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Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia.The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients.In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life.Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p 0.001). Patients who received empagliflozin had significant improvements in peak OEmpagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222).

Coronary revascularization is accomplished either by percutaneous coronary intervention (PCI), with low risk of immediate complications, or coronary artery bypass graft (CABG), with improved long-term, event-free survival attributable to use of the left internal mammary artery graft. Hybrid coronary revascularization (HCR) combines both. The left internal mammary artery graft is done by sternal-sparing approaches or by robotic-assisted, endoscopic surgery. HCR reduces bleeding, ventilator time, and length of stay compared with traditional CABG. Compared with PCI, HCR offers the durability and survival advantages of the left internal mammary artery. The large-scale National Heart, Lung, and Blood Institute-sponsored, randomized Hybrid Trial (Hybrid Coronary Revascularization Trial) was initiated to examine whether HCR is superior to multivessel PCI. However, enrollment was suboptimal, triggering premature study discontinuation. HCR integrates the positive features of both PCI and CABG, albeit requiring 2 procedures rather than 1. Adequately powered randomized trials are required to evaluate the outcomes and cost-effectiveness of HCR compared with CABG and multivessel PCI alone.

BACKGROUND: Hybrid PET/MR imaging has significant potential in cardiology due to its combination of molecular PET imaging and cardiac MR. Multi-tissue-class MR-based attenuation correction (MRAC) is necessary for accurate PET quantification. Moreover, for thoracic PET imaging, respiration is known to lead to misalignments of MRAC and PET data that result in PET artifacts. These factors can be addressed by using multi-echo MR for tissue segmentation and motion-robust or gated acquisitions. However, the combination of these strategies is not routinely available and can be prone to errors. In this study we examine the qualitative and quantitative impacts of multi-class MRAC compared to a more widely available, simple two-class MRAC for cardiac PET/MR. METHODS AND RESULTS: In a cohort of patients with cardiac sarcoidosis, we acquired MRAC data using multi-echo radial gradient-echo MR imaging. Water-fat separation was used to produce attenuation maps with up to 4 tissue classes including water-based soft tissue, fat, lung, and background air. Simultaneously acquired 18F-fluorodeoxyglucose PET data were subsequently reconstructed using each attenuation map separately. PET uptake values were measured in the myocardium and compared between different PET images. The inclusion of lung and subcutaneous fat in the MRAC maps significantly affected the quantification of 18F-fluorodeoxyglucose activity in the myocardium but only moderately altered the appearance of the PET image without introduction of image artifacts. CONCLUSIONS: Optimal MRAC for cardiac PET/MR applications should include segmentation of all tissues in combination with compensation for the respiratory-related motion of the heart. Simple two-class MRAC is adequate for qualitative clinical assessment.

Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079).

Background: SGLT2 inhibitors (SGLT2i) improve prognosis in HFrEF patients. We recently demonstrated in a porcine model of non-diabetic HFrEF that empagliflozin (EMPA) ameliorates adverse cardiac remodeling and improves LV systolic function. However, the effect of EMPA on left atrial (LA) dilatation has not yet been studied Hypothesis:: Empagliflozin ameliorates left atrial dilatation in non-diabetic HFrEF patients Methods: The EMPATROPISM clinical trial investigated the efficacy and safety of EMPA in non-diabetic HFrEF patients. 84 patients were randomized to EMPA 10mg daily for 6 months or placebo on top of optimal medical treatment, and were evaluated with cardiac magnetic resonance (CMR). LA Volumes were quantified by CMR using the Simpson method (the number of slices in the usual short axis SSFP cine sequence was increased to cover both LV and the whole of LA. The primary endpoint was change in LVEDV. Prespecified secondary endpoints were changes in maximal and minimal LA volumes (ΔMax LA Vol and ΔMin LA Vol) at the end of 6 months between both arms Results: 80 patients completed the follow up period. There were no differences at baseline in LVEDV (220±75 vs 209±68mL for EMPA vs placebo, p=0.5) or LVEF (36±8 vs 37±8%, p=0.7). There were no differences at baseline in both groups in either maximal or minimal LA volume (Table). In the primary endpoint, EMPA-treated patients showed decrease in LVEDV and increase in LVEF (ΔLVEDV -25±25 vs -1±25mL, p Conclusions: In HFrEF patients without diabetes, treatment with empagliflozin ameliorates left atrial dilatation. As LA volume is a surrogate for chronic filling pressures, this reduced LA volume suggest improved diastolic function with EMPA

