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3D printing is a fabrication technique used to transform digital objects into physical models, which builds structures of arbitrary geometry by depositing material in successive layers on the basis of specific digital design. Even though, the use of 3D bioprinting in cardiovascular medicine is relatively new development, advancement within this discipline is occurring at such a rapid rate. Most cardiologists believed the costs would be too high for routine use such that the price tag was better for academic applications.
Now as the prices are starting to lower, the idea of using 3D printed models of organs vessels and tissue manufactured based on CT, MRI and echocardiography might be beneficial according to Dr. Fadi Matar, professor at University of South Florida. He and his cardiology colleagues use 3D printed models to allow them to view patient’s complex anatomies before deciding what treatments to pursue. The models allow them to calculate the size and exact placement of devices which has led to shorter procedure time and better outcome.
In a study published in Academic Radiology, David Ballard, professor at University School of Medicine appraised the costs of setting up a 3D printing lab including the commercial printer plus software, lab space, materials and staffing. According to Ballard’s team, the commercial printers start at $12,000 but can be as high as high as $500,000.
According to American Medical Association-approved Category III Current Procedural Terminology (CPT) codes allows cardiology relief from setting up a new 3D printing lab such as Codes 0559T and 0560T, for individually prepared 3D-printed anatomical models with one or more components (including arteries and veins) and Codes 0561T and 0562T, which are for the production of personalized 3D-printed cutting or drilling tools that use patient imaging data and often are used to guide or facilitate surgery.
These codes have been met with enthusiasm by teams eyeing 3D printing, but there are noteworthy limitations to Category III codes—which are temporary codes describing emerging technologies, services and procedures that are used for tracking effectiveness data. It is important to note that Category III codes are not reimbursed but often are a step toward reimbursement.
New and improved materials also might lead to a sharper focus on 3D printing in cardiology. Dr. Fadi Matar says companies are working on materials that better mimic elements of the heart. Such “mimicry” ought to enhance the value of 3D-printed models since they will give cardiologists more realistic insights into how specific devices will interact with an individual patient’s heart. Even with the complex modalities of using 3D bioprinting, in time there would be less obstacles to being able to set up a 3D bioprinter lab.
The Cost to Value Conundrum in Cardiovascular Healthcare Provision
Author: Larry H. Bernstein, MD, FCAP
I write this introduction to Volume 2 of the e-series on Cardiovascular Diseases, which curates the basic structure and physiology of the heart, the vasculature, and related structures, e.g., the kidney, with respect to:
1. Pathogenesis
2. Diagnosis
3. Treatment
Curation is an introductory portion to Volume Two, which is necessary to introduce the methodological design used to create the following articles. More needs not to be discussed about the methodology, which will become clear, if only that the content curated is changing based on success or failure of both diagnostic and treatment technology availability, as well as the systems needed to support the ongoing advances. Curation requires:
meaningful selection,
enrichment, and
sharing combining sources and
creation of new synnthesis
Curators have to create a new perspective or idea on top of the existing media which supports the content in the original. The curator has to select from the myriad upon myriad options available, to re-share and critically view the work. A search can be overwhelming in size of the output, but the curator has to successfully pluck the best material straight out of that noise.
Part 1 is a highly important treatment that is not technological, but about the system now outdated to support our healthcare system, the most technolog-ically advanced in the world, with major problems in the availability of care related to economic disparities. It is not about technology, per se, but about how we allocate healthcare resources, about individuals’ roles in a not full list of lifestyle maintenance options for self-care, and about the important advances emerging out of the Affordable Care Act (ACA), impacting enormously on Medicaid, which depends on state-level acceptance, on community hospital, ambulatory, and home-care or hospice restructuring, which includes the reduction of management overhead by the formation of regional healthcare alliances, the incorporation of physicians into hospital-based practices (with the hospital collecting and distributing the Part B reimbursement to the physician, with “performance-based” targets for privileges and payment – essential to the success of an Accountable Care Organization (AC)). One problem that ACA has definitively address is the elimination of the exclusion of patients based on preconditions. One problem that has been left unresolved is the continuing existence of private policies that meet financial capabilities of the contract to provide, but which provide little value to the “purchaser” of care. This is a holdout that persists in for-profit managed care as an option. A physician response to the new system of care, largely fostered by a refusal to accept Medicaid, is the formation of direct physician-patient contracted care without an intermediary.
In this respect, the problem is not simple, but is resolvable. A proposal for improved economic stability has been prepared by Edward Ingram. A concern for American families and businesses is substantially addressed in a macroeconomic design concept, so that financial services like housing, government, and business finance, savings and pensions, boosting confidence at every level giving everyone a better chance of success in planning their personal savings and lifetime and business finances.
