ABSTRACT
Pulmonary hypertension (PH) consists of a heterogenous group of diseases that culminate in increased pulmonary arterial pressure and right ventricular (RV) dysfunction. We sought to investigate the role of FXYD1, a small membrane protein that modulates Na+-K+-ATPase function, in the pathophysiology of PH. We mined online transcriptome databases to assess FXYD1 expression in PH. We characterized the effects of FXYD1 knockout (KO) in mice on right and left ventricular (RV and LV) function using echocardiography and measured invasive hemodynamic measurements under normal conditions and after treatment with bleomycin sulfate or chronic hypoxia to induce PH. Using immunohistochemistry, immunoblotting, and functional assays, we examined the effects of FXYD1 KO on pulmonary microvasculature and RV and LV structure and assessed signaling via endothelial nitric oxide synthase (eNOS) and inflammatory pathways. FXYD1 lung expression tended to be lower in samples from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with controls, supporting a potential pathophysiological role. FXYD1 KO mice displayed characteristics of PH including significant increases in pulmonary arterial pressure, increased muscularization of small pulmonary arterioles, and impaired RV systolic function, in addition to LV systolic dysfunction. However, when PH was stimulated with standard models of lung injury-induced PH, there was no exacerbation of disease in FXYD1 KO mice. Both the lungs and left ventricles exhibited elevated nitrosative stress and inflammatory milieu. The absence of FXYD1 in mice results in LV inflammation and cardiopulmonary redox signaling changes that predispose to pathophysiological features of PH, suggesting FXYD1 may be protective.NEW & NOTEWORTHY This is the first study to show that deficiency of the FXYD1 protein is associated with pulmonary hypertension. FXYD1 expression is lower in the lungs of people with idiopathic pulmonary artery hypertension. FXYD1 deficiency results in both left and right ventricular functional impairment. Finally, FXYD1 may endogenously protect the heart from oxidative and inflammatory injury.
Subject(s)
Heart Failure , Hypertension, Pulmonary , Membrane Proteins , Phosphoproteins , Ventricular Dysfunction, Right , Animals , Humans , Mice , Heart Ventricles , Hypertension, Pulmonary/metabolism , Lung/metabolism , Oxidation-Reduction , Pulmonary Artery , Ventricular Function, Right , Membrane Proteins/metabolism , Phosphoproteins/metabolismABSTRACT
Studies utilizing intravascular imaging have replicated the findings of histopathological studies, identifying the most common substrates for acute coronary syndromes (ACS) as plaque rupture, erosion, and calcified nodule, with spontaneous coronary artery dissection, coronary artery spasm, and coronary embolism constituting the less common etiologies. The purpose of this review is to summarize the data from clinical studies that have used high-resolution intravascular optical coherence tomography (OCT) to assess culprit plaque morphology in ACS. In addition, we discuss the utility of intravascular OCT for effective treatment of patients presenting with ACS, including the possibility of culprit lesion-based treatment by percutaneous coronary intervention.