Background: SGLT2 inhibitors (SGLT2i) improve prognosis in HFrEF patients. We recently demonstrated in a porcine model of non-diabetic HFrEF that empagliflozin (EMPA) ameliorates adverse cardiac remodeling and improves LV systolic function. However, the effect of EMPA on interstitial myocardial fibrosis (IMF) and aortic stiffness has not yet been studied Hypothesis: Empagliflozin ameliorates IMF and aortic stiffness in non-diabetic HFrEF patients Methods: The EMPATROPISM clinical trial (NCT 03485222) investigated the efficacy and safety of EMPA in non-diabetic HFrEF patients. 84 patients were randomized to EMPA 10mg daily for 6 months or placebo on top of optimal medical treatment, and were evaluated with cardiac magnetic resonance (CMR). IMF was assessed by CMR using extracellular volume (ECV) by T1 mapping. Aortic stiffness was quantified by pulse wave velocity (PWV) by CMR. The primary endpoint was change in LVEDV. Prespecified secondary endpoints were changes in ECV (ΔECV) and PWV (ΔPWV) at 6 months between both arms Results: 80 patients completed the follow up period. There were no differences at baseline in LVEDV (220±75 vs 209±68mL for EMPA vs placebo, p=0.5) or LVEF (36±8 vs 37±8%, p=0.7). There were no differences at baseline in both groups in either ECV or PWV (Table). In the primary endpoint, EMPA-treated patients showed decrease in LVEDV and increase in LVEF (ΔLVEDV -25±25 vs -1±25mL, p Conclusions: In HFrEF patients without diabetes, treatment with empagliflozin ameliorates IMF and aortic stiffness. This may explain the benefits of SGLT2i in HFrEF even in the absence of diabetes

Background Thromboembolic disease is common in coronavirus disease-2019 (COVID-19). There is limited evidence on the association of in-hospital anticoagulation (AC) with outcomes and postm...

Coronary revascularization is accomplished either by percutaneous coronary intervention (PCI), with low risk of immediate complications, or coronary artery bypass graft (CABG), with improved long-term, event-free survival attributable to use of the left internal mammary artery graft. Hybrid coronary revascularization (HCR) combines both. The left internal mammary artery graft is done by sternal-sparing approaches or by robotic-assisted, endoscopic surgery. HCR reduces bleeding, ventilator time, and length of stay compared with traditional CABG. Compared with PCI, HCR offers the durability and survival advantages of the left internal mammary artery. The large-scale National Heart, Lung, and Blood Institute-sponsored, randomized Hybrid Trial (Hybrid Coronary Revascularization Trial) was initiated to examine whether HCR is superior to multivessel PCI. However, enrollment was suboptimal, triggering premature study discontinuation. HCR integrates the positive features of both PCI and CABG, albeit requiring 2 procedures rather than 1. Adequately powered randomized trials are required to evaluate the outcomes and cost-effectiveness of HCR compared with CABG and multivessel PCI alone.

Introduction: Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare coronary artery anomaly that carries 90% mortality in the first year of life when left untreated. The diagnosis of ALCAPA is rare in adulthood, and it includes a broad spectrum of clinical manifestations, including sudden cardiac death (SCD). Case report: We report a rare case of resuscitated sudden cardiac arrest in a 55-year-old female, who was diagnosed with ALCAPA and underwent successful surgical correction and implantable cardioverter defibrillator (ICD) implantation for secondary prevention. Discussion: ALCAPA diagnosis is not confined to childhood, and it represents a rare cause of life-threatening arrhythmias and SCD in the adult population. Surgical correction is recommended, regardless of age, presence of symptoms or inducible myocardial ischemia. Multimodality imaging is crucial for diagnosis, management planning and follow up. Assessment of the risk of recurrent ventricular arrhythmias, despite full revascularization, should be performed in all adults with ALCAPA. Myocardial scar detected via late gadolinium enhancement represents a potential irreversible substrate for ventricular arrhythmias, and it provides additional information to evaluate indication of an ICD for secondary prevention.

