Scott Kinlay

Effect of Endothelial Shear Stress on the Progression of Coronary Artery Disease, Vascular Remodeling, and In-Stent Restenosis in Humans In Vivo 6-Month Follow-Up Study

Background—Native atherosclerosis and in-stent restenosis are focal and evolve independently. The endothelium controls local arterial responses by transduction of shear stress. Characterization of endothelial shear stress (ESS) may allow for prediction of progression of atherosclerosis and in-stent restenosis. Methods and Results—By using intracoronary ultrasound, biplane coronary angiography, and measurement of coronary blood flow, we represented the artery in accurate 3D space and determined detailed characteristics of ESS and arterial wall/plaque morphology. Patients who underwent stent implantation and who had another artery with luminal obstruction <50% underwent intravascular profiling initially and after 6-month follow-up. Twelve arteries in 8 patients were studied: 6 native and 6 stented arteries. In native arteries, regions of abnormally low baseline ESS exhibited a significant increase in plaque thickness and enlargement of the outer vessel wall, such that lumen radius remained unchanged (outward remodeling). Regions of physiological ESS showed little change. Regions with increased ESS exhibited outward remodeling with normalization of ESS. In stented arteries, there was an increase in intima-medial thickness, a decrease in lumen radius, and an increase in ESS at all levels of baseline ESS. Conclusions—The present study represents the first experience in humans relating ESS to subsequent outcomes in native and stented arteries. Regions of low ESS develop progressive atherosclerosis and outward remodeling, areas of physiological ESS remain quiescent, and areas of increased ESS exhibit outward remodeling. ESS may have a limited role in in-stent restenosis. This technology can predict areas of minor plaque likely to exhibit progression of atherosclerosis.

High-Dose Atorvastatin Enhances the Decline in Inflammatory Markers in Patients With Acute Coronary Syndromes in the MIRACL Study

Background—Inflammation promotes acute coronary syndromes and ensuing clinical complications. Although statins reduce inflammatory markers in asymptomatic adults or in patients with stable angina, the effect of statins on the markedly heightened inflammation in patients with acute coronary syndromes is unknown. Methods and Results—We measured C-reactive protein (CRP), serum amyloid A (SAA), and interleukin 6 (IL-6) in 2402 subjects enrolled the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects with unstable angina or non–Q-wave myocardial infarction were randomized to atorvastatin 80 mg/d or placebo within 24 to 96 hours of hospital admission and treated for 16 weeks. The effect of treatment on inflammatory markers was assessed by ANCOVA after adjustment for presenting syndrome, country, and initial level of marker. All 3 markers were markedly elevated at randomization and declined over the 16 weeks in both treatment groups. Compared with placebo, atorvastatin significantly reduced CRP, −83% (95% CI, −84%, −81%) versus −74% (95% CI, −75%, −71%) (P <0.0001) and SAA, −80% (95% CI, −82%, −78%) versus −77% (−79%, −75%) (P =0.0006) but not IL-6, −55% (95% CI, −57%, −53%) versus −53% (95% CI, −55%, −51%) (P =0.3). Reductions in CRP and SAA were observed in patients with unstable angina and non–Q-wave myocardial infarction, with initial LDL cholesterol <3.2 or ≥3.2 mmol/L (125 mg/dL), age ≥65 or <65 years, and in men and women. By 16 weeks, CRP was 34% lower with atorvastatin than with placebo. Conclusions—High-dose atorvastatin potentiated the decline in inflammation in patients with acute coronary syndromes. This supports the value of early statin therapy in these patients.

Endothelial function and coronary artery disease.