Subject(s)
Acute Coronary Syndrome , Coronary Artery Disease , Plaque, Atherosclerotic , Humans , Acute Coronary Syndrome/diagnostic imaging , Acute Coronary Syndrome/therapy , Acute Coronary Syndrome/etiology , Treatment Outcome , Tomography, Optical Coherence/methods , Rupture, Spontaneous/complications , Rupture, Spontaneous/pathology , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/therapy , Coronary Artery Disease/complications , Coronary Vessels/diagnostic imaging , Coronary Vessels/pathology , Coronary Angiography/adverse effectsABSTRACT
BACKGROUND: Optical coherence tomography (OCT) is an adjunct to angiography-guided coronary stent placement. However, in the absence of dedicated, appropriately powered randomized controlled trials, the impact of OCT on clinical outcomes is unclear. OBJECTIVE: To conduct a systematic review and meta-analysis of all available studies comparing OCT-guided versus angiography-guided and intravascular ultrasound (IVUS)-guided coronary stent implantation. METHODS: MEDLINE and Cochrane Central were queried from their inception through July 2022 for all studies that sought to compare OCT-guided percutaneous coronary intervention (PCI) to angiography-guided and IVUS-guided PCI. The primary endpoint was minimal stent area (MSA) compared between modalities. Clinical endpoints of interest were all-cause and cardiovascular mortality, major adverse cardiovascular events (MACE), myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), and stent thrombosis (ST). Risk ratios (RRs) and mean differences (MDs) with their corresponding 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS: Thirteen studies (8 randomized control trials and 5 observational studies) enrolling 6312 participants were included. OCT was associated with a strong trend toward increased MSA compared to angiography (MD = 0.36, p = 0.06). OCT-guided PCI was also associated with a reduction in the incidence of all-cause mortality [RR = 0.59, 95% CI (0.35, 0.97), p = 0.04] and cardiovascular mortality [RR = 0.41, 95% CI (0.21, 0.80), p = 0.009] compared with angiography-guided PCI. Point estimates favored OCT relative to angiography in MACE [RR = 0.75, 95% CI (0.47, 1.20), p = 0.22] and MI [RR = 0.75, 95% CI (0.53, 1.07), p = 0.12]. No differences were detected in ST [RR = 0.71, 95% CI (0.21, 2.44), p = 0.58], TLR [RR = 0.71, 95% CI (0.17, 3.05), p = 0.65], or TVR rates [RR = 0.89, 95% CI (0.46, 1.73), p = 0.73]. Compared with IVUS guidance, OCT guidance was associated with a nonsignificant reduction in the MSA (MD = -0.16, p = 0.27). The rates of all-cause and cardiovascular mortality, MACE, MI, TLR, TVR, or ST were similar between OCT-guided and IVUS-guided PCI. CONCLUSIONS: OCT-guided PCI was associated with reduced all-cause and cardiovascular mortality compared to angiography-guided PCI. These results should be considered hypothesis generating as the mechanisms for the improved outcomes were unclear as no differences were detected in the rates of TLR, TVR, or ST. OCT- and IVUS-guided PCI resulted in similar post-PCI outcomes.
Subject(s)
Coronary Artery Disease , Myocardial Infarction , Percutaneous Coronary Intervention , Thrombosis , Humans , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/therapy , Coronary Artery Disease/complications , Coronary Angiography/adverse effects , Tomography, Optical Coherence/adverse effects , Ultrasonography, Interventional/adverse effects , Ultrasonography, Interventional/methods , Treatment Outcome , Stents/adverse effects , Myocardial Infarction/etiology , Thrombosis/etiology , Randomized Controlled Trials as TopicABSTRACT
PURPOSE OF REVIEW: To provide a review of recent literature on the treatment of moderate-to-severe calcification in coronary and peripheral vasculature with intravascular lithotripsy (Shockwave Medical, Santa Clara, CA). RECENT FINDINGS: Moderate-to-severe calcific plaques constitute a significant proportion of lesions treated with transcatheter interventions in the coronary and peripheral vascular beds and portend lower procedural success rates, increased periprocedural major adverse events, and unfavorable long-term clinical outcomes compared to non-calcific plaques. Intravascular lithotripsy (IVL) is a new technique that uses acoustic shock waves in a balloon-based system to induce fracture in the calcium deposits to facilitate luminal gain and stent expansion. IVL demonstrated high procedural success and low complication rates in the management of moderate-to-severe calcification in coronary and peripheral vascular beds and led to large luminal gain by modification of calcific plaque as assessed by optical coherence tomography. Further studies will determine the role of IVL in an integrated, protocolized approach to the treatment of severely calcified plaques in the coronary and peripheral vascular beds.
