The value of computed tomography for head trauma in patients presenting with out-of-hospital cardiac arrest before emergency percutaneous coronary intervention.

INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) caused by an ST-elevation myocardial infarction (STEMI) is often accompanied by a sudden loss of consciousness that may cause the patient to collapse with resulting head trauma, leading to a suspicion of possible intracranial haemorrhage. To rule out intracranial haemorrhage before emergency percutaneous coronary intervention (PCI), emergency computed tomography (CT) of the head might be useful but also causes a delay in percutaneous STEMI treatment. METHODS: The medical records of all adult patients that presented with OHCA to the emergency department (ED) of the University Medical Centre Utrecht (UMCU), the Netherlands between 16 February 2020 and 16 February 2022 were reviewed. RESULTS: A total of 263 patients presented to the ED with an OHCA; 50 presented with a STEMI requiring emergency PCI. Thirty-nine (78%) patients with a STEMI were immediately referred to the catheterisation laboratory and 11 (22%) STEMI patients underwent a CT scan prior to emergency angiography; in no case was PCI deferred on the basis of the CT findings. The dominant indication for CT of the head was collapse, reported by 10 patients and resulting in a visible traumatic head injury in 7 patients. In none of the patients was intracranial haemorrhage detected. However, there was a delay between presentation to the ED and arrival at the catheterisation laboratory in patients who underwent CT of the head (mean 63 ± 25 min) before emergency PCI compared to patients without a CT scan (mean 37 ± 21 min). CONCLUSION: CT of the head did not result in a diagnosis of intracranial haemorrhage or deferral of PCI but did delay PCI treatment for STEMI in patients presenting with OHCA.

NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction.

NLRP3-inflammasome-mediated signaling is thought to significantly contribute to the extent of myocardial damage after myocardial infarction (MI). The purpose of this study was to investigate the effects of the NLRP3-inflammasome inhibitor IZD334 on cardiac damage in a pig model of myocardial infarction. Prior to in vivo testing, in vitro, porcine peripheral blood mononuclear cells and whole blood were treated with increasing dosages of IZD334, a novel NLRP3-inflammasome inhibitor, and were stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). After determination of the pharmacological profile in healthy pigs, thirty female Landrace pigs were subjected to 75 min of transluminal balloon occlusion of the LAD coronary artery and treated with placebo or IZD334 (1 mg/kg, 3 mg/kg, or 10 mg/kg once daily) in a blinded randomized fashion. In vitro, NLRP3-inflammasome stimulation showed the pronounced release of interleukin (IL)-1ß that was attenuated by IZD334 (p < 0.001). In vivo, no differences were observed between groups in serological markers of inflammation nor myocardial IL-1ß expression. After 7 days, the ejection fraction did not differ between groups, as assessed with MRI (placebo: 45.1 ± 8.7%, 1 mg/kg: 49.9 ± 6.1%, 3 mg/kg: 42.7 ± 3.8%, 10 mg/kg: 44.9 ± 6.4%, p = 0.26). Infarct size as a percentage of the area at risk was not reduced (placebo: 73.1 ± 3.0%, 1 mg/kg: 75.5 ± 7.3%, 3 mg/kg: 80.3 ± 3.9%, 10 mg/kg: 78.2 ± 8.0%, p = 0.21). In this pig MI model, we did not observe attenuation of the inflammatory response after NLRP3-inflammasome inhibition in vivo. Consecutively, no difference was observed in IS and cardiac function, while in vitro inhibition successfully reduced IL-1ß release from stimulated porcine blood cells.

Experimental parameters and infarct size in closed chest pig LAD ischemia reperfusion models; lessons learned.

