Distinct Challenges of Eruptive and Non-Eruptive Calcified Nodules in Percutaneous Coronary Intervention.

PURPOSE OF REVIEW: To provide a summary of prevalence, pathogenesis, and treatment of coronary calcified nodules (CNs). RECENT FINDINGS: CNs are most frequently detected at the sites of hinge motion of severely calcified lesions such as in the middle segment of right coronary artery and left main coronary bifurcation. On histopathology, CNs exhibit two distinctive morphologies: eruptive and non-eruptive. Eruptive CNs, which have a disrupted fibrous cap with adherent thrombi, are biologically active. Non-eruptive CNs, which have an intact fibrous cap without thrombi, are biologically inactive, representing either healed eruptive CNs or protrusion of calcium due to plaque progression. Recent studies using optical coherence tomography (OCT) have shown a difference in the mechanism of stent failure in the two subtypes, demonstrating early reappearance of eruptive CNs in the stent (at ~ 6 months) as a unique mechanism of stent failure that does not seem to be preventable by simply achieving adequate stent expansion. The cause of CN reappearance in stent is not known and could be due to acute or subacute intrusion or continued growth of the CN. Whether modification of CN is needed, the most effective calcium modification modality and effectiveness of stent implantation in eruptive CNs has not been elucidated. In this review, we discuss pathogenesis of CNs and how intravascular imaging can help diagnose and manage patients with CNs. We also discuss medical and transcatheter therapies beyond conventional stent implantation for effective treatment of eruptive CNs that warrant testing in prospective studies.

Calcium Modification in Percutaneous Coronary Interventions.

Moderate-severe calcification increases procedural complications and impairs long-term prognosis post-PCI. Intravascular imaging (particularly optical coherence tomography [OCT]) is useful in guiding the treatment of calcified lesions. Weighted sum of calcium length, arc, and thickness on OCT can predict adequate stent expansion, identifying when atherectomy is required. With intravascular imaging guidance, various techniques alone or in combination may be used in an algorithmic fashion to modify calcified lesions. Calcium fracture by balloon angioplasty, cutting/scoring balloons, intravascular lithotripsy (IVL), atherectomy devices, or Excimer laser improves stent expansion. Intravascular imaging is essential in the treatment of in-stent restenosis when luminal and/or abluminal peri-strut calcium is present.

The Role of Colchicine in Atherosclerotic Cardiovascular Disease.

Colchicine, an inexpensive immunomodulatory drug used traditionally to treat gout and familial Mediterranean fever, is rapidly accumulating basic and clinical evidence for a therapeutic role in atherosclerotic cardiovascular disease. Its athero-protective properties are thought to be mainly related to its effect on tubulin polymerisation, enabling a broad range of effect on multiple atherosclerotic plaque cell types and cellular processes, including cell division, cell migration as well as pro-inflammatory cytokine and chemokine secretion. These properties indicate the potential to favourably affect all stages of atherosclerotic plaque development including formation, progression, destabilisation, and plaque rupture. This review focusses on the pharmacology of colchicine, the mechanisms by which it modulates atherosclerosis pathobiology, and summarises the current clinical evidence for its use along with the upcoming clinical trial landscape. Given the current lack of primary immunomodulatory drugs in the treatment of atherosclerosis, colchicine is a promising candidate to fill this therapeutic gap.

The year in review: advances in interventional cardiology in 2019.

PURPOSE OF REVIEW: Major studies in interventional cardiology in 2019 have added substantial new evidence for pharmaco-invasive management of coronary artery disease. The review highlights the main findings of a selection of these trials and summarizes their impact on clinical practice. RECENT FINDINGS: Recent randomized studies examining the efficacy of revascularization or medical treatment in stable ischemic heart disease (SIHD), treatment of acute coronary syndromes, emerging interventional devices, adjunctive pharmacotherapy, and intravascular imaging and physiology guidance have substantially advanced the evidenced-based knowledge in interventional cardiology. SUMMARY: Patients with SIHD and at least moderate myocardial ischemia have similar event-free survival after an initial conservative strategy of optimal medical therapy versus an upfront invasive strategy. Quality of life and angina-free status are significantly improved with revascularization. Percutaneous coronary intervention (PCI) and coronary artery bypass grafting provide similar 5-year outcomes in patients with left main coronary artery disease and low or intermediate disease complexity. An initially conservative management is equally effective as an early invasive approach in patients with out-of-hospital cardiac arrest without ongoing ischemia. Patients with ST-segment elevation myocardial infarction and multivessel disease benefit from staged complete revascularization after primary PCI. Post-PCI, patients with atrial fibrillation requiring anticoagulation can safely and effectively be treated with P2Y12 inhibitor monotherapy without aspirin. Lastly, intravascular imaging guidance improves post-PCI outcomes, warranting increased use in clinical practice.