Subject(s)
Lithotripsy , Vascular Calcification , Acoustics , Humans , Lithotripsy/adverse effects , Stents , Treatment Outcome , Vascular Calcification/diagnostic imaging , Vascular Calcification/etiology , Vascular Calcification/therapyABSTRACT
PURPOSE OF REVIEW: Moderate or severe calcification is present in approximately one third of coronary lesions in patients with stable ischemic heart disease and acute coronary syndromes and portends unfavorable procedural results and long-term outcomes. In this review, we provide an overview on the state-of-the-art in evaluation and treatment of calcified coronary lesions. RECENT FINDINGS: Intravascular imaging (intravascular ultrasound or optical coherence tomography) can guide percutaneous coronary intervention of severely calcified lesions. New technologies such as orbital atherectomy and intravascular lithotripsy have significantly expanded the range of available techniques to effectively modify coronary calcium and facilitate stent expansion. Calcium fracture improves lesion compliance and is essential to optimize stent implantation. Intravascular imaging allows for detailed assessment of patterns and severity of coronary calcium that are integrated into scoring systems to predict stent expansion, identifying which lesions require atherectomy for lesion modification. Guided by intravascular imaging, older technologies such as rotational atherectomy and excimer laser can be incorporated with newer technologies such as orbital atherectomy and intravascular lithotripsy into an algorithmic approach for the safe and effective treatment of patients with heavily calcified coronary lesions.
Subject(s)
Atherectomy, Coronary , Coronary Artery Disease , Disruptive Technology , Percutaneous Coronary Intervention , Vascular Calcification , Coronary Angiography , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/surgery , Humans , Treatment Outcome , Vascular Calcification/diagnostic imaging , Vascular Calcification/therapyABSTRACT
In pulmonary hypertension (PH) a proinflammatory milieu drives pulmonary vascular remodeling, maladaptive right ventricular (RV) remodeling, and right-sided heart failure. There is an unmet need for RV-targeted pharmaco-therapies to improve mortality. Targeting of the P2X7 receptor (P2X7R) reduces pulmonary pressures; however, its effects on the RV are presently unknown. We investigated the effect of P2X7 receptor (P2X7R) inhibition on the pulmonary vasculature and RV remodeling using the novel P2X7R antagonist PKT100. C57BL/6 mice were administered intratracheal bleomycin or saline and treated with PKT100 (0.2 mg·kg-1·day-1) or DMSO vehicle. RV was assessed by right heart catheterization and echocardiography, 21 days posttreatment. Cytokines in serum and bronchoalveolar lavage fluid (BALF) were analyzed by ELISA and flow cytometry. Lungs and hearts were analyzed histologically for pulmonary vascular and RV remodeling. Focused-PCR using genes involved in RV remodeling was performed. Right ventricular systolic pressure (RVSP) was elevated in bleomycin-treated mice (30.2 ± 1.1; n = 7) compared with control mice (23.5 ± 1.0; n = 10; P = 0.008). PKT100 treatment did not alter RVSP (32.4 ± 1.8; n = 9), but it substantially improved survival (93% vs. 57% DMSO). There were no differences between DMSO and PKT100 bleomycin mice in pulmonary inflammation or remodeling. However, RV hypertrophy was reduced in PKT100 mice. Bleomycin decreased echocardiographic surrogates of RV systolic performance, which were significantly improved with PKT100. Four genes involved in RV remodeling (RPSA, Rplp0, Add2, and Scn7a) were differentially expressed between DMSO and PKT100-treated groups. The novel P2X7R inhibitor, PKT100, attenuates RV hypertrophy and improves RV contractile function and survival in a mouse model of PH independently of effects on the pulmonary vasculature. PKT100 may improve ventricular response to increased afterload and merits further investigation into the potential role of P2X7R antagonists as direct RV-focused therapies in PH.NEW & NOTEWORTHY This study demonstrates the therapeutic potential for right-sided heart failure of a novel inhibitor of the P2X7 receptor (P2X7R). Inflammatory signaling and right ventricular function were improved in a mouse model of pulmonary fibrosis with secondary pulmonary hypertension when treated with this inhibitor. Importantly, survival was also improved, suggesting that this inhibitor, and other P2X7R antagonists, could be uniquely effective in right ventricle (RV)-targeted therapy in pulmonary hypertension. This addresses a major limitation of current treatment options, where the significant improvements in pulmonary pressures ultimately do not prevent mortality due to RV failure.
