Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) is considered necessary for initiating a profound sterile inflammatory response. NLRP3 forms multi-protein ...complexes with Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1, which activate pro-interleukin-1β (IL-1β) and pro-IL-18. The role of NLRP3 in cardiac cells is not known. Thus, we investigated the expression and function of NLRP3 during myocardial ischaemia.
Myocardial infarction (MI) was induced in adult C57BL/6 mice and Wistar rats by ligation of the coronary artery. A marked increase in NLRP3, IL-1β, and IL-18 mRNA expression was found in the left ventricle after MI, primarily located to myocardial fibroblasts. In vitro studies in cells from adult mice showed that myocardial fibroblasts released IL-1β and IL-18 when primed with lipopolysaccharide and subsequently exposed to the danger signal adenosine triphosphate, a molecule released after tissue damage during MI. When hearts were isolated from NLRP3-deficient mice, perfused and subjected to global ischaemia and reperfusion, a marked improvement of cardiac function and reduction of hypoxic damage was found compared with wild-type hearts. This was not observed in ASC-deficient hearts, potentially reflecting a protective role of other ASC-dependent inflammasomes or inflammasome-independent effects of NLRP3.
This study shows that the NLRP3 inflammasome is up-regulated in myocardial fibroblasts post-MI, and may be a significant contributor to infarct size development during ischaemia-reperfusion.
There is increasing recognition of the crucial role of the right ventricle (RV) in determining functional status and prognosis in multiple conditions. The normal RV is anatomically and functionally ...different from the left ventricle, which precludes direct extrapolation of our knowledge of left-sided physiopathology to the right heart. RV adaptation is largely determined by the level of exposure to hemodynamic overload (both preload and afterload) as well as its intrinsic contractile function. These 3 processes (pressure overload, volume overload, and RV cardiomyopathy) are associated with distinct clinical course and therapeutic approach, although in reality they often coexist in various degrees. The close relationship between the RV and left ventricle (ventricular interdependence) and its coupling to the pulmonary circulation further modulate RV behavior in different clinical scenarios. In this review, the authors summarize current knowledge of RV anatomic, structural, metabolic, functional, and hemodynamic characteristics in both health and disease.
The literature exploring the utility of advanced echocardiographic techniques (such as deformation imaging) in the diagnosis and prognostication of patients receiving potentially cardiotoxic cancer ...therapy has involved relatively small trials in the research setting. In this systematic review of the current literature, we describe echocardiographic myocardial deformation parameters in 1,504 patients during or after cancer chemotherapy for 3 clinically-relevant scenarios. The systematic review was performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the EMBASE (1974 to November 2013) and MEDLINE (1946 to November 2013) databases. All studies of early myocardial changes with chemotherapy demonstrate that alterations of myocardial deformation precede significant change in left ventricular ejection fraction (LVEF). Using tissue Doppler-based strain imaging, peak systolic longitudinal strain rate has most consistently detected early myocardial changes during therapy, whereas with speckle tracking echocardiography (STE), peak systolic global longitudinal strain (GLS) appears to be the best measure. A 10% to 15% early reduction in GLS by STE during therapy appears to be the most useful parameter for the prediction of cardiotoxicity, defined as a drop in LVEF or heart failure. In late survivors of cancer, measures of global radial and circumferential strain are consistently abnormal, even in the context of normal LVEF, but their clinical value in predicting subsequent ventricular dysfunction or heart failure has not been explored. Thus, this systematic review confirms the value of echocardiographic myocardial deformation parameters for the early detection of myocardial changes and prediction of cardiotoxicity in patients receiving cancer therapy.
The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal ...contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection.
Recent advances have enabled noninvasive mapping of cardiac arrhythmias with electrocardiographic imaging and noninvasive delivery of precise ablative radiation with stereotactic body radiation ...therapy (SBRT). We combined these techniques to perform catheter-free, electrophysiology-guided, noninvasive cardiac radioablation for ventricular tachycardia.
We targeted arrhythmogenic scar regions by combining anatomical imaging with noninvasive electrocardiographic imaging during ventricular tachycardia that was induced by means of an implantable cardioverter-defibrillator (ICD). SBRT simulation, planning, and treatments were performed with the use of standard techniques. Patients were treated with a single fraction of 25 Gy while awake. Efficacy was assessed by counting episodes of ventricular tachycardia, as recorded by ICDs. Safety was assessed by means of serial cardiac and thoracic imaging.
From April through November 2015, five patients with high-risk, refractory ventricular tachycardia underwent treatment. The mean noninvasive ablation time was 14 minutes (range, 11 to 18). During the 3 months before treatment, the patients had a combined history of 6577 episodes of ventricular tachycardia. During a 6-week postablation "blanking period" (when arrhythmias may occur owing to postablation inflammation), there were 680 episodes of ventricular tachycardia. After the 6-week blanking period, there were 4 episodes of ventricular tachycardia over the next 46 patient-months, for a reduction from baseline of 99.9%. A reduction in episodes of ventricular tachycardia occurred in all five patients. The mean left ventricular ejection fraction did not decrease with treatment. At 3 months, adjacent lung showed opacities consistent with mild inflammatory changes, which had resolved by 1 year.