The adipokine resistin has been proposed to link obesity, insulin resistance and diabetes. We have previously reported that diabetic hearts express high levels of resistin while overexpression of resistin in adult rat hearts gives rise to a phenotype resembling diabetic cardiomyopathy. The transcriptional regulation of resistin in diabetic cardiac tissue is currently unknown. This study investigated the mechanism of resistin upregulation and the role of Serca2a in its transcriptional suppression. We demonstrate that restoration of Ca2+ homeostasis in diabetic hearts, through normalization of Serca2a function genetically and pharmacologically, suppressed resistin expression via inhibition of NFATc. H9c2 myocytes stimulated with high-glucose concentration or Ca2+ time-dependently increased NFATc and resistin expression while addition of the Ca2+ chelator BAPTA-AM attenuated this effect. NFATc expression was enhanced in hearts from ob/ob diabetic and from cardiac-specific Serca2a−/− mice. Similarly, NFATc increased resistin expression in myocytes cultured in low glucose while the NFATc inhibitor VIVIT blocked glucose-induced resistin expression, suggesting that hyperglycemia/diabetes induces resistin expression possibly through NFATc activation. Interestingly, overexpression of Serca2a or VIVIT mitigated glucose-stimulated resistin and NFATc expression and enhanced AMPK activity, a downstream target of resistin signaling. NFATc direct activation of resistin was verified by resistin promoter luciferase activity and chromatin-immunoprecipitation analysis. Interestingly, activation of Serca2a by a novel agonist, CDN1163, mirrored the effects of AAV9-Serca2a gene transfer on resistin expression and its promoter activity and AMPK signaling in diabetic mice. These findings parse a role for Ca2+ in resistin transactivation and provide support that manipulation of Serca2a-NFATc-Resistin axis might be useful in hyper-resistinemic conditions.

Background Patients undergoing percutaneous mechanical circulatory support (pMCS)-assisted percutaneous coronary intervention (PCI) represent a high-risk group vulnerable to complications and readmissions. Hypothesis Thirty-day readmissions after pMCS-assisted PCI are common among patients with comorbidities and account for a significant amount of healthcare spending. Methods Patients undergoing PCI and pMCS (Impella, TandemHeart, or intra-aortic balloon pump) for any indication between January 1, 2012, and November 30, 2014, were selected from the Nationwide Readmissions Database. Patients were identified using appropriate ICD-9-CM codes. Clinical risk factors and complications were analyzed for association with 30-day readmission. Results Our analysis included 29 247 patients, of which 4535 (15.5%) were readmitted within 30 days. On multivariate analysis, age ≥ 65 years, female sex, hypertension, diabetes, chronic lung disease, heart failure, prior implantable cardioverter-defibrillator, liver disease, end-stage renal disease, and length of stay ≥5 days during index hospitalization were independent predictors of 30-day readmission. Cardiac etiologies accounted for ~60% of readmissions, of which systolic or diastolic heart failure (22%), stable coronary artery disease (11.1%), acute coronary syndromes (8.9%), and nonspecific chest pain (4.0%) were the most common causes. In noncardiac causes, sepsis/septic shock (4.6%), hypotension/syncope (3.2%), gastrointestinal bleed (3.1%), and acute kidney injury (2.6%) were among the most common causes of 30-day readmissions. Mean length of stay and cost of readmissions was 4 days and $16 191, respectively. Conclusions Thirty-day readmissions after pMCS-assisted PCI are common and are predominantly associated with increased burden of comorbidities. Reducing readmissions for common cardiac etiologies could save substantial healthcare costs.

Residual atherothrombotic risk remains higher in patients with versus without diabetes mellitus (DM) despite statin therapy. The underlying mechanisms are unclear. This is a retrospective post-hoc analysis of the YELLOW II trial, comparing patients with and without DM (non-DM) who received rosuvastatin 40 mg for 8–12 weeks and underwent intracoronary multimodality imaging of an obstructive nonculprit lesion, before and after therapy. In addition, blood samples were drawn to assess cholesterol efflux capacity (CEC) and changes in gene expression in peripheral blood mononuclear cells (PBMC). There was a significant reduction in low density lipoprotein-cholesterol (LDL-C), an increase in CEC and beneficial changes in plaque morphology including increase in fibrous cap thickness and decrease in the prevalence of thin cap fibro-atheroma by optical coherence tomography in DM and non-DM patients. While differential gene expression analysis did not demonstrate differences in PBMC transcriptome between the two groups on the single-gene level, weighted gene coexpression network analysis revealed two modules of coexpressed genes associated with DM, Collagen Module and Platelet Module, related to collagen catabolism and platelet function respectively. Bayesian network analysis revealed key driver genes within these modules. These transcriptomic findings might provide potential mechanisms responsible for the higher cardiovascular risk in DM patients.