Part 2 is a collection of scientific articles on the current advances in cardiac care by the best trained physicians the world has known, with mastery of the most advanced vascular instrumentation for medical or surgical interventions, the latest diagnostic ultrasound and imaging tools that are becoming outdated before the useful lifetime of the capital investment has been completed. If we tie together Part 1 and Part 2, there is ample room for considering clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go. Why should this be? Because for generations of IT support systems, they are historically focused on billing and have made insignificant inroads into the front-end needs of the clinical staff.
MicroRNA in Serum as Biomarker for Cardiovascular Pathologies: acute myocardial infarction, viral myocarditis, diastolic dysfunction, and acute heart failure
Reporter: Aviva Lev-Ari, PhD, RN
Increased MicroRNA-1 and MicroRNA-133a Levels in Serum of Patients With Cardiovascular Disease Indicate Myocardial Damage
From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Y. Kuwabara, K.O., T.H., H.N., K.N., M.K., S.W., O.B., Y. Kojima, S.S., M.I., T.T., T. Kimura); and Kobe City Medical Center General Hospital, Kobe, Japan (T. Kita).
Correspondence to Koh Ono, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawahara-cho, Sakyo-ku, Kyoto, Japan 606-8507. E-mail kohono@kuhp.kyoto-u.ac.jp
Abstract
Background—Recently, elevation of circulating muscle-specific microRNA (miRNA) levels has been reported in patients with acute myocardial infarction. However, it is still unclear from which part of the myocardium or under what conditions miRNAs are released into circulating blood. The purpose of this study was to identify the source of elevated levels of circulating miRNAs and their function in cardiovascular diseases.
Conclusions—These results suggest that elevated levels of circulating miRNA-133a in patients with cardiovascular diseases originate mainly from the injured myocardium. Circulating miR-133a can be used as a marker for cardiomyocytedeath, and it may have functions in cardiovascular diseases.
Ischemic Stable CAD: Medical Therapy and PCI no difference in End Point: Meta-Analysis of Contemporary Randomized Clinical Trials
Reporter: Aviva Lev-Ari, PhD, RN
SOURCE
Stergiopoulos K, Boden WE, Hartigan P, et al. Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: A collaborative meta-analysis of contemporary randomized clinical trials. JAMA Intern Med 2013; DOI:10.1001/jamainternmed.2013.12855. Available at:http://www.jamainternalmedicine.com.
NEW YORK, NY — A new analysis is calling into question the de facto rationale for many of the revascularization procedures taking place today, at least in patients with stable coronary artery disease[1]. In a meta-analysis of more than 5000 patients, PCI was no better than medical therapy in patients with documented ischemia by stress testing or fractional flow reserve (FFR).
“Cardiology has a long history of finding a marker of a bad outcome and treating that marker of that bad outcome as if it were the cause of the bad outcome,” senior author on the study, Dr David Brown (State University of New York [SUNY]–Stony Brook School of Medicine), told heartwire. In the case of proceeding to PCI on the basis of documented ischemia, that stems from evidence that patients with ischemia have a worse prognosis than patients who don’t.”It has gotten to the point that a positive stress test [is the gateway] to doing an intervention, even if the ischemia is not in the same ischemic territory as the vessel being treated,” he said. “The medical/industrial complex in cardiology is now focused on finding and treating ischemia, and I think that’s not justified, and these data suggest that that’s not justified.”
Brown and colleagues, with first author Dr Kathleen Stergiopoulus (SUNY–Stony Brook School of Medicine), reviewed the literature for randomized clinical trials of PCI and medical therapy for stable CAD conducted over the past 40 years, ultimately including five trials of 5286 patients. These were a small German trial published in 2004, plus MASS II, COURAGE,BARI 2D, and FAME 2. In all, 4064 patients had myocardial ischemia documented by exercise, nuclear or echo stress imaging, or FFR.
Over a median follow-up of five years, mortality, nonfatal MI, unplanned revascularization, and angina were no different between patients treated medically vs those treated with PCI.
Odds Ratio, PCI vs Medical Therapy
Outcome
Odds ratio
95% CI
Death
0.90
0.71–1.16
Nonfatal MI
1.24
0.99–1.56
Unplanned revascularization
0.64
0.35–1.17
Angina
0.91
0.57–1.44
“These findings are unique in that this is the first meta-analysis to our knowledge limited to patients with documented, objective findings of myocardial ischemia, almost all of whom underwent treatment with intracoronary stents and disease-modifying secondary-prevention therapy,” Stergiopoulus et al write.