Progression of coronary atherosclerosis in patients without standard modifiable risk factors.

BACKGROUND AND AIMS: The outcome of patients with clinical coronary artery disease despite traditional risk factors is poorly understood. METHODS: Clinical characteristics and plaque burden on serial intravascular ultrasonography were compared in patients without (n â€‹= â€‹165) and with (n â€‹= â€‹492) standard modifiable risk factors after matching on age, sex and use of statins from a database of 5823 patients participating in clinical trials of anti-atherosclerotic therapies. RESULTS: Patients without standard modifiable risk factors had lower baseline systolic blood pressure (118 â€‹± â€‹12 vs. 129 â€‹± â€‹17 â€‹mmHg, p â€‹< â€‹0.001), low-density lipoprotein cholesterol (87 â€‹± â€‹21 vs. 104 â€‹± â€‹34 â€‹mg/dl, p â€‹< â€‹0.001), triglycerides [106 vs. 136 â€‹mg/dl, p â€‹< â€‹0.001)] and C-reactive protein [1.5 vs. 2.1 â€‹mg/l, p â€‹= â€‹0.001]. At baseline, patients without modifiable risk factors had a lower percent atheroma volume (35.7 â€‹± â€‹8.6 vs. 38 â€‹± â€‹8.8%, p â€‹= â€‹0.004) and total atheroma volume (174.7 â€‹± â€‹80 vs. 190.9 â€‹± â€‹84 â€‹mm3, p â€‹= â€‹0.03) and less images with calcification (22.2 vs. 26.5%, p â€‹= â€‹0.025). The use of aspirin and statin prior to and during the trials was similar. The use of ACE inhibitors and beta blockers was lower in the no risk factor group prior to and during the trials. The change in percent atheroma volume (-0.2 â€‹± â€‹2.8 vs. -0.1 â€‹± â€‹3.6%, p â€‹= â€‹0.71), total atheroma volume (-5.5 â€‹± â€‹23.4 vs. -3.8 â€‹± â€‹22.7 â€‹mm3, p â€‹= â€‹0.42), and the percentage of patients demonstrating any degree of progression (50.9% vs 45.1%, p â€‹= â€‹0.20) were similar in those without and with standard modifiable risk factors, respectively. CONCLUSION: Patients who develop clinical coronary atherosclerosis without standard modifiable risk factors have similar rates of plaque progression to those with traditional risk factors.

Algorithmic Approach for Optical Coherence Tomography-Guided Stent Implantation During Percutaneous Coronary Intervention.

Intravascular imaging plays a key role in optimizing outcomes for percutaneous coronary intervention (PCI). Optical coherence tomography (OCT) utilizes a user-friendly interface and provides high-resolution images. OCT can be used as part of daily practice in all stages of a coronary intervention: baseline lesion assessment, stent selection, and stent optimization. Incorporating a standardized, algorithmic approach when using OCT allows for precision PCI.

Imaging-guided pre-dilatation, stenting, postdilatation (iPSP): a protocolized approach highlighting the importance of intravascular imaging for implantation of bioresorbable scaffolds

INTRODUCTION: The advent of the fully bioresorbable vascular scaffold (BVS) is the latest step in a series of advancements in the design of intracoronary stents over the past few decades. The novelty of this technology is in providing temporary vessel scaffolding and local antiproliferative therapy to prevent neointimal hyperplasia after percutaneous coronary intervention followed by gradual resorption of the scaffold to restore the native vessel anatomy and physiology­a process termed vascular reparative therapy. Areas covered: The first generation of BVS has not been able to fully match the high benchmark in safety and efficacy set by contemporary metallic drug-eluting stents. These shortcomings of BVS may be due to factors related to the device itself, the complexity of the underlying lesion, or the implantation technique. Expert commentary: Here, how intravascular imaging may be used to minimize these shortcomings is described and moreover, an imaging-guided step-by-step approach for BVS implantation that integrates the recently described pre-dilatation, stenting, post-dilatation (PSP) strategy is explained.

Oxidative and nitrosative signalling in pulmonary arterial hypertension - Implications for development of novel therapies.

Pulmonary arterial hypertension (PAH) is a syndrome characterised by an increase in pulmonary vascular resistance. This results in elevated resting pulmonary artery pressure and leads to progressive right ventricular (RV) failure, secondary to increased afterload. Although initially thought to be a disease driven primarily by endothelial dysfunction with a resultant vasoconstrictor versus vasodilator imbalance, it has become increasingly apparent that the rise in pulmonary vascular resistance that causes RV failure is also attributable to pulmonary vascular remodelling. This inflammatory, hyper-proliferative and anti-apoptotic phenotype is accompanied by a metabolic switch from physiological mitochondrial oxidative phosphorylation to aerobic glycolysis. The molecular pathways triggering this cellular metabolic shift have been the subject of extensive investigation, as their discovery will inevitably lead to new therapeutic targets. Reactive oxygen/nitrogen species (ROS/RNS) including hydrogen peroxide, superoxide and peroxynitrite are second messenger molecules that are involved in functional oxidative and nitrosative modification of proteins. Dysregulation of oxidative signalling caused by an excess of ROS and RNS relative to antioxidants has been heavily implicated in the underlying pathophysiology of PAH and likely participates in this metabolic reprogramming. This review will focus on the role of oxidative signalling and redox reactions to the molecular pathology of PAH. In addition, promising novel therapeutic agents targeting these pathways will be discussed.