Subject(s)
Heart Ventricles/drug effects , Hypertension, Pulmonary/drug therapy , Purinergic P2X Receptor Antagonists/therapeutic use , Animals , Blood Pressure , Bronchoalveolar Lavage Fluid/cytology , Cytokines/blood , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Heart Ventricles/metabolism , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Lung/blood supply , Lung/drug effects , Lung/metabolism , Male , Mice , Mice, Inbred C57BL , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Laminin/genetics , Receptors, Laminin/metabolism , Receptors, Purinergic P2X7/metabolism , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism , Ventricular Remodeling , Voltage-Gated Sodium Channels/genetics , Voltage-Gated Sodium Channels/metabolismABSTRACT
OBJECTIVES: We sought to assess plaque modification and stent expansion following orbital atherectomy (OA) for calcified lesions using optical coherence tomography (OCT). BACKGROUND: The efficacy of OA for treating calcified lesions is not well studied, especially using intravascular imaging in vivo. METHODS: OCT was performed preprocedure, post-OA, and post-stent (n = 58). Calcium modification after OA was defined as a round, concave, polished calcium surface. Calcium fracture was complete discontinuity of calcium. RESULTS: Comparing pre- vs post-OA OCT (n = 29), calcium area was significantly decreased post-OA (from 3.4 mm2 [2.4-4.7] to 2.9 mm2 [1.9-3.9], P < 0.001). Poststent percent calcium fracture (calcium fracture length/calcium length) correlated with post-OA percent calcium modification (calcium modification length/calcium length) (r = 0.31, P = 0.01). Among 75 calcium fractures in 35 lesions, maximum calcium thickness at the fracture site was greater with vs without calcium modification (0.58 mm [0.50-0.66] vs 0.45 mm [0.38-0.52], P = 0.003). Final optimal stent expansion, defined as minimum stent area ≥6.1 mm2 or stent expansion ≥90% (medians of this cohort) at the maximum calcium angle site, was observed in 41 lesions. Larger post-OA lumen area (odds ratio 2.64; 95% CI 1.21-5.76; P = 0.02) and the presence of calcium fracture (odds ratio 6.77; 95% CI 1.25-36.6; P = 0.03) were independent predictors for optimal stent expansion. CONCLUSIONS: Calcium modification by OA facilitates poststent calcium fracture even in thick calcium. Greater calcium modification correlated with greater calcium fracture, in turn resulting in better stent expansion.
Subject(s)
Angioplasty, Balloon, Coronary , Atherectomy, Coronary , Coronary Artery Disease/therapy , Coronary Vessels/diagnostic imaging , Tomography, Optical Coherence , Vascular Calcification/therapy , Aged , Angioplasty, Balloon, Coronary/adverse effects , Angioplasty, Balloon, Coronary/instrumentation , Atherectomy, Coronary/adverse effects , Coronary Artery Disease/diagnostic imaging , Female , Humans , Male , Middle Aged , Plaque, Atherosclerotic , Predictive Value of Tests , Retrospective Studies , Risk Factors , Stents , Treatment Outcome , Vascular Calcification/diagnostic imagingABSTRACT
Percutaneous coronary intervention (PCI) in patients with advanced chronic kidney disease (CKD) is challenging due to frequent presence of complex calcified lesions and the very high risk of contrast-induced nephropathy (CIN). We report a strategy of "zero contrast" PCI, guided by intravascular imaging and physiology, performed in three patients with advanced CKD in whom severe calcification necessitated rotational atherectomy (RA) to facilitate and optimize PCI. This approach resulted in safe and successful PCI while preserving renal function. © 2017 Wiley Periodicals, Inc.
