Joon S. Lee

Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients

Background Although transcatheter aortic‐valve replacement (TAVR) is an accepted alternative to surgery in patients with severe aortic stenosis who are at high surgical risk, less is known about comparative outcomes among patients with aortic stenosis who are at intermediate surgical risk. Methods We evaluated the clinical outcomes in intermediate‐risk patients with severe, symptomatic aortic stenosis in a randomized trial comparing TAVR (performed with the use of a self‐expanding prosthesis) with surgical aortic‐valve replacement. The primary end point was a composite of death from any cause or disabling stroke at 24 months in patients undergoing attempted aortic‐valve replacement. We used Bayesian analytical methods (with a margin of 0.07) to evaluate the noninferiority of TAVR as compared with surgical valve replacement. Results A total of 1746 patients underwent randomization at 87 centers. Of these patients, 1660 underwent an attempted TAVR or surgical procedure. The mean (±SD) age of the patients was 79.8±6.2 years, and all were at intermediate risk for surgery (Society of Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%). At 24 months, the estimated incidence of the primary end point was 12.6% in the TAVR group and 14.0% in the surgery group (95% credible interval [Bayesian analysis] for difference, ‐5.2 to 2.3%; posterior probability of noninferiority, >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic‐valve areas than surgery. Structural valve deterioration at 24 months did not occur in either group. Conclusions TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910.)

A comparison of bare-metal and drug-eluting stents for off-label indications.

BACKGROUND Recent reports suggest that off-label use of drug-eluting stents is associated with an increased incidence of adverse events. Whether the use of bare-metal stents would yield different results is unknown. METHODS We analyzed data from 6551 patients in the National Heart, Lung, and Blood Institute Dynamic Registry according to whether they were treated with drug-eluting stents or bare-metal stents and whether use was standard or off-label. Patients were followed for 1 year for the occurrence of cardiovascular events and death. Off-label use was defined as use in restenotic lesions, lesions in a bypass graft, left main coronary artery disease, or ostial, bifurcated, or totally occluded lesions, as well as use in patients with a reference-vessel diameter of less than 2.5 mm or greater than 3.75 mm or a lesion length of more than 30 mm. RESULTS Off-label use occurred in 54.7% of all patients with bare-metal stents and 48.7% of patients with drug-eluting stents. As compared with patients with bare-metal stents, patients with drug-eluting stents had a higher prevalence of diabetes, hypertension, renal disease, previous percutaneous coronary intervention and coronary-artery bypass grafting, and multivessel coronary artery disease. One year after intervention, however, there were no significant differences in the adjusted risk of death or myocardial infarction in patients with drug-eluting stents as compared with those with bare-metal stents, whereas the risk of repeat revascularization was significantly lower among patients with drug-eluting stents. CONCLUSIONS Among patients with off-label indications, the use of drug-eluting stents was not associated with an increased risk of death or myocardial infarction but was associated with a lower rate of repeat revascularization at 1 year, as compared with bare-metal stents. These findings support the use of drug-eluting stents for off-label indications.

Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease ☆: Results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) Study

OBJECTIVES We sought to develop and validate a definition of coronary microvascular dysfunction in women with chest pain and no significant epicardial obstruction based on adenosine-induced changes in coronary flow velocity (i.e., coronary velocity reserve). BACKGROUND Chest pain is frequently not caused by fixed obstructive coronary artery disease (CAD) of large vessels in women. Coronary microvascular dysfunction is an alternative mechanism of chest pain that is more prevalent in women and is associated with attenuated coronary volumetric flow augmentation in response to hyperemic stimuli (i.e., abnormal coronary flow reserve). However, traditional assessment of coronary volumetric flow reserve is time-consuming and not uniformly available. METHODS As part of the Womens Ischemia Syndrome Evaluation (WISE) study, 48 women with chest pain and normal coronary arteries or minimal coronary luminal irregularities (mean stenosis = 7%) underwent assessment of coronary blood flow reserve and coronary flow velocity reserve. Blood flow responses to intracoronary adenosine were measured using intracoronary Doppler ultrasonography and quantitative angiography. RESULTS Coronary volumetric flow reserve correlated with coronary velocity reserve (Pearson correlation = 0.87, p < 0.001). In 29 (60%) women with abnormal coronary microcirculation (mean coronary flow reserve = 1.84), adenosine increased coronary velocity by 89% (p < 0.001) but did not change coronary cross-sectional area. In 19 (40%) women with normal microcirculation (mean flow reserve = 3.24), adenosine increased coronary velocity and area by 179% (p < 0.001) and 17% (p < 0.001), respectively. A coronary velocity reserve threshold of 2.24 provided the best balance between sensitivity and specificity (90% and 89%, respectively) for the diagnosis of microvascular dysfunction. In addition, failure of the epicardial coronary to dilate at least 9% was found to be a sensitive (79%) and specific (79%) surrogate marker of microvascular dysfunction. CONCLUSIONS Coronary flow velocity response to intracoronary adenosine characterizes coronary microvascular function in women with chest pain in the absence of obstructive CAD. Attenuated epicardial coronary dilation response to adenosine may be a surrogate marker of microvascular dysfunction in women with chest pain and no obstructive CAD.

