Select Articles Published on the Topic of Coronary Heart Disease in 2013

Abstract

HomeCirculationVol. 129, No. 14Select Articles Published on the Topic of Coronary Heart Disease in 2013 Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBSelect Articles Published on the Topic of Coronary Heart Disease in 2013 The Editors The Editors Search for more papers by this author Originally published8 Apr 2014https://doi.org/10.1161/CIRCULATIONAHA.114.010015Circulation. 2014;129:e432–e441Lipoprotein Apheresis in Patients With Maximally Tolerated Lipid-Lowering Therapy, Lipoprotein(a)-Hyperlipoproteinemia, and Progressive Cardiovascular Disease: Prospective Observational Multicenter StudySummary—Evidence from prospective epidemiological studies has accumulated to firmly document an association of elevated circulating levels of lipoprotein(a) (Lp(a)) with cardiovascular disease (CVD) including coronary artery disease, cerebrovascular disease, and peripheral artery disease. Lipoprotein apheresis can lower low-density lipoprotein cholesterol and Lp(a) and is the final escalating option in severely hypercholesterolemic patients, including genetic or other forms of hypercholesterolemia resistant to or intolerant of the use of statins or combined lipid-lowering medication. The major effect of lipoprotein apheresis is the prevention of cardiovascular events. The Pro(a)LiFe study showed that commencing chronic lipoprotein apheresis could reduce the incidence rate of cardiovascular events in patients with Lp(a)-hyperlipoproteinemia and progressive CVD that persisted despite the maximal treatment of other concomitant cardiovascular risk factors. Results of this prospective study support the hypothesis that Lp(a) might be a causal factor for progression of CVD in patients with Lp(a)-hyperlipoproteinemia. Efforts must be made to identify these patients to optimize their treatment including multimodality approaches. The assessment of cardiovascular risk, in particular, for patients who are already at high risk owing to established CVD should include measurement of Lp(a). Lp(a) levels are generally not influenced by lifestyle. A widely useable substance for effective pharmacological lowering of Lp(a) is not yet available. Nicotinic acid at high doses has shown a Lp(a)-lowering effect in clinical practice. Limited by side effects, the use of nicotinic acid has not seen wide application. In Europe, nicotinic acid is no longer available. Lipoprotein apheresis can be regarded as a reasonable and available therapeutic option for high-risk patients with Lp(a)-hyperlipoproteinemia and progressive CVD.Conclusions—In patients with Lp(a)-hyperlipoproteinemia, progressive cardiovascular disease, and maximally tolerated lipid-lowering medication, LA effectively lowered the incidence rate of cardiovascular events.1Disturbed Coronary Hemodynamics in Vessels With Intermediate Stenoses Evaluated With Fractional Flow Reserve: A Combined Analysis of Epicardial and Microcirculatory Involvement in Ischemic Heart DiseaseSummary—Although impairment of myocardial blood supply in ischemic heart disease results from both obstructive and nonobstructive coronary involvement, its diagnosis is largely stenosis-centred. Fractional flow reserve (FFR) informs on whether treating epicardial stenoses may benefit the patient, but not on whether concomitant nonobstructive coronary disease, which might also influence outcome, is present. To investigate this, a comprehensive assessment of coronary hemodynamics with FFR (abnormal ≤0.80), coronary flow reserve (CFR, abnormal <2.0), and microcirculatory resistance (IMR) was performed in 93 vessels with intermediate stenoses. Interestingly, 63% of vessels with normal FFR>0.80 presented disturbed hemodynamics, revealed by abnormal CFR (52%) or microcirculatory disease (MCD, defined as IMR≥29.1) (33%). Indeed, and as theoretically expected, the presence of MCD almost invariably implied nonsignificant (>0.80) FFR values that could be wrongly interpreted as absence of significant disease. Four coronary hemodynamic patterns were generated based on dichotomous classification of FFR and CFR; nonagreement groups (accounting for 63% of vessels) seem to result from the presence of diffuse epicardial disease (CFR≤2.0 and FFR>0.80) or from focal epicardial narrowing with preserved microcirculatory function (FFR≤0.80 and preserved CFR>2.0). Future research should address whether if the first group might have a worse prognosis despite an FFR >0.80, whereas in the latter revascularization might be spared despite an FFR≤0.80 (as a result of preserved CFR). Overall, the observations serve as a preamble to a more