Subject(s)
Atherectomy, Coronary , Contrast Media/administration & dosage , Coronary Angiography , Coronary Artery Disease/therapy , Percutaneous Coronary Intervention , Renal Insufficiency, Chronic/complications , Ultrasonography, Interventional , Vascular Calcification/therapy , Aged , Aged, 80 and over , Atherectomy, Coronary/adverse effects , Contrast Media/adverse effects , Coronary Angiography/adverse effects , Coronary Artery Disease/complications , Coronary Artery Disease/diagnostic imaging , Female , Humans , Male , Percutaneous Coronary Intervention/adverse effects , Predictive Value of Tests , Renal Insufficiency, Chronic/diagnosis , Risk Factors , Treatment Outcome , Vascular Calcification/complications , Vascular Calcification/diagnostic imagingABSTRACT
Vascular remodeling is a dynamic process of structural and functional changes in response to biochemical and biomechanical signals in a complex in vivo milieu. While inherently adaptive, dysregulation leads to maladaptive remodeling. Reactive oxygen species participate in homeostatic cell signaling in tightly regulated- and compartmentalized cellular circuits. It is well established that perturbations in oxidation-reduction (redox) homeostasis can lead to a state of oxidative-, and more recently, reductive stress. We provide an overview of the redox signaling in the vasculature and review the role of oxidative- and reductive stress in maladaptive vascular remodeling. Particular emphasis has been placed on essential processes that determine phenotype modulation, migration and fate of the main cell types in the vessel wall. Recent advances in systems biology and the translational opportunities they may provide to specifically target the redox pathways driving pathological vascular remodeling are discussed.
Subject(s)
Oxidative Stress , Signal Transduction , Vascular Remodeling , Animals , Endothelial Cells/cytology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Homeostasis , Humans , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Nitric Oxide Synthase Type III/metabolism , Reactive Oxygen Species/metabolismABSTRACT
AIMS: The feasibility, safety, and clinical utility of percutaneous coronary intervention (PCI) without radio-contrast medium in patients with advanced chronic kidney disease (CKD) are unknown. In this series, we investigated a specific strategy for 'zero contrast' PCI with the aims of preserving renal function and preventing the need for renal replacement therapy (RRT) in patients with advanced CKD. METHODS AND RESULTS: A total of 31 patients with advanced CKD [creatinine = 4.2 mg/dL, inter-quartile range (IQR) 3.1-4.8, estimated glomerular filtration rate = 16 ± 8 mL/min/1.73 m2] who had clinical indication for PCI based on a prior minimal contrast coronary angiogram were included. Zero contrast PCI was performed at least 1 week after diagnostic angiography using real-time intravascular ultrasound (IVUS) guidance, with pre- and post-PCI measurements of fractional flow reserve and coronary flow reserve to confirm physiological improvement. This approach resulted in successful PCI, no major adverse cardiovascular events and preservation of renal function without the need for RRT within a follow-up time of 79 days (IQR 33-207) in all patients. CONCLUSION: In patients with advanced CKD who require revascularization, PCI may safely be performed without contrast using IVUS and physiological guidance with high procedural success and without complications.
Subject(s)
Percutaneous Coronary Intervention , Coronary Angiography , Creatinine , Humans , Renal Insufficiency, Chronic , Treatment OutcomeABSTRACT
The central role of oxidative signalling in cardiovascular pathophysiology positions biometric measures of redox state as excellent markers for research and clinical application. However, despite this tantalizing biological plausibility, no redox biomarker is currently in widespread clinical use. Major recent insights into the mechanistic complexities of redox signalling may yet provide the opportunity to identify markers that most closely reflect the underlying pathobiology. Such redox biomarkers may, in principle, quantify the integrated effects of various known and unknown pathophysiological drivers of cardiovascular disease processes. Recent advances with the greatest potential include assays measuring post-translational oxidative modifications that have significant cellular effects. However, analytical issues, including the relative instability of redox-modified products, remain a major technical obstacle. Appreciation of these challenges may facilitate future development of user-friendly markers with prognostic value in addition to traditional risk factors, and which could be used to guide personalized cardiovascular therapies. We review both established and recently identified biomarkers of redox signalling, and provide a realistic discussion of the many challenges that remain if they are to be incorporated into clinical practice. Despite the current lack of redox biomarkers in clinical application, the integral role of reactive oxygen species in pathogenesis of cardiovascular disease provides a strong incentive for continued efforts.
