfunction resulted from ERK hyperactivation and dysregulated autophagy, observed as accumulation of vesicles, vacuolar structures, and degenerated mitochondria. The diminished autophagic flux in SPRED2-/- hearts was reflected by a reduced LC3-II/LC3-I ratio and by decreased Atg7, Atg4B and Atg16L expression. Furthermore, the autophagosomal adaptors p62/SQSTM1 and NBR1 and lysosomal Cathepsin D accumulated in SPRED2-/- hearts. In wild-type hearts, SPRED2 interacted physically with p62/SQSTM1, NBR1, and Cathepsin D, indicating that SPRED2 is required for autophagolysosome formation in regular autophagy. Restored inhibition of MAPK signaling by selumetinib led to an increase in autophagic flux in vivo. Therefore, our study identifies SPRED2 as a novel, indispensable regulator of cardiac autophagy. Vice versa, SPRED2 deficiency impairs autophagy, leading to cardiac dysfunction and life-threatening arrhythmias.

Balloon aortic valvuloplasty (BAV) as a bridge to transcatheter aortic valve implantation (TAVI) is a well-established treatment option in patients who are in a critical state or who suffer from underlying comorbidities that disguise the severity of aortic stenosis (AS). If convalescence is achieved, TAVI can be performed with good results in high-gradient aortic stenosis (HG-AS) patients. Whether this approach is safe and effective in low-flow low-gradient aortic stenosis (LFLG-AS) has not been analyzed; therefore, we investigated whether BAV followed by TAVI as a staged procedure is an effective treatment option in patients with LFLG-AS.Patients with severe AS who received BAV followed by staged TAVI were identified. Baseline data, periprocedural and postprocedural information, echocardiographic data, and follow-up data were collected. The patient population was divided into LFLG-AS and HG-AS groups.From July 2009 until September 2017, we identified 38 eligible patients (16 LFLG-AS and 22 HG-AS). Log EuroScore I (51.8 ± 20.9% LFLG-AS vs 33.7 ± 19.1% HG-AS; P.01) differed significantly between groups, as did baseline echocardiographic data that were used to categorize groups. BAV and staged TAVI were carried out 100% successfully with comparable results. Instant symptom relief and pressure gradient reduction were accomplished after both procedures. Thirty-day mortality rates (0% LFLG-AS vs 9% HG-AS; P=.21) and 1-year mortality rates (18.8% LFLG-AS vs 27.2% HG-AS; P=.54) did not differ between groups.BAV followed by staged TAVI is a safe and effective treatment option in sick or questionable candidates, irrespective whether LFLG-AS or HG-AS is present.

Significance: In this review, we discuss the role of nitric oxide (NO) as a key physiological mechanotransducer modulating both local and systemic heterocellular communication and contributing to the integrated (patho)physiology of the cardiovascular system. A deeper understanding of mechanotransduction-mediated local and systemic nodes controlling heterocellular communication between the endothelium, blood cells, and other cell types (e.g., cardiomyocytes) may suggest novel therapeutic strategies for endothelial dysfunction and cardiovascular disease. Recent Advances: Mechanical forces acting on mechanoreceptors on endothelial cells activate the endothelial NO synthase (eNOS) to produce NO. NO participates in (i) abluminal heterocellular communication, inducing vasorelaxation, and thereby regulating vascular tone and blood pressure; (ii) luminal heterocellular communication, inhibiting platelet aggregation, and controlling hemostasis; and (iii) systemic heterocellular communication, contributing to adaptive physiological processes in response to exercise and remote ischemic preconditioning. Interestingly, shear-induced eNOS-dependent activation of vascular heterocellular communication constitutes the molecular basis of all methods applied in the clinical routine for evaluation of endothelial function. Critical Issues and Future Directions: The integrated physiology of heterocellular communication is still not fully understood. Dedicated experimental models are needed to analyze messengers and mechanisms underpinning heterocellular communication in response to physical forces in the cardiovascular system (and elsewhere). Antioxid. Redox Signal. 26, 917–935.

To determine the impact of red blood cell distribution width on outcome in anemic patients undergoing transcatheter aortic valve implantation (TAVI).In a retrospective single center cohort study we determined the impact of baseline red cell distribution width (RDW) and anemia on outcome in 376 patients with aortic stenosis undergoing TAVI. All patients were discussed in the institutional heart team and declined for surgical aortic valve replacement due to high operative risk. Collected data included patient characteristics, imaging findings, periprocedural in hospital data, laboratory results and follow up data. Blood samples for hematology and biochemistry analysis were taken from every patient before and at fixed intervals up to 72 h after TAVI including blood count and creatinine. Descriptive statistics were used for patient's characteristics. Kaplan-Meier survival curves were used for time to event outcomes. A recursive partitioning regression and classification was used to investigate the association between potential risk factors and outcome variables.Mean age in our study population was 81 ± 6.1 years. Anemia was prevalent in 63.6% (n = 239) of our patients. Age and creatinine were identified as risk factors for anemia. In our study population, anemia per se did influence 30-d mortality but did not predict longterm mortality. In contrast, a RDW14% showed to be highly predictable for a reduced short- and longterm survival in patients with aortic valve disease after TAVI procedure.Age and kidney function determine the degree of anemia. The anisocytosis of red blood cells in anemic patients supplements prognostic information in addition to that derived from the WHO-based definition of anemia.

Background Endothelial dysfunction is considered both as cause and consequence of oxidative stress. Mice lacking the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2 KO) can be considered as a model of chronic adaption of the organism to oxidative stress, as they miss a key master switch controlling the expression of antioxidant and protective enzymes involved in the regulation of the cellular redox state. In this study we aimed to investigate the coronary and vascular phenotype and systemic hemodynamics of these mice compared to wild type (WT) littermates.

Increased production of reactive oxygen species and failure of the antioxidant defense system are considered to play a central role in the pathogenesis of cardiovascular disease. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch controlling the expression of antioxidant and protective enzymes, and was proposed to participate in protection of vascular and cardiac function. This study was undertaken to analyze cardiac and vascular phenotype of mice lacking Nrf2. We found that Nrf2 knock out (Nrf2 KO) mice have a left ventricular (LV) diastolic dysfunction, characterized by prolonged E wave deceleration time, relaxation time and total diastolic time, increased E/A ratio and myocardial performance index, as assessed by echocardiography. LV dysfunction in Nrf2 KO mice was associated with cardiac hypertrophy, and a downregulation of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in the myocardium. Accordingly, cardiac relaxation was impaired, as demonstrated by decreased responses to β-adrenergic stimulation by isoproterenol ex vivo, and to the cardiac glycoside ouabain in vivo. Surprisingly, we found that vascular endothelial function and endothelial nitric oxide synthase (eNOS)-mediated vascular responses were fully preserved, blood pressure was decreased, and eNOS was upregulated in the aorta and the heart of Nrf2 KO mice. Taken together, these results show that LV dysfunction in Nrf2 KO mice is mainly associated with cardiac hypertrophy and downregulation of SERCA2a, and is independent from changes in coronary vascular function or systemic hemodynamics, which are preserved by a compensatory upregulation of eNOS. These data provide new insights into how Nrf2 expression/function impacts the cardiovascular system.