Michel T. Corban

Association of coronary wall shear stress with atherosclerotic plaque burden, composition, and distribution in patients with coronary artery disease.

Background Extremes of wall shear stress (WSS) have been associated with plaque progression and transformation, which has raised interest in the clinical assessment of WSS. We hypothesized that calculated coronary WSS is predicted only partially by luminal geometry and that WSS is related to plaque composition. Methods and Results Twenty‐seven patients with coronary artery disease underwent virtual histology intravascular ultrasound and Doppler velocity measurement for computational fluid dynamics modeling for WSS calculation in each virtual histology intravascular ultrasound segment (N=3581 segments). We assessed the association of WSS with plaque burden and distribution and with plaque composition. WSS remained relatively constant across the lower 3 quartiles of plaque burden (P=0.08) but increased in the highest quartile of plaque burden (P<0.001). Segments distal to lesions or within bifurcations were more likely to have low WSS (P<0.001). However, the majority of segments distal to lesions (80%) and within bifurcations (89%) did not exhibit low WSS. After adjustment for plaque burden, there was a negative association between WSS and percent necrotic core and calcium. For every 10 dynes/cm2 increase in WSS, percent necrotic core decreased by 17% (P=0.01), and percent dense calcium decreased by 17% (P<0.001). There was no significant association between WSS and percent of fibrous or fibrofatty plaque components (P=NS). Conclusions In patients with coronary artery disease: (1) Luminal geometry predicts calculated WSS only partially, which suggests that detailed computational techniques must be used to calculate WSS. (2) Low WSS is associated with plaque necrotic core and calcium, independent of plaque burden, which suggests a link between WSS and coronary plaque phenotype. (J Am Heart Assoc. 2012;1:e002543 doi: 10.1161/JAHA.112.002543.)

Myocardial bridging: contemporary understanding of pathophysiology with implications for diagnostic and therapeutic strategies.

Patients with myocardial bridging are often asymptomatic, but this anomaly may be associated with exertional angina, acute coronary syndromes, cardiac arrhythmias, syncope, or even sudden cardiac death. This review presents our understanding of the pathophysiology of myocardial bridging and describes prevailing diagnostic modalities and therapeutic options for this challenging clinical entity.

Combination of plaque burden, wall shear stress, and plaque phenotype has incremental value for prediction of coronary atherosclerotic plaque progression and vulnerability

AIMS Large plaque burden, certain phenotypes, and low wall shear stress (WSS) are associated with adverse outcomes and high WSS with development of plaque vulnerability. We aimed to investigate the incremental value of the combination of plaque burden, WSS and plaque phenotype for prediction of coronary atherosclerotic plaque progression and vulnerability. METHODS Twenty patients with CAD underwent baseline and 6-month follow-up coronary virtual histology-intravascular ultrasound (VH-IVUS) and computational fluid dynamics modeling for calculation of WSS. Low WSS was defined as <10 dynes/cm(2) and high WSS as ≥25 dynes/cm(2). Baseline plaque characteristics and WSS were related to plaque progression and vulnerability. RESULTS In 2249 VH-IVUS frames analyzed, coronary segments with both plaque burden >40% and low WSS had significantly greater change in plaque area at follow-up (+0.68 ± 1.05 mm(2)), compared to segments with plaque burden >40% without low WSS (-0.28 ± 1.32 mm(2)) or segments with low WSS and plaque burden ≤40% (+0.05 ± 0.71 mm(2)) (p = 0.047). Among plaque phenotypes, pathologic intimal thickening (PIT) had the greatest increase in necrotic core (NC) area (p = 0.06) and greatest decrease in fibro-fatty (FF) area (p < 0.0001). At follow-up, compared to segments with either plaque burden >60%, PIT, or high WSS, those with a combination of plaque burden >60%, PIT, and high WSS developed greater increase in NC area (p = 0.002), greater decrease in FF (p = 0.004) and fibrous areas (p < 0.0001), and higher frequency of expansive remodeling (p = 0.019). CONCLUSION Combination of plaque burden, WSS, and plaque phenotype has incremental value for prediction of coronary plaque progression and increased plaque vulnerability in patients with non-obstructive CAD.

High wall shear stress and high-risk plaque: an emerging concept.