Background The relative outcomes of intravascular ultrasound (IVUS)–guided percutaneous coronary intervention (PCI) compared with angiography-guided PCI with drug-eluting stent (DES) in complex lesions have not been established. We sought to compare the efficacy and safety of IVUS-guided PCI with angiography-guided PCI in patients with complex coronary lesions treated with DES. Methods Electronic databases were searched to identify all randomized trials comparing IVUS-guided vs angiography-guided DES implantation. We evaluated major adverse cardiac events (MACE), all-cause and cardiovascular death, myocardial infarction, target lesion revascularization (TLR), target vessel revascularization (TVR), and stent thrombosis outcomes at the longest reported follow-up. Random-effects modeling was used to calculate pooled relative risk (RR) and 95% CIs. Results Eight trials comprising 3,276 patients (1,635 IVUS-guided and 1,641 angiography-guided) enrolling only patients with complex lesions were included. Mean follow-up was 1.4±0.5years. Compared with angiography-guided PCI, patients undergoing IVUS-guided PCI had significantly lower MACE (RR 0.64, 95% CI 0.51-0.80, P =.0001), TLR (RR 0.62, 95% CI 0.45-0.86, P =.004), and TVR (RR 0.60, 95% CI 0.42-0.87, P =.007). There were no significant differences for stent thrombosis, cardiovascular death, or all-cause death. In meta-regression analysis, IVUS-guided PCI was of greatest benefit in reducing MACE in patients with acute coronary syndromes, diabetes, and long lesions. Conclusions The present meta-analysis demonstrates a significant reduction in MACE, TVR, and TLR with IVUS-guided DES implantation in complex coronary lesions.

El reemplazo de valvulas aorticas transcateter es una opcion de tratamiento excelente para pacientes con estenosis aortica severa sintomatica y riesgo alto o intermedio para cirugia. Con base en evidencia cientifica solida en reemplazo de valvulas aorticas transcateter, obtenida de estudios clinicos aleatorios y con ya cerca de ocho anos ˜ de experiencia comercial, ?por que importaria pensar en la durabilidad de estas valvulas y por que esta duda acaba de salir a la luz publica?

Background: Despite extensive evidence demonstrating the beneficial effects of statins on clinical outcomes, the mechanisms underlying these effects remain elusive.Objectives: This study as...

Diabetes mellitus (DM) and chronic kidney disease (CKD) separately are known to facilitate the progression of medial arterial calcification (MAC) in patients with symptomatic peripheral artery disease (PAD), but their combined effect on MAC and associated mediators of calcification is not well studied. The association of MAC and calcification inducer bone morphogenetic protein (BMP-2) and inhibitor fetuin-A, with PAD, is well known. Our aim was to investigate the association of MAC with alterations in BMP-2 and fetuin-A protein expression in patients with PAD with DM and/or CKD. Peripheral artery plaques (50) collected during directional atherectomy from symptomatic patients with PAD were evaluated, grouped into no-DM/no-CKD ( n = 14), DM alone ( n = 10), CKD alone ( n = 12), and DM+CKD ( n = 14). MAC density was evaluated using hematoxylin and eosin, and alizarin red stain. Analysis of inflammation, neovascularization, BMP-2 and fetuin-A protein density was performed by immunohistochemistry. MAC density, inflammation grade and neovessel content were significantly higher in DM+CKD versus no-DM/no-CKD and CKD ( p < 0.01). BMP-2 protein density was significantly higher in DM+CKD versus all other groups ( p < 0.01), whereas fetuin-A protein density was significantly lower in DM+CKD versus all other groups ( p < 0.001). The combined presence of DM+CKD may be associated with MAC severity in PAD plaques more so than DM or CKD alone, as illustrated in this study, where levels of calcification mediators BMP-2 and fetuin-A protein were related most robustly to DM+CKD. Further understanding of mechanisms involved in mediating calcification and their association with DM and CKD may be useful in improving management and developing therapeutic interventions.

ResumenLa isquemia miocárdica puede ser irreversible o reversible dependiendo de diferentes factores moleculares y fisiológicos. En la isquemia miocárdica irreversible se presentan tres tipos de muerte celular a nivel miocárdico: la necrosis, la apoptosis y la autofagia; mientras en la isquemia reversible la restauración de la función de los miocitos está determinada por factores como el restablecimiento temprano del flujo sanguíneo coronario y fenómenos de pre y posacondicionamiento isquémico. Conceptos como el miocardio aturdido (disfunción mecánica temporal luego de una lesión isquémica pero con flujo sanguíneo normal en ausencia de cualquier lesión irreversible) y el miocardio hibernante (región miocárdica viable, sin contractilidad) son formas quiescentes de la función cardiaca y explican un poco la capacidad del miocardio de restablecer su funcionamiento normal luego de un episodio de isquemia.AbstractMyocardial ischemia can be irreversible or reversible depending on multiple molecular and physiological factors. In irreversible myocardial ischemia there are three types of cell death on a myocardial level: necrosis, apoptosis and autophagy; whereas in reversible ischemia the restoration of the myocytes is determined by factors such as early recovery of coronary blood flow and pre- and postischemic conditioning phenomena. Concepts such as stunned myocardium (temporary mechanical dysfunction following an ischemic episode but with normal blood flow and without irreversible damage) and hibernating myocardium (viable myocardial region without contractility) are quiescent forms of the cardiac function and explain the ability of the myocardium to resume its normal functioning after an ischemic episode.