The endothelium produces a number of vasodilator and vasoconstrictor substances that not only regulate vasomotor tone, but also the recruitment and activity of inflammatory cells and the propensity towards thrombosis. Endothelial vasomotor function is a convenient way to assess these other functions, and is related to the long-term risk of cardiovascular disease. Lipids (particularly low density lipoprotein cholesterol) and oxidant stress play a major role in impairing these functions, by reducing the bioavailability of nitric oxide and activating pro-inflammatory signalling pathways such as nuclear factor kappa B. Biomechanical forces on the endothelium, including low shear stress from disturbed blood flow, also activate the endothelium increasing vasomotor dysfunction and promoting inflammation by upregulating pro-atherogenic genes. In contrast, normal laminar shear stress promotes the expression of genes that may protect against atherosclerosis. The sub-cellular structure of endothelial cells includes caveolae that play an integral part in regulating the activity of endothelial nitric oxide synthase. Low density lipoprotein cholesterol and oxidant stress impair caveolae structure and function and adversely affect endothelial function. Lipid-independent pathways of endothelial cell activation are increasingly recognized, and may provide new therapeutic targets. Endothelial vasoconstrictors, such as endothelin, antagonize endothelium-derived vasodilators and contribute to endothelial dysfunction. Some but not all studies have linked certain genetic polymorphisms of the nitric oxide synthase enzyme to vascular disease and impaired endothelial function. Such genetic heterogeneity may nonetheless offer new insights into the variability of endothelial function.

Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial

BACKGROUND Cardiac transplantation is associated with oxidant stress, which may contribute to the development of accelerated coronary arteriosclerosis. We postulated that treatment with antioxidant vitamins C and E would retard the progression of transplant-associated arteriosclerosis. METHODS In a double-blind prospective study, 40 patients (0-2 years after cardiac transplantation) were randomly assigned vitamin C 500 mg plus vitamin E 400 IU, each twice daily (n=19), or placebo (n=21) for 1 year. The primary endpoint was the change in average intimal index (plaque area divided by vessel area) measured by intravascular ultrasonography (IVUS). Coronary endothelium-dependent vasoreactivity was assessed with intracoronary acetylcholine infusions. IVUS, coronary vasoreactivity, and vitamin C and E plasma concentrations were assessed at baseline and at 1 year follow-up. All patients received pravastatin. Analyses were by intention to treat. FINDINGS Vitamin C and E concentrations increased in the vitamin group (vitamin C 43 [SD 21] to 103 [43] mmol/L; vitamin E 24 [14] to 65 [27] mmol/L) but did not change in the placebo group (vitamin C 45 [15] vs 43 [16] mmol/L; vitamin E 27 [14] vs 27 [9] mmol/L; p<0.0001 for difference between groups). During 1 year of treatment, the intimal index increased in the placebo group by 8% (SE 2) but did not change significantly in the treatment group (0.8% [1]; p=0.008). Coronary endothelial function remained stable in both groups. INTERPRETATION Supplementation with antioxidant vitamins C and E retards the early progression of transplant-associated coronary arteriosclerosis.

2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA

Cardiac Event Recorders Yield More Diagnoses and Are More Cost-effective than 48-Hour Holter Monitoring in Patients with Palpitations: A Controlled Clinical Trial