comprehensive, yet required, intracoronary assessment of ischemic heart disease, which may improve prognostic characterization and guide therapeutic strategies aiming to both obstructive and nonobstructive coronary disease.Conclusions—A substantial number of coronary arteries with stenoses showing an FFR>0.80 present disturbed hemodynamics. Integration of FFR, CFR, and IMR supports the existence of differentiated patterns of ischemic heart disease that combine focal and diffuse coronary narrowings with variable degrees of MCD.2Novel Small Leucine-Rich Repeat Protein Podocan Is a Negative Regulator of Migration and Proliferation of Smooth Muscle Cells, Modulates Neointima Formation, and Is Expressed in Human AtheromaSummary—Smooth muscle cells (SMCs) critically influence the clinical course of vascular disease. The close regulation of SMC migration and proliferation within the intimal space is critical in maintaining a delicate balance between insufficient and excessive atherosclerotic plaque repair. When SMC proliferation is too suppressed, the ensuing weakening of the fibrous cap can result in the plaque vulnerability that underlies acute coronary syndrome, and when SMC proliferation is excessive, intimal hyperplasia can follow, such as in restenosis after percutaneous coronary intervention. Although stents have vastly improved on the recoil and constrictive remodeling component of restenosis, the problem of accelerated intimal SMC growth has remained. The current approach of delivering stents that release nonspecific agents that promote cell death or inhibition of proliferation has been successful in reducing the need for recurrent vascular interventions; however, this success comes at the expense of delaying vascular healing, the ultimate long-term clinical impact of which is still being evaluated. Short- and long-term negative effects on the healing arterial wall, such as delayed reendothelialization, increased inflammation, and enhanced thrombogenicity, are undisputed. These side effects of drug-eluting stents are being masked by prolonged and aggressive antiplatelet therapy, which exposes patients, especially the elderly, to increased bleeding risks, complicates clinical decision making through fear of too early treatment cessation, demands rigorous patient compliance, and is costly. These issues are not trivial in daily clinical practice. The possible role of podocan as a novel selective inhibitor of the SMC response and the Wnt-TCF pathway opens the door to modulation of vascular SMCs in a smarter and more physiological way.Conclusions—Podocan appears to be a potent negative regulator of the migration and proliferation of both murine and human SMCs. The lack of podocan results in excessive arterial repair and prolonged SMC proliferation, which likely is mediated by the Wnt-TCF pathway.3Impaired Cholesterol Metabolism and Enhanced Atherosclerosis in Clock Mutant MiceSummary—Heart attacks happen mainly in the early hours of the day, suggesting that their occurrence might be related to circadian rhythms seen in various behavioral, physiological, and biochemical activities. Here, we show that disruption of circadian Clock activity as a result of a dominant-negative mutation (ClockΔ19/Δ19) increases susceptibility to atherosclerosis in various mouse models. ClockΔ19/Δ19 mice fed an atherogenic diet had increased plasma cholesterol, triglycerides, and atherosclerotic lesions compared with their wild-type siblings. Similarly, ClockΔ19/Δ19 protein increased cholesterolemia and atherosclerosis in Ldlr−/− and Apoe−/− mice fed a chow or Western diets. Physiological studies revealed that high plasma cholesterol in ClockΔ19/Δ19Apoe−/− mice was due in part to increased cholesterol uptake by enterocytes. In addition, macrophages in ClockΔ19/Δ19Apoe−/− mice displayed higher lipid uptake and reduced cholesterol efflux compared with Apoe−/− siblings. Molecular studies demonstrated that knockdown of Clock gene expression in wild-type macrophages reduces ABCA1 expression and cholesterol efflux. Furthermore, Clock overexpression increases ABCA1 transcription. Evidence is presented to suggest that USF2 could participate in the modulatory effect of Clock on ABCA1 expression. These studies provide significant evidence for the importance of Clock in the proper physiological functioning of enterocytes and macrophages. Hence, disruptions in Clock function as a result of either mutations or other environmental factors such as a high-fat diet, transcontinental flights, and night shift work might deregulate enterocyte and macrophage function, increasing the risk for atherosclerosis.Conclusions—ClockΔ19/Δ19 protein enhances