Feasibility of Combined Percutaneous Transluminal Angioplasty and Minimally Invasive Direct Coronary Artery Bypass in Patients With Multivessel Coronary Artery Disease

BACKGROUND Angioplasty has become an accepted treatment of patients with coronary artery disease and is now commonly used to treat patients with multivessel disease. The major disadvantage of angioplasty has been restenosis requiring repeat interventions with resultant loss of initial cost savings. Compared with the right and the circumflex coronary arteries, the left anterior descending artery (LAD) has been more adversely affected by restenosis. Recently, minimally invasive direct coronary artery bypass (MIDCAB) to the LAD through a small left anterior thoracotomy using the left internal mammary artery has been performed in some centers with excellent early results and with reduced costs compared with standard bypass surgery. METHODS AND RESULTS We retrospectively reviewed the first 31 consecutive patients treated in our institution with integrated coronary revascularization (ICR): MIDCAB to the LAD combined with PTCA of the other diseased vessels in patients with multivessel disease. Postoperative angiography in 84% of patients revealed a patent anastomosis and normal flow in the graft and bypassed vessel. Thirty-eight (97%) of 39 vessels were successfully treated percutaneously. At a mean follow-up of 7 months, all patients are currently asymptomatic. There have been 2 adverse clinical events, both related to angioplasty and not to MIDCAB. The average length of stay at the hospital after MIDCAB was 2.79+/-1.05 days. CONCLUSIONS These preliminary results with ICR are encouraging and suggest that a randomized, prospective clinical trial comparing ICR with standard coronary artery bypass surgery for the revascularization of symptomatic patients with multivessel disease involving the LAD is warranted.

Impact of drug-eluting stents among insulin-treated diabetic patients: a report from the National Heart, Lung, and Blood Institute Dynamic Registry.

OBJECTIVES This study sought to evaluate the safety and efficacy of drug-eluting stents (DES) compared with bare-metal stents (BMS) in patients with insulin- and noninsulin-treated diabetes. BACKGROUND Diabetes is a powerful predictor of adverse events after percutaneous coronary interventions (PCI), and insulin-treated diabetic patients have worse outcomes. The DES are efficacious among patients with diabetes; however, their safety and efficacy, compared with BMS, among insulin-treated versus noninsulin-treated diabetic patients is not well established. METHODS Using the National Heart, Lung, and Blood Institute Dynamic Registry, we evaluated 1-year outcomes of insulin-treated (n = 817) and noninsulin-treated (n = 1,749) patients with diabetes who underwent PCI with DES versus BMS. RESULTS The use of DES, compared with BMS, was associated with a lower risk for repeat revascularization for both noninsulin-treated patients (adjusted hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.45 to 0.76) and insulin-treated subjects (adjusted HR = 0.63, 95% CI 0.44 to 0.90). With respect to safety in the overall diabetic population, DES use was associated with a reduction of death or myocardial infarction (adjusted HR = 0.75, 95% CI 0.58 to 0.96). However, this benefit was confined to the population of noninsulin-treated patients (adjusted HR = 0.57, 95% CI 0.41 to 0.81). Among insulin-treated patients, there was no difference in death or myocardial infarction risk between DES- and BMS-treated patients (adjusted HR = 0.95, 95% CI 0.65 to 1.39). CONCLUSIONS Drug-eluting stents are associated with lower risk for repeat revascularization compared with BMS in treating coronary artery disease among patients with either insulin- or noninsulin-treated diabetes. In addition, DES use is not associated with any significant increased safety risk compared with BMS. These findings suggest that DES should be the preferred strategy for diabetic patients.