BACKGROUND: Preclinical models that resemble the clinical setting as closely as possible are essential in translating promising therapies for the treatment of acute myocardial infarction. Closed chest pig left anterior descending coronary artery (LAD) ischemia reperfusion (I/R) models are valuable and clinically relevant. Knowledge on the influence of experimental design on infarct size (IS) in these models is a prerequisite for suitable models. To this end, we investigated the impact of several experimental features (occlusion and follow-up time and influence of area at risk (AAR)) on IS. METHODS: A total of fifty-one female Landrace pigs were subjected to closed chest LAD balloon occlusion and evaluated in three substudies with varying protocols. To assess the relationship between time of occlusion and the IS, 18 pigs were subjected to 60-, 75- and 90 min of occlusion and terminated after 24 h of follow-up. Influence of prolonged follow-up on IS was studied in 18 pigs after 75 min of occlusion that were terminated at 1, 3 and 7 days. The relation between AAR and IS was studied in 28 pigs after 60 min of occlusion and 24 h of follow-up. The relation between VF, number of shocks and IS was studied in the same 28 pigs after 60 min of occlusion. RESULTS: Increasing occlusion time resulted in an increased IS as a ratio of the AAR (IS/AAR). This ranged from 53 ± 23% after 60 min of occlusion to 88 ± 2.2% after 90 min (P = 0.01). Increasing follow-up, from 1 to 3 or 7 days after 75 min of occlusion did not effect IS/AAR. Increasing AAR led to a larger IS/AAR (r2 = 0.34, P = 0.002), earlier VF (r2 = 0.32, P = 0.027) and a higher number of shocks (r2 = 0.29, P = 0.004) in pigs subjected to 60 min of occlusion. CONCLUSIONS: These experiments describe the association of occlusion time, follow-up duration, AAR and VF with IS in closed chest pig LAD I/R models. These results have important implications for future I/R studies in pigs and can serve as a guideline for the selection of appropriate parameters and the optimal experimental design.

The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease.

Chronic inflammation drives the development of atherosclerosis. Despite optimal treatment of classical cardiovascular risk factors, a substantial portion of the population has elevated inflammatory biomarkers and develops atherosclerosis-related complications, indicating that a residual inflammatory risk drives atherosclerotic cardiovascular disease in these patients. Additional anti-inflammatory therapeutic strategies are therefore required. The co-stimulatory molecule CD40 and its ligand CD40L (CD154) have a central role in the regulation of the inflammatory response during the development of atherosclerosis by modulating the interaction between immune cells and between immune cells and non-immune cells. In this review, we discuss the role of the CD40-CD40L dyad in atherosclerosis, and we discuss recent studies on the therapeutic potential of novel CD40-CD40L targeting strategies in cardiovascular medicine.

The transverse aortic constriction heart failure animal model: a systematic review and meta-analysis.

The transverse aortic constriction (TAC) model is frequently used to study adverse cardiac remodeling upon pressure overload. We set out to define the most important characteristics that define the degree of cardiac remodeling in this model. A systematic review and meta-analyses were performed on studies using the TAC mouse/rat model and reporting echocardiographic outcome parameters. We included all animal studies in which a constriction around the transverse aorta and at least one of the predefined echocardiography or MRI outcome parameters were assessed. A total of 502 articles and > 3000 wild-type, untreated animals undergoing TAC were included in this study and referenced to a control group. The duration of aortic constriction correlated to the degree of adverse remodeling. However, the mouse data is strongly biased by the preferential use of male C57Bl/6 mice (66% of studies). Furthermore, mostly ketamine/xylazine anesthetics, 27G needle constriction, and silk sutures are used. Nonetheless, despite the homogeneity in experimental design, the model contained a substantial degree of heterogeneity in the functional outcome measures. When looking at study quality, only 12% reported randomization, 23% mentioned any sort of blinding, 25% adequately addressed the outcomes, and an amazingly low percentage (2%) showed sample size calculation. Meta-analyses did not detect specific study characteristics that explained the heterogeneity in the reported outcome measures, however this might be related to the strong bias towards the use of specific mouse lines, sex as well as age or to poor reporting of characteristics of study quality.

Immunomodulation of the NLRP3 Inflammasome in Atherosclerosis, Coronary Artery Disease, and Acute Myocardial Infarction.

Cardiovascular disease (CVD) remains the leading cause of mortality and morbidity worldwide. Atherosclerosis is responsible for the majority of cardiovascular disorders with inflammation as one of its driving processes. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, responsible for the release of the pro-inflammatory cytokines, interleukin-1ß (IL-1ß), and interleukin-18 (IL-18), has been studied extensively and showed to play a pivotal role in the progression of atherosclerosis, coronary artery disease (CAD), and myocardial ischemia reperfusion (I/R) injury. Both the NLRP3 inflammasome and its downstream cytokines, IL-1ß and IL-18, could therefore be promising targets in cardiovascular disease. This review summarizes the role of the NLRP3 inflammasome in atherosclerosis, CAD, and myocardial I/R injury. Furthermore, the current therapeutic approaches targeting the NLRP3 inflammasome and its downstream signaling cascade in atherosclerosis, CAD, and myocardial I/R injury are discussed.