Palpitation is a common symptom that sometimes results from a substantial cardiac arrhythmia. Establishing the cause of palpitations may be difficult because historical clues are not always accurate [1]. A 24-hour ambulatory (Holter) monitor is usually used, but the yield of this instrument is low in patients whose symptoms occur infrequently [2-5]. Another instrument used to study palpitations is a transtelephonic post-event recorder. These hand-held devices are given to patients and are applied to the chest when symptoms occur. The patient presses a button to record about 30 seconds of the cardiac rhythm, which is stored in the memory of the device. The recording is later transmitted over the telephone for printing and interpretation. Although this instrument has been available for many years, concerns have been expressed about the quality of recording and the extent to which an unselected group of patients can provide diagnostic recordings. Because no randomized, controlled trials have compared these devices with Holter monitoring, we compared the yields of Holter monitoring with those of event recorders in diagnosing palpitations in an unselected population. Methods Patients We considered for our study all 634 men and women referred to the cardiovascular unit at the John Hunter Hospital for Holter monitoring. We excluded patients being monitored for silent ischemia (7%), assessment of therapy (18%), syncope (18%), or other research studies or inpatient monitoring (8%); patients considered too old, too feeble, or too young to use the event monitor (16%); and patients who had previously had Holter monitoring for their symptoms (16%). The remaining 108 patients (17%) were eligible for the study. One investigator interviewed eligible patients to confirm that their symptoms were palpitations. We asked patients to estimate how frequently they had symptoms, the length of their longest attack, whether their palpitations were regular, and whether they smoked or had a history of hypertension or ischemic heart disease. Each patient provided informed consent, and the Hunter Health Service ethics committee approved the study. Our study was a randomized crossover trial. Each patient was randomly allocated to have either 48 hours of Holter monitoring (Marquette Electronics, Sydney, New South Wales, Australia) or an event monitor (Aerotel, Israel; Medtronic, Minneapolis, Minnesota). The patient kept the event monitor until two recordings were obtained during symptoms or until 3 months had passed. After the first monitor was returned, the patient was given the other device. During Holter monitoring, patients were asked to record in a diary when their index palpitation symptoms occurred during the 48-hour recording period. Patients also recorded the symptoms associated with their palpitations, including dizziness, nausea, shortness of breath, chest discomfort or pain, and arm pain. We defined these criteria before the study. To check the correctness of the interpretation of arrhythmias, we used a full-disclosure method that allowed review of all 48 hours of electrogram recording. A cardiologist blinded to the results from the event recorder read the reports and electrocardiogram printouts of arrhythmias during symptomatic and asymptomatic periods. Tracings for the event recorder were read by another cardiologist who was also blinded to patient data and results of 48-hour Holter monitoring. End Points The primary end point was an electrocardiogram rhythm strip obtained while symptoms occurred that would establish a cardiac or noncardiac cause of the symptoms. The secondary end point was a clinically significant cardiac arrhythmia defined before the study as symptomatic sustained supraventricular tachycardia (supraventricular rate, more than 15 beats/min), atrial fibrillation or flutter, sustained ventricular tachycardia (ventricular rate, more than 10 beats/min), sinus pause longer than 3 seconds, non-Wenckebach second-degree heart block, or third-degree heart block. Statistical Analysis We analyzed the data using the STATA program (Stata, College Station, Texas). Because all patients received both devices, we used an exact binomial test of untied pairs to determine the statistical significance of the primary and secondary end points [6]. Cost-Effectiveness Analysis We calculated incremental cost-effectiveness ratios (the additional cost per additional health outcome) of event monitors compared with Holter monitors for the primary and secondary end points. All costs were in 1994-1995 Australian dollars. The analysis was based on a time horizon of 21.5 weeks, which we estimated to be the period during which the study cohort of 43 patients (who could use either monitor) would present for monitoring. Assuming that the event monitors would be given to patients for 6 weeks, approximately 13 event monitors were required to monitor these 43 patients for 21.5 weeks. We used a societal perspective in our analysis and estimated direct medical costs of capital, labor, and consumable goods and nondirect medical costs of telephone calls (event monitors only). We excluded overhead costs for central administration, cleaning, heating, and so forth (direct medical costs) and for travel expenses (direct nonmedical costs) on the assumption that these variables would not differ between the devices. We calculated equivalent annual costs for capital using an annuitization procedure in which we assumed an expected life span of 5 years for both monitors and a 5% discount rate. The five Holter monitors and the analysis system in our unit cost approximately

Effect of Atorvastatin on Risk of Recurrent Cardiovascular Events After an Acute Coronary Syndrome Associated With High Soluble CD40 Ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study

106 193; this results in an equivalent annual cost of

Oxidized Low-Density Lipoprotein Augments and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Limit CD40 and CD40L Expression in Human Vascular Cells