ResumenLa isquemia miocárdica es el conjunto de una serie de fenómenos fisiológicos que se manifiesta por condiciones clínicas como isquemia silente, angina estable y síndromes coronarios agudos. Diversos mecanismos de la regulación del flujo sanguíneo, la demanda miocárdica, la liberación de adenosina y la función del endotelio en las arterias coronarias son claves para mantener la irrigación miocárdica y han sido la base fisiológica para el desarrollo de pruebas de detección de isquemia como lo es el flujo de reserva fraccional, que hoy día hace parte de las recomendaciones de las guías.AbstractMyocardial ischaemia as a whole is a series of physiological phenomena manifested by clinical conditions such as silent ischaemia, stable angina and acute coronary syndromes. Various blood flow regulation mechanisms, myocardial demand, adenosine release and endothelial function in the coronary arteries are vital for maintaining myocardial irrigation, and have been the physiological basis for tests like fractional flow reserve, developed to detect ischaemia, that today forms part of the guideline recommendations.

Neointimal cellular proliferation of fibroblasts and myofibroblasts is documented in coronary artery restenosis, however, their role in peripheral arterial disease (PAD) restenosis remains unclear. Our aim was to investigate the role of fibroblasts, myofibroblasts, and collagens in restenotic PAD.Nineteen PAD restenotic plaques were compared with 13 de novo plaques. Stellate cells (HE), fibroblasts (FSP-1), myofibroblasts (α-actin/vimentin/FSP-1), cellular proliferation (Ki-67), and apoptosis (caspase-3 with poly ADP-ribose polymerase) were evaluated by immunofluorescence. Collagens were evaluated by picro-sirius red stain with polarization microscopy. Smooth muscle myosin heavy chain (SMMHC), IL-6 and TGF-β cytokines were analyzed by immunohistochemistry.Restenotic plaques demonstrated increased stellate cells (2.7 ± 0.15 vs.1.3 ± 0.15) fibroblasts (2282.2 ± 85.9 vs. 906.4 ± 134.5) and myofibroblasts (18.5 ± 1.2 vs.10.6 ± 1.0) p = 0.0001 for all comparisons. In addition, fibroblast proliferation (18.4% ± 1.2 vs.10.4% ± 1.1; p = 0.04) and apoptosis (14.6% ± 1.3 vs.11.2% ± 0.6; p = 0.03) were increased in restenotic plaques. Finally, SMMHC (2.6 ± 0.12 vs.1.4 ± 0.15; p = 0.0001), type III collagen density (0.33 ± 0.06 vs. 0.17 ± 0.07; p = 0.0001), IL-6 (2.08 ± 1.7 vs.1.03 ± 2.0; p = 0.01), and TGF-β (1.80 ± 0.27 vs. 1.11 ± 0.18; p = 0.05) were increased in restenotic plaques.Our study suggests proliferation and apoptosis of fibroblast and myofibroblast with associated increase in type III collagen may play a role in restenotic plaque progression. Understanding pathways involved in proliferation and apoptosis in neointimal cells, may contribute to future therapeutic interventions for the prevention of restenosis in PAD.

This review discusses the possibilities offered by new modalities of non-invasive and invasive coronary imaging in an effort to optimize risk stratification for coronary artery disease, and identify subgroups at high risk that may benefit from an aggressive, personalized approach, with access to a growing number of novel drugs and interventions. Special emphasis is placed on the progress of novel invasive imaging techniques such as near infrared spectroscopy and optical coherence tomography that can reliably identify thin-capped fibroatheromas. Multiple trials are exploring the feasibility of these techniques to guide modulation of risk factor control and treatment of non-flow limiting lesions at high risk of destabilization and progression in patients undergoing clinically mandated angioplasty of angiographically critical lesions. Asymptomatic patients at high risk of cardiovascular ischaemic events may also benefit, with the intermediate step of a wider application of calcium score and angiography with multi-slice computed tomography, by a selective use of invasive imaging.