In recent years, there has been a significant effort to identify high-risk plaques in vivo prior to acute events. While number of imaging modalities have been developed to identify morphologic characteristics of high-risk plaques, prospective natural-history observational studies suggest that vulnerability is not solely dependent on plaque morphology and likely involves additional contributing mechanisms. High wall shear stress (WSS) has recently been proposed as one possible causative factor, promoting the development of high-risk plaques. High WSS has been shown to induce specific changes in endothelial cell behavior, exacerbating inflammation and stimulating progression of the atherosclerotic lipid core. In line with experimental and autopsy studies, several human studies have shown associations between high WSS and known morphological features of high-risk plaques. However, despite increasing evidence, there is still no longitudinal data linking high WSS to clinical events. As the interplay between atherosclerotic plaque, artery, and WSS is highly dynamic, large natural history studies of atherosclerosis that include WSS measurements are now warranted. This review will summarize the available clinical evidence on high WSS as a possible etiological mechanism underlying high-risk plaque development.

Comprehensive Assessment of Coronary Plaque Progression With Advanced Intravascular Imaging, Physiological Measures, and Wall Shear Stress: A Pilot Double‐Blinded Randomized Controlled Clinical Trial of Nebivolol Versus Atenolol in Nonobstructive Coronary Artery Disease

Background We hypothesized that nebivolol, a β‐blocker with nitric oxide–mediated activity, compared with atenolol, a β‐blocker without such activity, would decrease oxidative stress and improve the effects of endothelial dysfunction and wall shear stress (WSS), thereby reducing atherosclerosis progression and vulnerability in patients with nonobstructive coronary artery disease. Methods and Results In this pilot double‐blinded randomized controlled trial, 24 patients treated for 1 year with nebivolol 10 mg versus atenolol 100 mg plus standard medical therapy underwent baseline and follow‐up coronary angiography with assessments of inflammatory and oxidative stress biomarkers, microvascular function, endothelial function, and virtual histology intravascular ultrasound. WSS was calculated from computational fluid dynamics. Virtual histology intravascular ultrasound segments were assessed for vessel volumetrics and remodeling. There was a trend toward more low‐WSS segments in the nebivolol cohort (P=0.06). Low‐WSS regions were associated with greater plaque progression (P<0.0001) and constrictive remodeling (P=0.04); conversely, high‐WSS segments demonstrated plaque regression and excessive expansive remodeling. Nebivolol patients had decreased lumen and vessel areas along with increased plaque area, resulting in more constrictive remodeling (P=0.002). There were no significant differences in biomarker levels, microvascular function, endothelial function, or number of thin‐capped fibroatheromas per vessel. Importantly, after adjusting for β‐blocker, low‐WSS segments remained significantly associated with lumen loss and plaque progression. Conclusion Nebivolol, compared with atenolol, was associated with greater plaque progression and constrictive remodeling, likely driven by more low‐WSS segments in the nebivolol arm. Both β‐blockers had similar effects on oxidative stress, microvascular function, and endothelial function. Clinical Trial Registration URL: https://clinicaltrials.gov/. Unique identifier: NCT01230892.

Elevated Levels of Serum Fibrin and Fibrinogen Degradation Products Are Independent Predictors of Larger Coronary Plaques and Greater Plaque Necrotic Core

BACKGROUND Co-existence of vulnerable plaque and pro-thrombotic state may provoke acute coronary events. It was hypothesized that elevated serum levels of fibrin and fibrinogen degradation products (FDP) are associated with larger total plaque and necrotic core (NC) areas. METHODSANDRESULTS Seventy-five patients presenting with stable anginal symptoms (69%) or stabilized acute coronary syndrome (ACS; 31%), and found to have non-obstructive coronary artery disease (CAD) with a fractional flow reserve >0.8, were studied. Invasive virtual histology intravascular ultrasound (VH-IVUS) was performed in 68 LAD arteries, 6 circumflex arteries, and 1 right coronary artery. Serum FDP levels were measured using ELISA technique. Plaque volumetrics and composition were assessed in each VH-IVUS frame and averaged. The median age of patients was 56 (47-63) years; 52% were men and 23% had diabetes. The average length of coronary artery studied was 62 mm. After adjustment for systemic risk factors, medications, CRP levels and ACS, male gender (P<0.001) and serum FDP levels (P=0.02) were independent predictors of a larger NC area. Older age (P<0.001), male gender (P<0.0001) and increased serum FDP level (P=0.03) were associated with a larger plaque area. CONCLUSIONS In patients with CAD, a higher serum level of FDP is independently associated with larger plaques and greater plaque NC.