atherosclerosis by increasing intestinal cholesterol absorption, augmenting uptake of modified lipoproteins by macrophages, and reducing cholesterol efflux from macrophages. These studies establish that circadian Clock activity is crucial in maintaining low plasma cholesterol levels and in reducing atherogenesis in mice.4Effect of Early Metoprolol on Infarct Size in ST-Segment–Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention: The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) TrialSummary—The capacity of β-blockers to reduce infarct size was evaluated extensively in the prereperfusion era with controversial results. In the context of reperfusion as the treatment of choice for ST-segment–elevation myocardial infarction (STEMI), this has been poorly investigated. Experimental data suggest that the β-blocker metoprolol is able to reduce infarct size only when administered intravenously before reperfusion. Here, we present the results of the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial, the first randomized, clinical trial prospectively evaluating the effect of early intravenous β-blockade on infarct size in conjunction with primary angioplasty. A total of 270 patients with anterior STEMI (Killip class II or less) revascularized within 6 hours after symptom onset were randomized to receive intravenous metoprolol or not before reperfusion. All patients received oral metoprolol according to clinical guidelines (first dose, 12–24 hours after infarction). Infarct size, evaluated by MRI and creatine kinase release, was significantly reduced in the intravenous metoprolol group with no excess side effects. Left ventricular ejection fraction was higher in the intravenous metoprolol group. This cardioprotective effect appeared to be restricted to patients with a preangioplasty Thrombolysis in Myocardial Infarction grade 0 to 1 flow. Here, we show that an inexpensive medication already approved in the context of STEMI can significantly reduce infarct size just by administering it intravenously before reperfusion in patients with no contraindications. Given the important role of final infarct size as a main determinant of long-term mortality in STEMI survivors, the possibility of applying inexpensive strategies available to a wide proportion of STEMI patients is of clinical value.Conclusions—In patients with anterior Killip class II or less ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, early intravenous metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours after STEMI.5Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without InflammationSummary—Elevated levels of both nonfasting remnant cholesterol and low-density lipoprotein cholesterol are causally associated with ischemic heart disease, but whether both lipoproteins also are associated with low-grade inflammation is unknown. This is a clinically important question because atherosclerosis is a disease with an inflammatory component and because randomized, clinical intervention trials have shown that statins prevent cardiovascular disease in individuals with low-grade inflammation with moderately elevated levels of C-reactive protein, even when low-density lipoprotein cholesterol levels are relatively low. The reason could be that statins lower not only low-density lipoprotein cholesterol levels but also triglycerides levels and thus remnant cholesterol levels. In this study, we found both elevated levels of nonfasting remnant cholesterol and elevated levels of low-density lipoprotein cholesterol to be causally associated with increased risk of ischemic heart disease, but only elevated levels of nonfasting remnant cholesterol were causally associated with low-grade inflammation. Taken together, this suggests that elevated low-density lipoprotein cholesterol levels cause atherosclerosis without a major inflammatory component, whereas an inflammatory component of atherosclerosis is driven by elevated nonfasting remnant cholesterol levels. Thus, we here point toward a new direction for reducing cardiovascular disease beyond that achieved through low-density lipoprotein cholesterol lowering.Conclusions—Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation.6Inhibition of MicroRNA-92a Protects Against Ischemia/Reperfusion Injury in a Large-Animal ModelSummary—Although revascularization of an infarct-related artery is state-of-the-art treatment of acute coronary syndromes, ischemia/reperfusion induces cellular stress and damage, potentially inflicting organ dysfunction. Treatment options are required to simultaneously prevent cardiomyocyte damage, endothelial dysfunction, and overwhelming postischemic