24 528. Because Holter equipment is used for purposes other than investigating palpitations, we apportioned joint costs on the basis of the percentage of use attributed to patients with intermittent palpitations (17%). We apportioned an annual service cost, estimated to be 4.1% of the capital cost, on the same basis. The cost of 13 event monitors was estimated to be

Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis

6500 (Micromedical Industries, Labrador, Queensland, Australia), which resulted in an annual equivalent cost of

Characterization of Human Atherosclerotic Plaques by Intravascular Magnetic Resonance Imaging

1561. We estimated labor costs for technicians, secretaries, and cardiologists according to time and motion for the last five patients investigated. Our technicians spent an average of 113 minutes to explain how to use, put on, and remove the Holter monitor and how to analyze and download the tapes. Thirty-five minutes was needed to explain the event recorders and to prepare the rhythm strip for reporting. A cardiologist could interpret the Holter monitor recordings in about 16 minutes and could interpret the event monitor recordings in 2 minutes; the respective times for secretarial work were 10 minutes and 5 minutes. We assigned a value to these services using wages that were positively adjusted for annual and sick leave, superannuation entitlements, and workers compensation premiums. We assessed the robustness of the results in multiway sensitivity analyses that examined the changes in the discount rate (0% and 10%), a 20% increase and decrease in service and labor costs, and a reduction of the proportion of Holter monitor costs attributed to Holter monitor use from 17% to 10%. The effectiveness was also varied by the 95% CIs. Results Of the 108 eligible patients, we asked 45 (40%) to participate in the study. We did not ask the others to participate because the two chief investigators were not available to interview them. Of the 45 patients asked, 43 (96%) completed the study. Two persons withdrew before receiving the event monitor because the Holter monitor leads were too uncomfortable. Thirty-eight participants (88%) were women, and the mean age of all patients (SD) was 45 19 years. Thirty-four patients (81%) reported that palpitations occurred at least every 2 weeks, and 24 (56%) believed that their palpitations were regular; the average estimate of the longest attack was 74 159 minutes. The mean resting pulse rate was 76 15 beats/min; systolic blood pressure was 131 26 mm Hg; and diastolic blood pressure was 77 12 mm Hg. Four patients reported a history of ischemic heart disease, 14 (33%) reported a history of hypertension, and 7 (16%) were smokers. Twenty-four patients (56%) were randomly allocated to receive the 48-hour Holter monitor before receiving the event recorder. Table 1 lists the results for the primary and secondary end points. Thirty patients (70%) sent in at least one electrocardiogram recorded by the event monitor while symptoms occurred. Two patients had a technically inadequate electrocardiogram recording transmission, but 1 patient subsequently sent two rhythm strips showing sinus rhythm. Therefore, 29 patients (67%) sent at least one recording from an event recorder that could be interpreted compared with the approximately one third of patients who obtained recordings during symptoms with the Holter monitor (P < 0.001). Furthermore, the Holter monitor detected no clinically significant arrhythmias. During event recorder monitoring, a clinically significant arrhythmia was documented in each of 8 patients (19%) (Table 1 and Table 2; Figure 1). Table 1. Number of Patients with an Electrocardiogram Recorded during Symptoms or with Clinically Significant Arrhythmia* Table 2. Types of Cardiac Rhythm from Electrocardiograms Recorded during Symptoms Figure 1. Electrocardiogram recording from an event recorder showing atrial fibrillation during palpitations. Of the 29 patients who recorded an electrocardiogram with the event monitor, 20 (69%) made two recordings and returned the monitor before the maximum 3 months allowed. For 13 patients (65%) who sent in two recordings, the two recordings showed the same rhythm. For the remaining 7 patients, the discordant rhythms were supraventricular tachycardia and sinus tachycardia in 3 patients (2 of whom had supraventricular tachycardia on the first recording), atrial flutter and ventricular premature beats