In five patients with refractory ventricular tachycardia, noninvasive treatment with electrophysiology-guided cardiac radioablation markedly reduced the burden of ventricular tachycardia. (Funded by Barnes-Jewish Hospital Foundation and others.).
Cells of the adult human heart Litviňuková, Monika; Talavera-López, Carlos; Maatz, Henrike ...
Nature (London),
12/2020, Letnik:
588, Številka:
7838
Journal Article
Recenzirano
Odprti dostop
Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved ...in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.
Aims
Angiotensin receptor–neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). ...Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin‐induced diabetic mice.
Methods and results
Male C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26–28 in each group). Cardiac function was assessed by a pressure–volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor‐β (TGF‐β) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group.
Conclusion
The ARNi LCZ696 improved cardiac function with the reduction of fibrosis in an HF‐rEF model in diabetic mice, by suppressing TGF‐β. This effect may be due to the specific inhibition of neprilysin, beyond the ARB effect of LCZ696.
Allopurinol (ALP) attenuates oxidative stress and diabetic cardiomyopathy (DCM), but the mechanism is unclear. Activation of nuclear factor erythroid 2‐related factor 2 (Nrf2) following the ...disassociation with its repressor Keap1 under oxidative stress can maintain inner redox homeostasis and attenuate DCM with concomitant attenuation of autophagy. We postulated that ALP treatment may activate Nrf2 to mitigate autophagy over‐activation and consequently attenuate DCM. Streptozotocin‐induced type 1 diabetic rats were untreated or treated with ALP (100 mg/kg/d) for 4 weeks and terminated after heart function measurements by echocardiography and pressure‐volume conductance system. Cardiomyocyte H9C2 cells infected with Nrf2 siRNA or not were incubated with high glucose (HG, 25 mmol/L) concomitantly with ALP treatment. Cell viability, lactate dehydrogenase, 15‐F2t‐Isoprostane and superoxide dismutase (SOD) were measured with colorimetric enzyme‐linked immunosorbent assays. ROS, apoptosis, was assessed by dihydroethidium staining and TUNEL, respectively. The Western blot and qRT‐PCR were used to assess protein and mRNA variations. Diabetic rats showed significant reductions in heart rate (HR), left ventricular eject fraction (LVEF), stroke work (SW) and cardiac output (CO), left ventricular end‐systolic volume (LVVs) as compared to non‐diabetic control and ALP improved or normalized HR, LVEF, SW, CO and LVVs in diabetic rats (all P < .05). Hearts of diabetic rats displayed excessive oxidative stress manifested as increased levels of 15‐F2t‐Isoprostane and superoxide anion production, increased apoptotic cell death and cardiomyocytes autophagy that were concomitant with reduced expressions of Nrf2, heme oxygenase‐1 (HO‐1) and Keap1. ALP reverted all the above‐mentioned diabetes‐induced biochemical changes except that it did not affect the levels of Keap1. In vitro, ALP increased Nrf2 and reduced the hyperglycaemia‐induced increases of H9C2 cardiomyocyte hypertrophy, oxidative stress, apoptosis and autophagy, and enhanced cellular viability. Nrf2 gene silence cancelled these protective effects of ALP in H9C2 cells. Activation of Nrf2 subsequent to the suppression of Keap1 and the mitigation of autophagy over‐activation may represent major mechanisms whereby ALP attenuates DCM.
Background Current understanding of metabolic heart disease consists of a myriad of different pathophysiological mechanisms. Epicardial adipose tissue (EAT) is increasingly recognized as ...metabolically active and associated with adverse cardiovascular outcomes. The present study aimed to investigate the effect of increased EAT volume index on left ventricular (LV) myocardial fat content and burden of interstitial myocardial fibrosis and their subsequent effects on LV myocardial contractile function. Methods and Results A total of 40 volunteers (mean age, 35±10 years; 26 males) of varying body mass index (25.0±4.1 kg/m
; range, 19.3-36.3 kg/m
) and without diabetes mellitus or hypertension were prospectively recruited. EAT volume index, LV myocardial fat content, and extracellular volume were quantified by magnetic resonance imaging. LV myocardial contractile function was quantified by speckle tracking echocardiography global longitudinal strain on the same day as magnetic resonance imaging examination. Mean total EAT volume index, LV myocardial fat content, and extracellular volume were 30.0±19.6 cm
/m
, 5.06%±1.18%, and 27.5%±0.5%, respectively. On multivariable analyses, increased EAT volume index and insulin resistance were independently associated with both increased LV myocardial fat content content and higher burden of interstitial myocardial fibrosis. Furthermore, increased EAT volume index was independently associated with LV global longitudinal strain. Conclusions Increased EAT volume index and insulin resistance were independently associated with increased myocardial fat accumulation and interstitial myocardial fibrosis. Increased EAT volume index was associated with detrimental effects on myocardial contractile function as evidenced by a reduction in LV global longitudinal strain.
PDF