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success.

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient's circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.

Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure.

BACKGROUND: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in non-ischemic heart failure (HF). Small molecule inhibitors of CD40-TRAF6 have shown to be effective in multiple animal-models of chronic inflammatory disease, such as obesity and atherosclerosis. METHODS & RESULTS: Mice were subjected to transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD40-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks after TAC with a reduced end systolic volume (TAC-placebo group: 71.9 ±â€¯8.8 vs TAC-CD40-TRAF6 inhibitor: 53.7 ±â€¯6.1 µl, p = 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 ±â€¯2.8 vs TAC-CD40-TRAF6 inhibitor: 35.5 ±â€¯3.3%, p = 0.02). Within the myocardium, CD40-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardiomyocyte hypertrophy was observed in the CD40-TRAF6 inhibitor group compared to placebo. CONCLUSION: CD40-TRAF6 inhibition improves cardiac function in non-ischemic HF in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium, accompanied by a reduction in cardiac fibrosis and hypertrophy.

The Inflammasomes in Cardiovascular Disease.

Cardiovascular disease (CVD) is the number one cause of death worldwide. The pathogenesis of various disease entities that comprise the area of CVD is complex and multifactorial. Inflammation serves a central role in these complex aetiologies. The inflammasomes are intracellular protein complexes activated by danger-associated molecular patterns (DAMPs) present in CVD such as atherosclerosis and myocardial infarction (MI). After a two-step process of priming and activation, inflammasomes are responsible for the formation of pro-inflammatory cytokines interleukin-1ß and interleukin-18, inducing a signal transduction cascade resulting in a strong immune response that culminates in disease progression. In the past few years, increased interest has been raised regarding the inflammasomes in CVD. Inflammasome activation is thought to be involved in the pathogenesis of various disease entities such as atherosclerosis, MI and heart failure (HF). Interference with inflammasome-mediated signalling could reduce inflammation and attenuate the severity of disease. In this chapter we provide an overview of the current literature available on the role of inflammasome inhibition as a therapeutic intervention and the possible clinical implications for CVD.

Complement 5a Receptor deficiency does not influence adverse cardiac remodeling after pressure-overload in mice.

Hypertension is one of the most common risk factors for the development heart failure in the general population. Inflammation plays a central role in this adverse remodeling and eventually to the development of heart failure. Circulating levels of Complement factor 5a (C5a) are increased in hypertensive patients and the C5a receptor is associated with the presence of cardiac fibrosis and inflammation in an experimental hypertension model. To test if C5aR is involved in adverse cardiac remodeling following pressure-overload, we induced transverse aortic constriction (TAC) in wildtype and C5a receptor deficient mice (C5aR-/-). Six weeks after TAC, C5aR-/- animals showed a similar degree of cardiac hypertrophy and decrease in cardiac function as wild type mice (End Systolic Volume; 50.30±5.32 µl vs. 55.81±8.16 µl). In addition, other features of adverse cardiac remodeling like cardiomyocyte cell size (WGA staining), fibrosis (picrosirius red staining) or collagen degradation (matrix metalloproteinase activity assay) did not differ either. In conclusion, full body C5aR deficiency does not affect adverse cardiac remodeling after pressure-overload. However, our finding are in contrast with C5a inhibition studies. Our observations do present the role of C5a-C5aR in adverse cardiac remodeling and heart failure as controversial at the least.

Right ventricular dysfunction in left-sided heart failure with preserved versus reduced ejection fraction.