Notch1 Promotes the Pro-Osteogenic Response of Human Aortic Valve Interstitial Cells via Modulation of ERK1/2 and Nuclear Factor-κB Activation

Objective—Calcific aortic valve disease is a leading cardiovascular disease in the elderly, and progressive calcification results in the failure of valvular function. Aortic valve interstitial cells (AVICs) from stenotic valves express higher levels of bone morphogenetic protein-2 in response to Toll-like receptor 4 stimulation. We recently found that Toll-like receptor 4 interacts with Notch1 in human AVICs. This study tests the hypothesis that Notch1 promotes the pro-osteogenic response of human AVICs. Approach and Results—AVICs isolated from diseased human valves expressed higher levels of bone morphogenetic protein-2 and alkaline phosphatase after lipopolysaccharide stimulation. The augmented pro-osteogenic response is associated with elevated cellular levels of Notch1 and enhanced Notch1 cleavage in response to lipopolysaccharide stimulation. Inhibition or silencing of Notch1 suppressed the pro-osteogenic response in diseased cells, and the Notch 1 ligand, Jagged1, enhanced the response in AVICs isolated from normal human valves. Interestingly, extracellular signal-regulated protein kinases 1/2 (ERK1/2) and nuclear factor-&kgr;B phosphorylation induced by lipopolysaccharide was markedly reduced by inhibition or silencing of Notch1 and enhanced by Jagged1. Inhibition of ERK1/2 or nuclear factor-&kgr;B also reduced bone morphogenetic protein-2 and alkaline phosphatase expression induced by lipopolysaccharide. Conclusions—Notch1 mediates the pro-osteogenic response to Toll-like receptor 4 stimulation in human AVICs. Elevated Notch1 levels and enhanced Notch1 activation play a major role in augmentation of the pro-osteogenic response of AVICs of stenotic valves through modulation of ERK1/2 and nuclear factor-&kgr;B activation. These pathways could be potential therapeutic targets for prevention of the progression of calcific aortic valve disease.

Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study)

BACKGROUND Optical coherence tomography (OCT) is a novel intravascular imaging modality with excellent spatial resolution. This study explored the utility of OCT in cardiac transplantation for the detection and characterization of early changes associated with coronary allograft vasculopathy (CAV). METHODS Fifteen consecutive patients, 1 to 4 years after transplant with no angiographic evidence of CAV, underwent successful OCT imaging using the Fourier-domain OCT system (C7-XR, St. Jude Medical, St. Paul, MN) in the left anterior descending artery. Analysis included measurements of the lumen, intima, and media layers, and characterization of atherosclerotic plaques. Patients were stratified by intima-to-media (I/M) ratio and classified as normal (≤1) or abnormal (>1). RESULTS Patients were a mean of 2.8 years after transplant, 58 years old, and 92% were men. OCT imaging revealed 8 of 15 patients had intimal hyperplasia with an I/M ratio >1. Comparing those with I/M ratio of ≤1 and >1, the median (interquartile range) intimal thickness was greater (75 [70-101] vs 206 [97-269]μm, p = 0.03), whereas the media thickness was no different (72 [70-103] vs 94 [73-113]μm, p = 0.53). In addition, 7 of 15 patients had lipid-rich or calcified atherosclerotic plaques. CONCLUSIONS OCT provides high-resolution quantitative imaging of the coronary arteries and its use allows for detailed assessment of the coronary artery wall and early morphologic changes that occur after cardiac transplantation. The clinical predictive value of these OCT-derived measurements remains to be determined.

Impact of Anemia on Platelet Response to Clopidogrel in Patients Undergoing Percutaneous Coronary Stenting