Subject(s)
Biomarkers/metabolism , Cardiovascular Diseases/metabolism , Antioxidants/physiology , Cardiovascular Diseases/prevention & control , DNA/metabolism , Forecasting , Glycation End Products, Advanced/metabolism , Humans , Lipid Peroxidation/physiology , Oxidation-Reduction , Proteins/metabolism , Reactive Oxygen Species/metabolism , Risk Factors , Signal Transduction/physiologyABSTRACT
Dysregulated nitric oxide (NO)- and superoxide (O2 (·-))-dependent signaling contributes to the pathobiology of diabetes-induced cardiovascular complications. We examined if stimulation of ß3-adrenergic receptors (ß3-ARs), coupled to endothelial NO synthase (eNOS) activation, relieves oxidative inhibition of eNOS and the Na(+)-K(+) pump induced by hyperglycemia. Hyperglycemia was established in male New Zealand White rabbits by infusion of the insulin receptor antagonist S961 for 7 days. Hyperglycemia increased tissue and blood indexes of oxidative stress. It induced glutathionylation of the Na(+)-K(+) pump ß1-subunit in cardiac myocytes, an oxidative modification causing pump inhibition, and reduced the electrogenic pump current in voltage-clamped myocytes. Hyperglycemia also increased glutathionylation of eNOS, which causes its uncoupling, and increased coimmunoprecipitation of cytosolic p47(phox) and membranous p22(phox) NADPH oxidase subunits, consistent with NADPH oxidase activation. Blocking translocation of p47(phox) to p22(phox) with the gp91ds-tat peptide in cardiac myocytes ex vivo abolished the hyperglycemia-induced increase in glutathionylation of the Na(+)-K(+) pump ß1-subunit and decrease in pump current. In vivo treatment with the ß3-AR agonist CL316243 for 3 days eliminated the increase in indexes of oxidative stress, decreased coimmunoprecipitation of p22(phox) with p47(phox), abolished the hyperglycemia-induced increase in glutathionylation of eNOS and the Na(+)-K(+) pump ß1-subunit, and abolished the decrease in pump current. CL316243 also increased coimmunoprecipitation of glutaredoxin-1 with the Na(+)-K(+) pump ß1-subunit, which may reflect facilitation of deglutathionylation. In vivo ß3-AR activation relieves oxidative inhibition of key cardiac myocyte proteins in hyperglycemia and may be effective in targeting the deleterious cardiac effects of diabetes.
Subject(s)
Adrenergic beta-3 Receptor Agonists/therapeutic use , Hyperglycemia/metabolism , Oxidative Stress/drug effects , Receptor, Insulin/antagonists & inhibitors , Receptors, Adrenergic, beta-3/metabolism , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Adrenergic beta-3 Receptor Agonists/pharmacology , Amino Acid Sequence , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Dioxoles/pharmacology , Dioxoles/therapeutic use , Hyperglycemia/drug therapy , Male , Molecular Sequence Data , Oxidative Stress/physiology , RabbitsABSTRACT
Calcified nodules (CNs) are among the most challenging lesions to treat in contemporary percutaneous coronary intervention. CNs may be divided into 2 subtypes, eruptive and noneruptive, which have distinct histopathological and prognostic features. An eruptive CN is a biologically active lesion with a disrupted fibrous cap and possibly adherent thrombus, whereas a noneruptive CN has an intact fibrous cap and no adherent thrombus. The use of intravascular imaging may allow differentiation between the 2 subtypes, thus potentially guiding treatment strategy. Compared with noneruptive CNs, eruptive CNs are more likely to be deformable, resulting in better stent expansion, but are paradoxically associated with worse clinical outcomes, in part because of their frequent initial presentation as an acute coronary syndrome and subsequent reprotrusion of the CN into the vessel lumen through the stent struts. Pending the results of ongoing studies, a tailored therapeutic approach based on the distinct features of the different CNs may be of value.