Plaque rupture, defined as direct exposure of the necrotic core to flowing blood, is a major cause of arterial thrombosis, acute myocardial infarction, and sudden coronary death. A highly thrombogenic necrotic core is separated from the lumen by a thin fibrous cap that is the last barrier between

If you always do what you always did, you will always get what you always got —Albert Einstein [(1)][1] Four decades ago, we believed in a dogma that acute myocardial infarction (MI) resulted from near total luminal obstruction by progressive thickening of coronary atheroma. At that time

Collagen cross-linking is mediated by lysyl oxidase (LOX) enzyme in the extracellular matrix (ECM) of mitral valve leaflets. Alterations in collagen content and LOX protein expression in the ECM of degenerative mitral valve may enhance leaflet expansion and disease severity.Twenty posterior degenerative mitral valve leaflets from patients with severe mitral regurgitation were obtained at surgery. Five normal posterior mitral valve leaflets procured during autopsy served as controls. Valvular interstitial cells (VICs) density was quantified by immunohistochemistry, collagen Types I and III by picro-sirius red staining and immunohistochemistry, and proteoglycans by alcian blue staining. Protein expression of LOX and its mediator TGFβ1 were quantified by immunofluorescence and gene expression by PCR.VIC density was increased, structural Type I collagen density was reduced, while reparative Type III collagen and proteoglycan densities were increased (P.0001) with an increase in spongiosa layer thickness in myxomatous valves. These changes were associated with a reduction in LOX (P.0001) and increase in TGFβ1 protein expression (P.0001). However, no significant change was seen in gene expression. Linear regression analysis identified a correlation between Type I collagen density and LOX grade (RReduced Type I collagen density with a simultaneous increase in Type III collagen and proteoglycan densities possibly contributes to spongiosa layer expansion resulting in incompetent mitral valve leaflets. Observed changes in Type I and III collagen densities in Degenerative Mitral Valve Disease may be secondary to alterations in LOX protein expression, contributing to disorganization of ECM and disease severity.

Carotid artery stenosis (CAS) is common in older adults undergoing transcatheter aortic valve replacement (TAVR). CAS may be associated with increased risk of periprocedural stroke (PPS) and major cardiovascular events. Carotid filter protection (sentinel system) systems are frequently used to

Yesterday is not ours to recover, but tomorrow is ours to win or to lose —Lyndon B. Johnson [(1)][1] Current prevention of major adverse cardiovascular events (MACE) after acute coronary syndromes (ACS) is based on aggressive medical therapy, and guideline-driven treatment of traditional

Objectives To compare the discriminatory value of differing risk scores for predicting clinical outcomes following PCI in routine practice. Background Various risk scores predict outcomes after PCI. However, these scores consider markedly different factors, from purely anatomical (SYNTAX risk score [SRS]) to purely clinical (ACEF, modified ACEF [ACEFmod], NCDR), while other scores combine both elements (Clinical SYNTAX score [CSS], NY State Risk Score [NYSRS]). Methods Patients with triple vessel and/or LM disease with 12 month follow-up were studied from a single center PCI registry. Exclusion criteria included STEMI presentation, prior revascularization and shock. Clinical events at 12 months were compared to baseline risk scores, according to score tertiles and area under receiver-operating-characteristic curves (AUC). Results We identified 584 eligible patients (69.8±12.3yrs, 405 males). All scores were predictive of mortality, with the SRS being least predictive (AUC=0.66). The most accurate scores for mortality were the CSS and ACEF (AUC=0.76 for both: P = 0.019 and 0.08 vs. SRS, respectively). For TLR, while the SRS trended toward being positively predictive (P = 0.075), several scores trended towards a negative association, which reached significance for the NCDR (P = 0.045). The SRS and CSS were the only scores predictive of MI (both P

Objectives This study sought to determine the impact of short-term intensive statin therapy on intracoronary plaque lipid content. Background Statin therapy significantly reduces the risk for thrombotic events. Whether or not these benefits are attributable to reduction in plaque lipid content remains to be properly documented in human obstructive coronary artery disease (CAD). Methods We randomized 87 patients with multivessel CAD undergoing percutaneous coronary intervention and at least 1 other severely obstructive (fractional flow reserve [FFR] ≤0.8) nontarget lesion (NTL) to intensive (rosuvastatin 40 mg daily) or standard-of-care lipid-lowering therapy. NTLs were evaluated at baseline and after 7 weeks of therapy with FFR, near-infrared spectroscopy, and intravascular ultrasound. The primary endpoint was the change in lipid-core burden index at the 4-mm maximal segment (LCBI4mm max), wherever this occurred within the lesion. Results Upon follow-up, median reduction (95% confidence interval) in LCBI4mm max was significantly greater in the intensive versus standard group (-149.1 [-210.9 to -42.9] vs. 2.4 [-36.1 to 44.7]; p = 0.01). Results remained consistent after adjustment for baseline differences in LCBI between groups and use of change in LCBI across the entire lesion as the dependent outcome. Conclusions Short-term intensive statin therapy may reduce lipid content in obstructive lesions. These hypothesis-generating findings warrant confirmation in larger studies with longer follow-up. (Reduction in YEllow Plaque by Aggressive Lipid LOWering Therapy [YELLOW]); NCT01567826).