BACKGROUND: Right ventricular (RV) dysfunction is recognized as a major prognostic factor in left-sided heart failure (HF). However, the relative contribution of RV dysfunction in HF with preserved (HFpEF) vs. reduced ejection fraction (HFrEF) is unclear. METHODS AND RESULTS: Right ventricular longitudinal strain (RVLS), tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were determined by echocardiography in 657 age- and gender-matched groups of patients with HFpEF [left ventricular ejection fraction (LVEF) ≥50%; n=219] and HFrEF (LVEF <50%; n=219) and in controls without HF (n=219) from an Asian population-based cohort study. Across control to HFpEF and HFrEF groups, RV function deteriorated as measured by RVLS (-26.7 ± 5%, -22.7±6.6% and -18.2 ± 6.7%, respectively) and TAPSE (21.0 ± 3.9, 17.5 ± 5.1 and 14.7 ± 4.7 mm, respectively), whereas PASP increased (26.8 ± 7.1, 34.5 ± 11.9 and 39.3 ± 16.2 mmHg, respectively) (all P<0.001). Controlling for PASP in control, HFpEF and HFrEF subjects, the magnitude of RVLS/PASP (-1.06 ± 0.32, -0.75 ± 0.32 and -0.56 ± 0.36, respectively) and TAPSE/PASP ratios (0.83 ± 0.23, 0.54 ± 0.24 and 0.55 ± 0.29, respectively) similarly decreased across groups. Right ventricular dysfunction (by both TAPSE and RVLS) was independently associated with left ventricular systolic dysfunction and atrial fibrillation, but not with PASP. Among patients with HF, both TAPSE/PASP and RVLS/PASP ratios were related to the composite endpoint of all-cause death and HF hospitalization, even after multivariable adjustment [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.74 and HR 3.09; 95% CI 1.52-6.26, respectively], with no difference between HFrEF and HFpEF. CONCLUSIONS: Right ventricular dysfunction is present in HFpEF and is even more pronounced in HFrEF for any given degree of pulmonary hypertension. It is independently predicted by left ventricular dysfunction but not by PASP. Right ventricular-arterial coupling is prognostically important in HF regardless of LVEF.

The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction.

AIMS: Myocardial infarction (MI) triggers an intense inflammatory response that is associated with infarct expansion and is detrimental for cardiac function. Interleukin (IL)-1ß and IL-18 are key players in this response and are controlled by the NLRP3-inflammasome. In the current study, we therefore hypothesized that selective inhibition of the NLRP3-inflammasome reduces infarct size and preserves cardiac function in a porcine MI model. METHODS AND RESULTS: Thirty female landrace pigs were subjected to 75 min transluminal balloon occlusion and treated with the NLRP3-inflammasome inhibitor MCC950 (6 or 3 mg/kg) or placebo for 7 days in a randomized, blinded fashion. After 7 days, 3D-echocardiography was performed to assess cardiac function and Evans blue/TTC double staining was executed to assess the area at risk (AAR) and infarct size (IS). The IS/AAR was lower in the 6 mg/kg group (64.6 ± 8.8%, P = 0.004) and 3 mg/kg group (69.7 ± 7.2%, P = 0.038) compared with the control group (77.5 ± 6.3%). MCC950 treatment markedly preserved left ventricular ejection fraction in treated animals (6 mg/kg 47 ± 8%, P = 0.001; 3 mg/kg 45 ± 7%, P = 0.031; control 37 ± 6%). Myocardial neutrophil influx was attenuated in treated compared with non-treated animals (6 mg/kg 132 ± 72 neutrophils/mm2, P = 0.035; 3 mg/kg 207 ± 210 neutrophils/mm2, P = 0.5; control 266 ± 158 neutrophils/mm2). Myocardial IL-1ß levels were dose-dependently reduced in treated animals. CONCLUSIONS: NLRP3-inflammasome inhibition reduces infarct size and preserves cardiac function in a randomized, blinded translational large animal MI model. Hence, NLRP3-inflammasome inhibition may have therapeutic potential in acute MI patients.

Platelets enter atherosclerotic plaque via intraplaque microvascular leakage and intraplaque hemorrhage: a histopathological study in carotid plaques.

BACKGROUND: Platelets foster an inflammatory environment that influences atherosclerotic lesion progression and facilitates plaque rupture, in addition to their role in acute thrombus formation. The route of entry of platelets into the atherosclerotic plaque and their exact location inside the plaque are however not completely understood. METHODS AND RESULTS: 188 carotid plaques were examined for the presence of platelets using immunohistochemistry (CD42b), and 76/188 (40.4%) were platelet positive. Platelets were observed in intraplaque hemorrhages, around plaque microvessels, mostly without leakage of erythrocytes; and in mural thrombi. Platelet positive staining was associated with a higher plaque microvessel density, and elevated plaque-levels of interleukin-8. CONCLUSION: Due to their short life span, platelets reflect recent bleeding. It can be hypothesized that platelets might serve as a marker for leaky microvessels inside atherosclerotic plaques that are at risk for development, or progression of plaque hemorrhage.