CORONARY SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR RELEASE IS A BIOMARKER OF ENDOTHELIAL-DEPENDENT MICROVASCULAR DYSFUNCTION

Soluble Urokinase Plasminogen Activator Receptor (suPAR) is a pro-inflammatory biomarker associated with immune activation and fibrinolysis inhibition. suPAR, coronary epicardial endothelial dysfunction (ED) and endothelial-dependent microvascular dysfunction (MD) have been associated with adverse

Microvascular obstruction in non-infarct related coronary arteries is an independent predictor of major adverse cardiovascular events in patients with ST segment-elevation myocardial infarction

BACKGROUND Coronary microvascular obstruction (MVO) in infarct-related artery (IRA) territory has been associated with worse cardiovascular outcomes in patients presenting with ST-segment elevation myocardial infarction. However, the prognostic value of non-IRA MVO in this patient population remains unknown. METHODS AND RESULTS One hundred ninety nine patients presenting to our institution with STEMI were enrolled. All patients underwent primary percutaneous coronary intervention per institutional STEMI protocol followed by a cardiac MRI within 1 week of presentation and the IRA and non-IRA MVO segments were determined. All cause death, recurrent myocardial infarction, hospitalization for heart failure, and ventricular tachycardia were counted as major adverse cardiovascular events (MACE). Patients with non-IRA MVO had lower composite MACE free survival at 6 months (HR 2.15, 95% CI, 1.06-4.35; p = 0.029) compared to those without non-IRA MVO. In a sub-analysis of patients with multi vessel disease (MVD), patients with non-IRA MVO also had lower composite MACE-free survival at 6 months as compared to those without non-IRA MVO (HR 2.47, 95% CI, 1.02-5.97; p = 0.037). Non-IRA MVO continued to be predictive of MACE in a cox proportional hazards model adjusting for additional prognostic factors using inverse probability weighting (p = 0.007). Non-IRA MVO was more prevalent in patients with LAD culprit vessel STEMI rather than those with RCA or Circumflex culprit vessels (p < 0.001). CONCLUSIONS Patients presenting with STEMI and non-IRA MVO have significantly lower MACE free survival at 6 months as compared to those without non-IRA MVO.