Background Optical coherence tomography (OCT) imaging is considered to be the only imaging modality with sufficient resolution to measure fibrous cap thickness (FCT) in vivo. However, reproducibility of the measurements in vivo has been unsatisfactory. Objectives The authors aimed to investigate whether satisfactory reproducibility of FCT measurements by OCT in vivo can be achieved between independent observers. Methods One hundred seventy OCT pullbacks were analyzed by 2 independent observers with intravascular imaging expertise in accordance with current guidelines to assess the interobserver variability of FCT measurement by intraclass correlation coefficient (ICC). The main sources of the variability were analyzed and incorporated in lesion assessment criteria. The same 170 OCT pullbacks were reanalyzed by the same observers using the developed criteria, and the interobserver reproducibility of the measurements was reassessed. On the basis of the developed criteria, a third independent observer interpreted all 170 OCT images. Assessment of the maximal lipid arc was also undertaken similarly before and after the development of interpretation criteria. Results The original ICC of the FC thickness was 0.56 (95% confidence interval [CI]: 0.38 to 0.69). The poor definition of necrotic core facing border of FC and the neointimal presence of macrophages and calcification contributed to the high interobserver variability of FCT measurement. The ICC of FCT measurements by OCT in vivo was 0.88 (95% CI: 0.80 to 0.93) after we developed lesion assessment criteria. The ICC for the maximal lipid arc assessment before and after was 0.76 and 0.82 respectively. The third independent observer was extensively coached and returned the ICC of 0.82 (95% CI: 0.74 to 0.87) with observer 1 and 0.90 (95% CI: 0.86 to 0.94) with observer 2. Conclusions Careful consideration of OCT features mimicking fibroatheroma lesions and imaging artifacts contributed to significantly higher levels of interobserver agreement. Interobserver variation can be partially resolved by development of standard interpretation algorithms.

Objective— Haptoglobin (Hp) protein is responsible for hemoglobin clearance after intra-plaque hemorrhage. Hp gene exists as Hp-1 and Hp-2 alleles and the phenotypes show important molecular heterogeneity. We tested the hypothesis that hemoglobin clearance may be deficient in diabetic atheroma from patients with Hp2-2, triggering increased oxidative, inflammatory, and angiogenic patterns compared with controls. Methods and Results— Forty patients with diabetes mellitus were genotyped and their peripheral plaques compared after atherectomy. Plaque hemorrhage, iron content, hemoglobin-binding protein CD163, and heme-oxygenase-1 were quantified. Oxidative, inflammatory, and angiogenic patterns were evaluated by measuring myeloperoxidase, interleukin-10, macrophages, vascular cell adhesion molecule-1, smooth muscle actin, and plaque neovascularization (CD34/CD31). Plaques with Hp2-2 (n=7) had increased hemorrhage ( P P P P P P P P P P =0.001), smooth muscle actin ( P =0.002) scores, and neovessels density ( P Conclusion— Genotype-dependent impairment of hemoglobin clearance after intra-plaque hemorrhage is associated with increased oxidative, inflammatory, and angiogenic response in human diabetic atherosclerosis.

Objectives The purpose of this study was to test the hypothesis that increased oxidative stress is associated with apoptosis in human plaques with the haptoglobin (Hp) 2-2 genotype. Background Intraplaque hemorrhage releases free hemoglobin (Hb). Impaired Hb clearance induces oxidative stress leading to plaque progression. The binding of Hp to Hb attenuates iron-induced oxidative reactions. Methods Twenty-six human aortic plaques were Hp genotyped. Hp2-2 plaques (n = 13) were compared with control (Hp1-1/2-1) (n = 13). The iron grade was measured by Perl's staining. Immunostaining was used to detect oxidation-specific epitopes (OSEs) reflecting oxidized phospholipids and malondialdehyde-like epitopes. The percentages of apoptotic cells and apoptotic morphological features were quantified. DNA fragmentation and active caspase-3 were measured by in situ end-labeling and immunohistochemistry, respectively. Results In Hp2-2 plaques, iron content was increased (1.22 ± 0.15 vs. 0.54 ± 0.08; p Conclusions These findings provide insights into genetic predisposition to oxidative stress and the relationship between OSEs and macrophage apoptosis that may explain advanced atherosclerosis in human Hp2-2 plaques.