Surviving Right Atrial Rupture From Blunt Thoracic Trauma After Pericardiectomy.

Right atrial rupture secondary to blunt trauma is exceedingly rare. We present a case report of blunt chest trauma and right atrial rupture in a patient with a background of pericardiectomy that were successfully managed surgically. Right atrial rupture must be considered as a differential diagnosis in patients with blunt chest trauma. In patients with previous pericardiectomy, this injury may manifest with massive hemothorax, and insertion of a chest drain should be performed with extreme caution. In our experience, urgent exploratory thoracotomy and repair of the defect are the mainstays of acute management.

Glutathionylation mediates angiotensin II-induced eNOS uncoupling, amplifying NADPH oxidase-dependent endothelial dysfunction.

BACKGROUND: Glutathionylation of endothelial nitric oxide synthase (eNOS) "uncouples" the enzyme, switching its function from nitric oxide (NO) to O2(•-) generation. We examined whether this reversible redox modification plays a role in angiotensin II (Ang II)-induced endothelial dysfunction. METHODS AND RESULTS: Ang II increased eNOS glutathionylation in cultured human umbilical vein endothelial cells (HUVECs), rabbit aorta, and human arteries in vitro. This was associated with decreased NO bioavailability and eNOS activity as well as increased O2(•-) generation. Ang II-induced decrease in eNOS activity was mediated by glutathionylation, as shown by restoration of function by glutaredoxin-1. Moreover, Ang II-induced increase in O2(•-) and decrease in NO were abolished in HUVECs transiently transfected, with mutant eNOS rendered resistant to glutathionylation. Ang II effects were nicotinamide adenine dinucleotide phosphate (NADPH) oxidase dependent because preincubation with gp 91ds-tat, an inhibitor of NADPH oxidase, abolished the increase in eNOS glutathionylation and loss of eNOS activity. Functional significance of glutathionylation in intact vessels was supported by Ang II-induced impairment of endothelium-dependent vasorelaxation that was abolished by the disulfide reducing agent, dithiothreitol. Furthermore, attenuation of Ang II signaling in vivo by administration of an angiotensin converting enzyme (ACE) inhibitor reduced eNOS glutathionylation, increased NO, diminished O2(•-), improved endothelium-dependent vasorelaxation and reduced blood pressure. CONCLUSIONS: Uncoupling of eNOS by glutathionylation is a key mediator of Ang II-induced endothelial dysfunction, and its reversal is a mechanism for cardiovascular protection by ACE inhibition. We suggest that Ang II-induced O2(•-) generation in endothelial cells, although dependent on NADPH oxidase, is amplified by glutathionylation-dependent eNOS uncoupling.

No association of G-protein-coupled receptor kinase 5 or ß-adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort.

AIMS: Takotsubo cardiomyopathy (TC) is an increasingly recognized syndrome in which patients present with chest pain and ST changes, and are observed to have reversible LV apical ballooning in the absence of angiographically significant coronary artery stenosis. Although the pathophysiology remains unclear, the syndrome occurs almost exclusively in women, and is often triggered by stress. Recent small studies have reported association of TC with functional variants in the G-protein-coupled receptor kinase 5 (GRK5) gene, as well as in the ß1-adrenergic receptor (ß1AR) and ß2AR. METHODS AND RESULTS: We tested these associations in a larger cohort of 92 TC patients. In addition we examined for the association of polymorphisms in the oestrogen receptor α (ERα) and catechol-O-methyl transferase (COMT) with the occurrence of TC, by comparing the allele frequency of these variants in the TC cohort with that in previously genotyped large Caucasian cohorts. Ninety-two patients with TC were recruited from four Australian centres; they had an age range of 41-90 years (mean ± SD = 66.3 ± 9) and 89/92 were female. There were no significant differences in allelic frequency in the TC group vs. the historic control database for any of the loci. CONCLUSION: In the largest genotyped TC cohort in the literature, we have found no association of genetic variants in the ERα, ß1AR, ß2AR, or COMT genes, or with the previously implicated GRK5, with occurrence of the syndrome.

Protein kinase-dependent oxidative regulation of the cardiac Na+-K+ pump: evidence from in vivo and in vitro modulation of cell signalling.