High residual platelet reactivity (HRPR) on clopidogrel is a predictor of recurrent ischemic events in patients undergoing percutaneous coronary interventions (PCI). Significant intraindividual variability in platelet aggregation on repeat testing has been reported. To understand factors contributing to the variability in platelet aggregation testing, we examined clinical and laboratory elements linked to HRPR in 255 consecutive patients tested ≥12 hours after PCI using light transmission aggregometry (LTA) in response to adenosine diphosphate 5 μmol/L and VerifyNow P2Y12 assay (VNP2Y12; Accumetrics). HRPR was defined as >46% residual aggregation for LTA and >236 P2Y12 response units (PRUs) for VNP2Y12. On multivariate analysis the only variable independently associated with HRPR with both LTA and VNP2Y12 was laboratory-defined anemia. Prevalences of HRPR by LTA were 34.3% in anemic patients, 15.6% in patients with normal hemoglobin levels, and 59.8% versus 25.9% by VNP2Y12 (p <0.005 for the 2 comparisons). In a subgroup of 50 patients, testing was done before and after the clopidogrel loading dose. At baseline there were no differences in platelet aggregation with either assay; however, absolute decrease in reactivity after the clopidogrel load was significantly less in anemic patients compared to patients with normal hemoglobin (change in residual aggregation by LTA 15.8 ± 5.8% vs 28.8 ± 3.2%, p <0.05; change in PRU by VNP2Y12 56.5 ± 35.5 vs 145.0 ± 14.2 PRUs, p <0.05, respectively). In conclusion, anemia is an important contributor to apparent HRPR on clopidogrel and may explain some of the intraindividual variability of platelet aggregation testing.

Practical Implementation of the Coronary Revascularization Heart Team

Multidisciplinary decision making has been shown to be highly effective in various aspects of medicine, most notably with the concept of tumor boards and transplant committees.1 ,2 The most updated guidelines for percutaneous coronary intervention (PCI), published jointly by the American College of Cardiology Foundation, American Heart Association, and the Society for Cardiovascular Angiography and Interventions, assign a class IC recommendation for the use of a collaborative Heart Team approach in the treatment of patients with complex coronary artery disease (CAD).3 The guidelines assert that this recommendation is based on retrospective analyses showing that patients with complex CAD referred for revascularization based on a Heart Team consensus have improved mortality compared with patients merely assigned to a particular strategy in the context of their trial enrollment. Despite the suggestion of improved mortality in this retrospective comparison, the Heart Team approach has not been adopted widely in the current clinical practice of cardiovascular medicine. This multidisciplinary innovation remains in its infancy, and numerous questions remain about its practicality, feasibility, and efficacy. For several reasons, there remains significant variability in the care delivered to patients with complex CAD.4 Numerous reports show that although differences in patient characteristics may explain some of the variability in revascularization decisions, much of this variance is physician driven, such as practicing in a fee-for-service model or high-risk anatomy for low-volume operators.4,5 As emphasis grows on informed decision making and patient-centered care, a critical evaluation of these difficult questions will be essential to discovering whether there is a clinically meaningful effect of the Heart Team approach on patients with complex CAD. Although the longstanding use of tumor boards in the field of oncology represents a functioning model of interdisciplinary care on which the Heart Team may be based, it is critical …

Assessing computational fractional flow reserve from optical coherence tomography in patients with intermediate coronary stenosis in the left anterior descending artery

Background—Intravascular optical coherence tomography (OCT) imaging provides limited information on the functional assessment of coronary stenosis. We evaluated a new approach to OCT image–based computation modeling, which can be used to estimate the fractional flow reserve (FFR) in patients with intermediate coronary stenosis. Methods and Results—Ninety-two patients with intermediate diameter stenosis in the left anterior descending artery underwent both FFR measurement with pressure wires and OCT examination. Using the OCT data, a computational fluid dynamics algorithm was used to calculate the computational FFR (FFROCT). The diagnostic performance of the FFROCT was assessed based on the pressure wire–based FFR. The median FFR and FFROCT values were 0.86 (0.79–0.89) and 0.89 (0.82–0.94), respectively. The average diameter stenosis in quantitative coronary angiography and area stenosis in OCT were 58.1±13.4% and 67.5±13.5%, respectively. The FFROCT was better correlated to the FFR than were the anatomic variables (r=0.72; P<0.001 versus r=0.46; P<0.001 for minimal luminal diameter on quantitative coronary angiography or r=0.57; P<0.001 for minimal lumen area on OCT). When functionally significant stenosis was defined as an FFR cutoff value of ⩽0.8, FFROCT resulted in 88.0% accuracy, 68.7% sensitivity, and 95.6% specificity. The positive and negative predictive values were 84.2% and 89.0%, respectively. Conclusions—The computation of FFROCT enables assessment not only of anatomic information, but also of the functional significance of intermediate stenosis. This measurement may be a useful approach for the simultaneous evaluation of the functional and anatomic severity of coronary stenosis.