Subject(s)
Coronary Artery Disease , Percutaneous Coronary Intervention , Stents , Vascular Calcification , Humans , Percutaneous Coronary Intervention/instrumentation , Percutaneous Coronary Intervention/adverse effects , Vascular Calcification/diagnostic imaging , Vascular Calcification/therapy , Treatment Outcome , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/therapy , Risk Factors , Predictive Value of Tests , Coronary Vessels/diagnostic imaging , Plaque, Atherosclerotic , Ultrasonography, Interventional , Coronary Angiography , Clinical Decision-MakingABSTRACT
BACKGROUND: The importance of complete revascularization after percutaneous coronary intervention (PCI) in patients with left main coronary artery disease is uncertain. We investigated the clinical impact of complete revascularization in patients with left main coronary artery disease undergoing PCI in the EXCEL trial (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization). METHODS: Composite rates of death or myocardial infarction (MI) following PCI during 5-year follow-up were examined in 903 patients based on core laboratory definitions of anatomic and functional complete revascularization, residual SYNTAX score (The Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery), and residual Jeopardy Score (rJS). RESULTS: The risk of death or MI did not vary based on anatomic, functional, or residual SYNTAX score complete revascularization but did differ according to the rJS (5-year rates 17.6%, 19.5%, and 38.9% with rJS 0, 2, and ≥4, respectively; P=0.006). The higher rate of death or MI with rJS≥4 versus rJS≤2 was driven conjointly by increased mortality (adjusted hazard ratio, 2.29 [95% CI, 1.11-4.71]; P=0.02) and spontaneous MI (adjusted hazard ratio, 2.89 [95% CI, 1.17-7.17]; P=0.02). The most common location for untreated severe stenoses in the rJS≥4 group was the left circumflex artery (LCX), and the post-PCI absence, compared with the presence, of any untreated lesion with diameter stenosis ≥70% in the LCX was associated with reduced 5-year rates of death or MI (18.9% versus 35.2%; hazard ratio, 0.48 [95% CI, 0.32-0.74]; P<0.001). The risk was the highest for residual ostial/proximal LCX lesions. CONCLUSIONS: Among patients undergoing PCI in EXCEL trial, incomplete revascularization according to the rJS was associated with increased rates of death and spontaneous MI. Post-PCI untreated high-grade lesions in the LCX (especially the ostial/proximal LCX) drove these outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01205776.
Subject(s)
Coronary Artery Disease , Myocardial Infarction , Percutaneous Coronary Intervention , Humans , Constriction, Pathologic , Coronary Artery Bypass/adverse effects , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/therapy , Myocardial Infarction/etiology , Percutaneous Coronary Intervention/adverse effects , Risk Factors , Treatment OutcomeABSTRACT
By the time it was appreciated that the positive inotropic effect of cardiac glycosides is due to inhibition of the membrane Na(+)-K(+) pump, glycosides had been used for treatment of heart failure on an empiric basis for ~200 years. The subsequent documentation of their lack of clinical efficacy and possible harmful effect largely coincided with the discovery that a raised Na(+) concentration in cardiac myocytes plays an important role in the electromechanical phenotype of heart failure syndromes. Consistent with this, efficacious pharmacological treatments for heart failure have been found to stimulate the Na(+)-K(+) pump, effectively the only export route for intracellular Na(+) in the heart failure. A paradigm has emerged that implicates pump inhibition in the raised Na(+) levels in heart failure. It invokes protein kinase-dependent activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and glutathionylation, a reversible oxidative modification, of the Na(+)-K(+) pump molecular complex that inhibits its activity. Since treatments of proven efficacy reverse the oxidative Na(+)-K(+) pump inhibition, the pump retains its status as a key pharmacological target in heart failure. Its role as a target is well integrated with the paradigms of neurohormonal abnormalities, raised myocardial oxidative stress and energy deficiency implicated in the pathophysiology of the failing heart. We propose that targeting oxidative inhibition of the pump is useful for the exploration of future treatment strategies. This article is part of a Special Issue entitled "Na(+)Regulation in Cardiac Myocytes".
Subject(s)
Cardiotonic Agents/pharmacology , Heart Failure/drug therapy , Sodium-Potassium-Exchanging ATPase/metabolism , Amino Acid Sequence , Animals , Cardiotonic Agents/therapeutic use , Heart Failure/enzymology , Humans , Membrane Proteins/chemistry , Molecular Sequence Data , Oxidation-Reduction , Phosphoproteins/chemistry , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinases/metabolism , Protein Processing, Post-Translational , Signal Transduction , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitorsABSTRACT
Optical coherence tomography (OCT) provides high-resolution imaging of coronary arteries and can be used to optimize percutaneous coronary intervention (PCI). Intracoronary OCT, however, has had limited adoption in clinical practice. Novelty and relative complexity of OCT interpretation compared with the more established intravascular ultrasound, lack of a standardized algorithm for PCI guidance, paucity of data from randomized trials, and lack of rebate for intravascular imaging have contributed to the modest practical adoption of OCT. We provide a practical step-by-step guide on how to use OCT in PCI, including device set-up, simplified image interpretation, and an algorithmic approach for PCI. optimization.