The widely reported stimulation of the cardiac Na(+)-K(+) pump by protein kinase A (PKA) should oppose other effects of PKA to increase contractility of the normal heart. It should also reduce harmful raised myocyte Na(+) levels in heart failure, yet blockade of the ß1 adrenergic receptor (AR), coupled to PKA signalling, is beneficial. We treated rabbits with the ß1 AR antagonist metoprolol to modulate PKA activity and studied cardiac myocytes ex vivo. Metoprolol increased electrogenic pump current (Ip) in voltage clamped myocytes and reduced glutathionylation of the ß1 pump subunit, an oxidative modification causally related to pump inhibition. Activation of adenylyl cyclase with forskolin to enhance cAMP synthesis or inclusion of the catalytic subunit of PKA in patch pipette solutions abolished the increase in Ip in voltage clamped myocytes induced by treatment with metoprolol, supporting cAMP/PKA-mediated pump inhibition. Metoprolol reduced myocardial PKA and protein kinase C (PKC) activities, reduced coimmunoprecipitation of cytosolic p47(phox) and membranous p22(phox) NADPH oxidase subunits and reduced myocardial O2(•-)-sensitive dihydroethidium fluorescence. Treatment also enhanced coimmunoprecipitation of the ß1 pump subunit with glutaredoxin 1 that catalyses de-glutathionylation. Since angiotensin II induces PKC-dependent activation of NADPH oxidase, we examined the effects of angiotensin-converting enzyme inhibition with captopril. This treatment had no effect on PKA activity but reduced the activity of PKC, reduced ß1 subunit glutathionylation and increased Ip. The PKA-induced Na(+)-K(+) pump inhibition we report should act with other mechanisms that enhance contractility of the normal heart but accentuate the harmful effects of raised cytosolic Na(+) in the failing heart. This scheme is consistent with the efficacy of ß1 AR blockade in the treatment of heart failure.

ß-Adrenergic regulation of the cardiac Na+-K+ ATPase mediated by oxidative signaling.

Activation of ß-adrenergic receptors (ARs) elicits responses arising from protein kinase A (PKA)-mediated phosphorylation of target proteins that regulate Ca(2+)-dependent excitation-contraction coupling. Some important targets for ß-AR- and PKA-dependent pathways, including the sarcolemmal Na(+)-K(+) pump, also undergo oxidative modifications in response to activation of receptor-coupled redox signaling pathways in cardiac myocytes. Here, we highlight how ß(1)- and ß(3)-AR signaling have opposing effects on functionally important oxidative modification of the Na(+)-K(+) pump molecular complex and how the addition of redox dependence to the canonical phosphorylation dependence of the scheme for ß-AR signaling in general expands its versatility but also its complexity. The expanded scheme integrates increased oxidative stress into the pathophysiological effects of adrenergic hyperactivity and provides mechanistic explanation for the efficacy of ß-AR blockers in heart failure in which raised intracellular Na(+) levels are detrimental-an explanation not provided by traditionally held views on ß-AR-mediated regulation of the pump function.

Susceptibility of ß1 Na+-K+ pump subunit to glutathionylation and oxidative inhibition depends on conformational state of pump.

Glutathionylation of cysteine 46 of the ß1 subunit of the Na(+)-K(+) pump causes pump inhibition. However, the crystal structure, known in a state analogous to an E2·2K(+)·P(i) configuration, indicates that the side chain of cysteine 46 is exposed to the lipid bulk phase of the membrane and not expected to be accessible to the cytosolic glutathione. We have examined whether glutathionylation depends on the conformational changes in the Na(+)-K(+) pump cycle as described by the Albers-Post scheme. We measured ß1 subunit glutathionylation and function of Na(+)-K(+)-ATPase in membrane fragments and in ventricular myocytes. Signals for glutathionylation in Na(+)-K(+)-ATPase-enriched membrane fragments suspended in solutions that preferentially induce E1ATP and E1Na(3) conformations were much larger than signals in solutions that induce the E2 conformation. Ouabain further reduced glutathionylation in E2 and eliminated an increase seen with exposure to the oxidant peroxynitrite (ONOO(-)). Inhibition of Na(+)-K(+)-ATPase activity after exposure to ONOO(-) was greater when the enzyme had been in the E1Na(3) than the E2 conformation. We exposed myocytes to different extracellular K(+) concentrations to vary the membrane potential and hence voltage-dependent conformational poise. K(+) concentrations expected to shift the poise toward E2 species reduced glutathionylation, and ouabain eliminated a ONOO(-)-induced increase. Angiotensin II-induced NADPH oxidase-dependent Na(+)-K(+) pump inhibition was eliminated by conditions expected to shift the poise toward the E2 species. We conclude that susceptibility of the ß1 subunit to glutathionylation depends on the conformational poise of the Na(+)-K(+) pump.