Ubiquitous yet unseen: microvascular endothelial dysfunction beyond the heart

Coronary microvascular dysfunction is not uncommon. The prevalence of non-obstructive coronary artery disease (CAD) in patients undergoing coronary angiography for chest pain is 30–50%. Out of those patients, over 60% have coronary microvascular dysfunction (CMD). In addition to angina, CMD has been associated with a sixfold increase in adjusted mortality and higher risk of major adverse cardiovascular events (MACE), including acute coronary syndrome, myocardial infarction, progressive congestive heart failure, and sudden cardiac death. CMD can be classified into two categories: 1) endothelialindependent CMD related to inadequate vascular smooth muscle relaxation in response to intraluminal pressure changes sensed by vascular smooth muscle stretch receptors on medium-sized microvessels (40–100 mm diameter) and 2) endothelial-dependent CMD related to impaired endothelial-mediated vasomotion of larger-sized pre-arterioles and microvessels (100–500 mm diameter). Given that the endothelium is the front frontier to encounter cardiovascular risk factors and is considered the largest body organ, microvascular endothelial dysfunction is bound to affect a number of susceptible organs beyond the heart. Non-invasive studies of endothelial function using reactive hyperaemia have linked systemic endothelial dysfunction to coronary endothelial microvascular disease and increased risk of MACE. Moreover, a growing body of evidence has linked systemic endothelial dysfunction and microvascular disease to increased risk of cerebrovascular accidents (transient ischaemic attacks, and ischaemic and haemorrhagic strokes), cognitive decline and lacunar infarcts, retinopathy, vascular nephropathy, thromboembolism in antiphospholipid syndrome, and heart failure with preserved ejection fraction (Take home figure). Therefore, endothelial dysfunction is clearly a disease with noticeable systemic manifestations. In this issue of the European Heart Journal, an elegant study conducted by Ford et al. further confirms the systemic nature of microvascular dysfunction in patients with microvascular angina (MVA) and epicedial vasospastic angina (VSA). The authors show that in the absence of obstructive CAD, and in comparison to a control group of patients with normal epicardial and microvascular endothelial function, both MVA patients and VSA patients exhibit endothelial-dependent functional abnormalities of the gluteal microvessels (315–345 mm diameter range). The diameter size of these systemic microvessels is particularly meaningful, given that blood flow regulation in this category of microvessels is primarily endothelialdependent. The potent vasoconstrictor endothelin-1 (ET-1), the proinflammatory vasoconstrictor thromboxane A2, angiotensin-II, and increased oxidative stress, as well as decreased activity of the endothelium-derived vasodilator nitric oxide (NO), have all been associated with CMD. Indeed, this study demonstrates the striking imbalance between NO-dependent impaired relaxation of systemic microvessels in response to acetylcholine and the concomitant augmented vasoconstriction of these microvessels in response to endothelium-derived vasoconstrictors such as (ET-1) and the thromboxane agonist U46619, both of which are characteristic findings of systemic microvascular endothelial dysfunction. On the other hand, systemic endothelium-independent relaxation in response to sodium nitroprusside was similar among controls, MVA patients, and VSA patients, underscoring the selective impairment in NOregulated vasomotion in these patients. The current findings may have important diagnostic and therapeutic implications. A growing body of evidence, linking systemic microvascular endothelial dysfunction to disease development and major adverse events across multiple organs and systems, warrants a shift in our research paradigm and clinical focus. It is imperative to recognize and appreciate the diffuse nature of this disease, so that the detection of microvascular endothelial dysfunction in one organ should trigger a search for it in other organs. Importantly, identifying a high-risk population through invasive or non-invasive screening for endothelial function, and the development of novel pharmacotherapies to restore the balance between endothelial-dependent attenuated vascular relaxation and augmented vasoconstriction, may not only

055 RELIABILITY OF RESTING CORONARY HAEMODYNAMICS WHEN REPEATED AFTER 6 MONTHS

Background Vasodilator-free indices of coronary stenosis severity require stability of resting coronary hemodynamics. It is unknown whether resting hemodynamics are sufficiently reproducible to be reliable over an extended period. We evaluate the long-term stability of resting and hyperaemic intracoronary pressure and flow velocity measurements over a 6-month period. Methods 17 patients (mean age 55±12), with 18 anatomically mild-to-moderate lesions (17 in the mid-left anterior descending artery and 1 circumflex artery) had invasive simultaneous pressure and flow velocity measurements made at rest and during intravenous adenosine infusion (140 µg/kg/min). Measurements were repeated after 6 months at the same vessel location. Changes in coronary flow velocity and microcirculatory resistance were compared using Student t test and the F test. Results Mean flow velocity at rest was similar at baseline and 6 months (22.2±8.5 cm/s vs 21.6±8.5 cm/s, p=0.78); hyperaemic mean flow (43.3±14.1 cm/s vs 46.5±11.5 cm/s, p=0.47) similarly did not significantly change. The mean change between baseline and 6 months was 4% and 17% for resting and hyperaemic flow respectively and this was not significantly different (p=0.27). Peak coronary flow velocity was also similar at both time points at rest (53.5±27.2 cm/s vs 46.9±20.3 cm/s, p=0.38) and hyperaemia (88.0±22.5 cm/s vs 90.4±24.6 cm/s, p=0.75); the mean change was 3.0% and 9.0% respectively (p=0.50). Microcirculatory resistance measured at rest was unchanged between baseline and 6 months at rest (4.97±2.37 mm Hg/cm.s vs 5.23±2.25 mm Hg/cm.s, p=0.58) and during hyperaemia (1.94±0.72 vs 1.95±0.67, p=0.98). The mean change in resistance was 17.8% at rest and 11.9% for hyperaemia, with no significant difference (p=0.64). Conclusions Coronary flow velocity and microcirculatory resistance when measured over rest or hyperaemia, vary to a similar degree over 6 months. This suggests that coronary haemodynamics during resting conditions are stable, consistent and reproducible in a manner similar to that observed during adenosine-mediated hyperaemia.