inflammation. MicroRNA (miR) inhibition might meet these requirements because miRs target multiple signaling pathways, thereby providing pleiotropic effects. miR-92a, a member of the miR17-92 cluster, is upregulated after acute myocardial infarction, and its inhibition enhanced neovascularization in a murine infarct model. Here, we demonstrate that regional miR-92a inhibition via locked nucleic acid–modified antisense miR-92a (LNA-92a) improved cardiac function and reduced ischemia/reperfusion–induced cardiomyocytic cell death, endothelial dysfunction, and inflammation. Regional application of LNA-92a might offer a novel therapeutic option to improve cardiac function after acute myocardial ischemia/reperfusion injury.Conclusions—Regional LNA-92a delivery reduces miR-92a levels and infarct size and postischemic loss of function. LNA-92a exerts cell-protective, proangiogenic, and anti-inflammatory effects. miR-92a inhibition might be a novel therapeutic tool to preserve cardiac function after ischemia.7Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO TrialSummary—The risk of stent thrombosis, a life-threatening complication of stent placement, is reduced by antiplatelet therapy combining aspirin and a P2Y12platelet receptor antagonist such as clopidogrel. When platelet inhibition is inadequate, the risk increases. Clopidogrel produces moderate and variable P2Y12inhibition. Ticagrelor, a reversibly acting nonthienopyridine P2Y12 antagonist that provides more potent and consistent platelet inhibition, was compared with clopidogrel in patients with acute coronary syndromes in the Platelet Inhibition and Patient Outcomes (PLATO) trial and reduced the primary outcome of cardiovascular death, myocardial infarction, and stroke, as well as cardiovascular mortality. This analysis describes the effects of ticagrelor compared with clopidogrel on the risk of stent thrombosis in patients with stents in the PLATO trial. Of 18 624 patients hospitalized for acute coronary syndromes, 61% had at least 1 intracoronary stent and were analyzed. Ticagrelor reduced definite stent thrombosis compared with clopidogrel (hazard ratio, 0.67; 95% confidence interval, 0.50–0.90; P=0.0091) but also definite or probable and any stent thrombosis. The reduction in definite stent thrombosis was consistent regardless of acute coronary syndromes type, the presence of diabetes mellitus, stent type (drug-eluting or bare metal stent), CYP2C19 genetic status, loading dose of aspirin, dose of clopidogrel before randomization, and use of glycoprotein IIb/IIIa inhibitors at randomization. Randomization to ticagrelor was a strong independent inverse predictor of definite stent thrombosis in multivariable Cox regression analyses. Ticagrelor compared with clopidogrel reduced the incidence of stent thrombosis in acute coronary syndromes patients across a broad range of patient, stent, and treatment characteristics.Conclusions—Ticagrelor compared with clopidogrel reduces the incidence of stent thrombosis in patients with acute coronary syndromes, with consistent benefit across a broad range of patient, stent, and treatment characteristics.8AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy: An Analysis From the LDL-C Assessment With Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)–Thrombolysis in Myocardial Infarction (TIMI) 57 TrialSummary—Lipoprotein(a) [Lp(a)] is a circulating lipoprotein composed of an apolipoprotein B100 molecule covalently bound to a liver-derived glycoprotein, apolipoprotein(a). In epidemiological and genetic analyses, Lp(a) has emerged as an important risk factor for the development of cardiovascular disease. The 2011 European Society of Cardiology/European Atheroscloerosis Society guidelines recommend screening for elevated Lp(a) in people at high risk for cardiovascular disease or with a strong family history of premature atherothrombotic disease. There are limited therapeutic options for lowering Lp(a) levels. We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a) levels in the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)–Thrombolysis in Myocardial Infarction (TIMI) 57 trial, a randomized, phase 2 trial of AMG145 versus placebo. We found that compared with placebo, AMG145 significantly lowers Lp(a) in subjects with hypercholesterolemia receiving background therapy with statin with or without ezetimibe. Specifically, we observed dose-response relationships at both dosing frequencies, with progressively more robust reductions in Lp(a), up to 32%, from baseline to week 12. We found that the reduction in Lp(a) with AMG145 was consistent across several important subgroups including age, sex, race, history