Subject(s)
Coronary Artery Disease , Percutaneous Coronary Intervention , Humans , Coronary Artery Disease/diagnosis , Coronary Artery Disease/surgery , Coronary Angiography/methods , Tomography, Optical Coherence/methods , Percutaneous Coronary Intervention/methods , Ultrasonography, Interventional/methods , Treatment OutcomeABSTRACT
Efficacy of therapies that target the downstream nitric oxide (NO) pathway in pulmonary arterial hypertension (PAH) depends on the bioavailability of NO. Reduced NO level in PAH is secondary to "uncoupling" of endothelial nitric oxide synthase (eNOS). Stimulation of ß3 adrenergic receptors (ß3 ARs) may lead to the recoupling of NOS and therefore be beneficial in PAH. We aimed to examine the efficacy of ß3 AR agonism as a novel pathway in experimental PAH. In hypoxia (5 weeks) and Sugen hypoxia (hypoxia for 5 weeks + SU5416 injection) models of PAH, we examined the effects of the selective ß3 AR agonist CL316243. We measured echocardiographic indices and invasive right ventricular (RV)-pulmonary arterial (PA) hemodynamics and compared CL316243 with riociguat and sildenafil. We assessed treatment effects on RV-PA remodeling, oxidative stress, and eNOS glutathionylation, an oxidative modification that uncouples eNOS. Compared with normoxic mice, RV systolic pressure was increased in the control hypoxic mice (p < 0.0001) and Sugen hypoxic mice (p < 0.0001). CL316243 reduced RV systolic pressure, to a similar degree to riociguat and sildenafil, in both hypoxia (p < 0.0001) and Sugen hypoxia models (p < 0.03). CL316243 reversed pulmonary vascular remodeling, decreased RV afterload, improved RV-PA coupling efficiency and reduced RV stiffness, hypertrophy, and fibrosis. Although all treatments decreased oxidative stress, CL316243 significantly reduced eNOS glutathionylation. ß3 AR stimulation improved RV hemodynamics and led to beneficial RV-PA remodeling in experimental models of PAH. ß3 AR agonists may be effective therapies in PAH.
Subject(s)
Hypertension, Pulmonary , Pulmonary Arterial Hypertension , Mice , Animals , Pulmonary Arterial Hypertension/drug therapy , Pulmonary Arterial Hypertension/metabolism , Hypertension, Pulmonary/metabolism , Sildenafil Citrate/pharmacology , Sildenafil Citrate/therapeutic use , Pulmonary Artery/metabolism , Hemodynamics , Adrenergic beta-Agonists/pharmacology , HypoxiaABSTRACT
PURPOSE: Saphenous vein graft (SVG) failure is a complex phenomenon, with technical, biologic, and local factors contributing to early and medium- and long-term failure after coronary artery bypass graft. Both technical and conduit factors may have significant impact on early SVG failure. DESCRIPTION: We review the complex factors that play a pathogenic role in SVG failure, followed by review of the existing literature on potential utility of high-definition optical coherence tomography (OCT) in comprehensive intraoperative assessment of SVGs. EVALUATION: We describe a new technique for intraoperative acquisition of OCT images in the harvested SVGs and introduce a classification system for pathologic processes that can be detected in the harvested SVG conduits by OCT. CONCLUSIONS: The potential impact on early graft failure of the exclusion of segments of SVGs that are less than optimal (ie, containing fibroatheroma, retained thrombus, sclerotic valves, or procurement injury) will be examined in the randomized controlled OCTOCAB (Intraoperative Optical Coherence Tomography of the Saphenous Vein Conduit in Patients Undergoing Coronary Artery Bypass Surgery) trial.