Objectives To define the incidence of stent thrombosis (ST) and/or AMI (ST/AMI) associated with temporary or permanent suspension of dual anti-platelet therapy (DAPT) after coronary drug eluting stent (DES) implantation in ‘real-world’ patients, and additional factors influencing these events.

Objectives The purpose of this study was to correlate adverse events at long-term follow-up in patients after an acute coronary syndrome with coronary plaque characteristics derived from simultaneous evaluation of their mechanical and compositional properties using virtual histology (intravascular ultrasound virtual histology) and palpography. Background Fibroatheroma is the plaque morphology with the highest risk of causing adverse cardiac events. Palpography can potentially assess the local mechanical plaque properties with the possibility of identifying fibroatheroma with the highest risk of rupture. Methods A total of 114 patients with acute coronary syndrome from the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial underwent a single ultrasound imaging investigation of their 3 coronary vessels with the co-registration of intravascular ultrasound virtual histology and palpography. Major adverse cardiac events (MACE) (cardiac death, cardiac arrest, myocardial infarction, or unstable or progressive angina) were collected up to a median follow-up of 3.4 years and adjudicated to originally treated culprit versus untreated nonculprit lesions. Results In total, 488 necrotic core–rich plaques were identified and subclassified as thin-cap fibroatheroma (n = 111), calcified thick-cap fibroatheroma (n = 213), and noncalcified thick-cap fibroatheroma (n = 164) and matched to their co-registered palpography data. A total of 16 MACE, adjudicated to untreated nonculprit lesions, were recorded at follow-up. In patients in whom MACE developed, fibroatheroma were larger (plaque area 10.0 mm 2 [range: 8.4 to 11.6 mm 2 ] vs. 8.2 mm 2 [range: 7.7 to 8.8 mm 2 ] (p = 0.03) compared with patients who were MACE free. By palpography, the maximum and the density strain values did not differ between the varying subtypes of fibroatheroma of patients with or without MACE during follow-up. Conclusions In acute coronary syndromes, patients treated with stents and contemporary pharmacotherapy, palpography did not provide additional diagnostic information for the identification of fibroatheroma with a high risk of rupture and MACE during long-term follow-up. ( Providing Regional Observations to Study Predictors of Events in the Coronary Tree [PROSPECT]: An Imaging Study in Patients With Unstable Atherosclerotic Lesions; NCT00180466 )

Mounting data support a 'calcification paradox', whereby reduced bone mineral density is associated with increased vascular calcification. Furthermore, reduced bone mineral density is prevalent in older persons with lower body mass index (BMI). Therefore, although BMI and coronary artery calcification (CAC) exhibit a positive relationship in younger persons, it is predicted that in older persons and/or those at risk for osteoporosis, an inverse relationship between BMI and CAC may apply. We sought to explore this hypothesis in a large group of patients with coronary artery disease undergoing percutaneous coronary intervention (PCI).We accessed our single-center registry for 07/01/1999 to 06/30/2009, extracting data on all patients that underwent PCI. To minimize bias we excluded those at the extremes of age or BMI and non-Black/Hispanic/Caucasians, leaving 9993 study subjects (age 66.6±9.9 years). Index lesion calcification (ILC) was analyzed with respect to BMI. Comparing index lesions with no angiographic calcification to those with the most severe, mean BMI decreased by 1.11 kgm(-2); a reduction of 3.9% (P0.0001). By multivariable modeling, BMI was an independent inverse predictor of moderate-severe ILC (m-sILC; odds ratio [OR] 0.967, 95% CI 0.953-0.980, P0.0001). Additional fully adjusted models identified that, compared to those with normal BMI, obese patients had an OR of 0.702 for m-sILC (95% CI 0.596-0.827, P0.0001).In a large group of PCI patients, we identified an inverse correlation between BMI and index lesion calcification. These associations are consistent with established paradigms and suggest a complex interrelationship between BMI, body size and vascular calcification.

Studies on the impact of concomitant coronary artery disease (CAD) on clinical outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) have shown conflicting results. We analyzed 803 consecutive patients enrolled in a single center TAVR registry between 2012 and 2016. Patients

Whereas statins are well-known to contribute to atheromatic plaque stability and regression of atherosclerosis burden, possible interactions with anti-retroviral therapy have led to sub-prescription in this cohort. However, exactly how statins affect the angiographic phenotype, coronary lesion