of diabetes mellitus, and background statin regimen. Although the clinical benefit of Lp(a) reduction remains undefined, these data lend further support to studying the impact of PCSK9 inhibition with AMG145 in a phase 3 clinical outcomes trial.Conclusions—AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient’s atherogenic lipid profile.9Rosiglitazone and Outcomes for Patients With Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) TrialSummary—Rosiglitazone is a thiazolidinedione that improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding its association with increased cardiovascular hazard, and the cardiovascular effects of rosiglitazone for patients with established coronary artery disease remain unknown. The association between rosiglitazone use and cardiovascular events was examined among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial during 4.5 years of follow-up using both Cox proportional hazards models for on-treatment events and propensity-matched analyses. Among patients undergoing treatment with rosiglitazone, there was a significantly lower adjusted incidence of the composite outcome of death, myocardial infarction, and stroke, as well as of stroke, whereas the incidences of myocardial infarction, congestive heart failure, and death were not significantly different. Among propensity-matched patients, the risks of major ischemic cardiovascular events and congestive heart failure were not significantly different. There was a higher incidence of fractures observed among rosiglitazone-treated patients. An interaction was also observed between use of metformin and rosiglitazone that appeared to mitigate an increased risk of congestive heart failure with rosiglitazone. The results of these analyses from BARI 2D do not support an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events among patients with type 2 diabetes mellitus and established coronary artery disease.Conclusions—Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events.10Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species Through Effects on Smooth Muscle Cells and Monocytes and Correlates With Higher-Risk Plaques in HumansSummary—Damage to mitochondria, the powerhouse of the cell, has been found in human atherosclerosis and is associated with increased levels of free radicals and oxidative stress. Indeed, to date, it has been thought that free radicals mediate almost all of the effect of mitochondrial DNA (mtDNA) damage in atherosclerosis. We show that mtDNA damage occurs early in atherosclerosis in both the vessel wall and circulating cells and is sufficient to cause mitochondrial dysfunction. Using mice, we show that mtDNA damage directly promotes atherosclerosis and features of unstable plaques independently of oxidative stress. mtDNA damage inhibits cell proliferation, promotes cell death, and increases the proinflammatory activity of monocytes. Using virtual histology intravascular ultrasound, we show that mtDNA damage is associated with higher-risk plaques in patients, is independent of other risk factors, and decreases after treatment in patients with acute coronary syndrome. Thus, mtDNA damage in the vessel wall and circulating cells is widespread and causative, indicates higher risk in atherosclerosis, and can promote disease independently of oxidative stress. mtDNA damage may be useful as a biomarker for high-risk atherosclerosis, and protection against mtDNA damage and improvement in mitochondrial function are potential areas for new therapeutics.Conclusions—We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.11Mechanically Unloading the Left Ventricle Before Coronary Reperfusion Reduces Left Ventricular Wall Stress and Myocardial Infarct SizeSummary—Each year, nearly 8 million people worldwide suffer a heart attack, which is commonly caused by a blocked coronary artery leading to reduced oxygen supply to the heart, known as ischemia. Every minute of occlusion directly correlates with ongoing heart muscle damage. Treatment focuses on quickly re-establishing blood flow to the heart, known as reperfusion. However, despite timely reperfusion, ≈5% to 10% of patients die in the hospital, and 25% develop chronic heart failure. Using a porcine model of an acute heart attack, we studied whether first reducing the workload of the heart with a mechanical pump despite delaying coronary reperfusion would reduce myocardial damage. We identified that a percutaneously delivered left atrial–to–femoral artery circuit driven by a centrifugal pump reduces left ventricular wall stress, work, and strain while maintaining systemic arterial pressure. Next, we observed that mechanically unloading the heart despite delaying reperfusion promotes phosphorylation of proteins involved in myocardial salvage. Finally, we showed that compared with controls, myocardial damage was reduced with initiation of mechanical support in the setting of a heart attack. These findings suggest that initially reducing the workload of the heart despite delaying coronary reperfusion reduces myocardial injury. The clinical implications of these findings require further study.Conclusions—These data support that first unloading the left ventricle despite delaying coronary reperfusion during an acute MI reduces myocardial injury.12Perivascular Adipose Tissue Potentiates Contraction of Coronary Vascular Smooth Muscle: Influence of ObesitySummary—Adipose tissue normally surrounds the major conduit coronary arteries on the surface of the heart. The volume of this perivascular adipose tissue (PVAT) expands with obesity and has been shown to be a strong independent predictor of coronary atherosclerosis. Recent studies implicate PVAT as a ready source of vasoactive factors and inflammatory mediators capable of influencing vasomotor function; however, the vascular effects of coronary PVAT have not been clearly defined. Data from this investigation provide novel evidence that coronary PVAT is capable of releasing factors that initiate/potentiate contraction of coronary arteries independently of the effects on the endothelium. Importantly, the vascular influence of PVAT is specific to anatomic location and is augmented in the setting of obesity. Our findings support that this augmented effect of PVAT is related to alterations in Rho-dependent signaling, increased functional expression of CaV1.2 channels, or diminished or altered activity of K+ channels in obese coronary arteries. Marked alterations in the expression profile of the coronary PVAT proteome in the setting of obesity uncover new potential therapeutic target proteins (eg, calpastatin) and signaling pathways that may contribute not only to the regulation of vascular smooth muscle tone but also to the initiation of smooth muscle differentiation and proliferation observed in obesity-induced cardiovascular disease.Conclusions—Vascular effects of PVAT vary according to anatomic location and are influenced by an obese phenotype. Augmented contractile effects of obese coronary PVAT are related to alterations in the PVAT proteome (eg, calpastatin), Rho-dependent signaling, and the functional contribution of K+ and CaV1.2 channels to smooth muscle tone.13Serum Proprotein Convertase Subtilisin/Kexin Type 9 and Cell Surface Low-Density Lipoprotein Receptor: Evidence for a Reciprocal RegulationSummary—We show novel posttranscriptional regulatory mechanisms determining serum levels and function of proprotein convertase subtilisin/kexin type 9 (PCSK9): clearance via the low-density lipoprotein (LDL) receptor (LDLR) and transport on LDL in a quantitatively significant but less active form. Although PCSK9 is known to regulate LDLR levels, we report here that the reverse is also true and that the main exit route for serum PCSK9 is via LDLR. Thus, LDLR mutations may have larger effects on LDL metabolism if they affect not only LDL internalization but also PCSK9 clearance. We foresee a clinical scenario in which LDLR mutations that affect PCSK9 clearance in addition to LDL clearance (eg, receptor negative) can aggravate hypercholesterolemia via the effect of accumulated PCSK9, resulting from defective clearance, on the normal LDLR allele product. Along this line of thinking, it is also possible to forecast hypercholesterolemia resulting from an LDLR mutation that only causes defective PCSK9 clearance. It is interesting that carriers of LDLR-negative mutations have indeed been reported to show significantly higher LDL levels compared with carriers of dysfunctional LDLR mutations. Our finding that about one third of serum PCSK9 is part of LDL and is in a monomeric, less active form suggests that peripheral distribution and function of this regulator of LDLR levels are influenced by the lipoprotein that acts as a canonical ligand for LDLR. Maneuvers that increase the PCSK9 content of LDL in serum may allow us to broaden the search for inhibitory strategies of PCSK9 action, currently limited to blocking the interaction between PCSK9 and LDLR via antibodies.Conclusions—Our results support a scenario in which LDLR represents the main route of elimination of PCSK9 and a reciprocal regulation between these 2 proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.14Myocardial Injury After Noncardiac Surgery and its Association With Short-Term MortalitySummary—Perioperative adv