The findings, they continue, “strongly suggest that the relationship between ischemia and mortality is not altered or ameliorated by catheter-based revascularization of obstructive, flow-limiting coronary stenosis.”
To heartwire, Brown pointed out that their analysis could not separate out patients who had small amounts of ischemia from those with larger ischemic territories. “Maybe that’s where the differentiating factor will be,” he acknowledged, adding that the 8000-patient ISCHEMIAtrial, still ongoing, will hopefully yield some insights.
Current practice, however, is to check for ischemia and to proceed with catheterization and, usually, revascularization when ischemia is confirmed by stress testing or during FFR. “But if that doesn’t improve outcomes, why are we doing it?” Brown asked. “We think that needs to be rethought.”
Commenting on the study for heartwire, Dr Peter Berger(Geisinger Health System, Danville, PA) pointed out: “There is no question that PCI is more effective than medical therapy for relief of symptoms: the more severe the angina and the more active the patient, the greater the superiority of PCI.” And, as Berger noted, most of the studies included in this analysis documented ischemia but did not report on the frequency or severity of angina at baseline.
That said, “Patients with minimal angina—and certainly those with silent ischemia but no angina—are unlikely to have a significantly greater reduction of symptoms with PCI, and PCI is rarely beneficial in such patients.”
Moreover, Berger continued, it has been clearly established that PCI does not reduce the risk of death or MI in most such patients.
“I very much agree with the authors, however, that just because more severe ischemia has been shown to be associated with a worse long-term prognosis, reducing the ischemic burden ought not be assumed to reduce the likelihood of death or MI. In most such patients, it does not.”
Stergiopoulos and Brown had no disclosures. Disclosures for the coauthors are listed in the paper.
Intracoronary Transplantation of Progenitor Cells after Acute MI
Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Transcoronary Transplantation of Progenitor Cells after Myocardial Infarction
Birgit Assmus, M.D., Jörg Honold, M.D., Volker Schächinger, M.D., Martina B. Britten, M.D., Ulrich Fischer-Rasokat, M.D., et al.
From the Division of Cardiology and Molecular Cardiology, Department of Medicine III (B.A., J.H., V.S., M.B.B., U.F.-R., R.L., C.T., K.P., S.D., A.M.Z.), Division of Hematology, Department of Medicine II (H.M.), and the Department of Diagnostic and Interventional Radiology (N.D.A.), Johann Wolfgang Goethe University; and the Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service, Baden–Württem-berg–Hessen (T.T.) — both in Frankfurt, Germany.
N Engl J Med 2006;355:1222-32.
Background
Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown.
METHODS
After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myocardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients)into the patent coronary artery supplying the most dyskinetic left ventricular area. The patients in the control group were
subsequently randomly assigned to receive CPC or BMC, and
the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months’ follow-up.
RESULTS
The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (−0.4 percentage point, P = 0.003) or no infusion (−1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly
enhanced regional contractility in the area targeted by intracoronary infusion of BMC.
The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular function, regardless of whether patients crossed over from control to BMC or from CPC to BMC.
CONCLUSIONS
Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months. (ClinicalTrials.gov number, NCT00289822.)
Introduction
HRONIC HEART FAILURE IS COMMON, and its prevalence continues to increase.1 Ischemic heart disease is the principal cause of heart failure.2 Although myocardial salvage due to early reperfusion therapy has significantly reduced early mortality rates,3
postinfarction heart failure resulting from ventricular remodeling remains a problem.4
One possible approach to reversing postinfarction heart failure is
enhancement of the regeneration of cardiac myocytes as well as
stimulation of neovascularization within the infarcted area.
Initial clinical pilot studies have suggested that
intracoronary infusion of progenitor cells is feasible and may
beneficially affect postinfarction remodeling processes in patients with acute myocardial infarction.5-9
However, it is currently unknown whether such a treatment strategy may also be associated with
improvements in cardiac function in patients with persistent left ventricular dysfunction due to healed myocardial infarction with established scar formation.
Therefore, in the prospective TOPCARE-CHD (Transplantation of Progenitor Cells and Recovery of LV [Left Ventricular] Function in Patients with Chronic Ischemic Heart Disease) trial, we investigated
whether intracoronary infusion of progenitor cells into the infarct-related artery at least 3 months after myocardial infarction improves global and regional left ventricular function.
Patient Outcome Criteria
The primary end point of the study was the absolute change in global left ventricular ejection fraction (LVEF)as measured by quantitative left ventricular angiography 3 months after cell infusion. Secondary end points included quantitative variables relating to the regional left ventricular function of the target area, as well as left ventricular volumes derived from serial left ventricular angiograms. In addition, functional status was assessed by NYHA classification. Finally, event-free survivalwas defined as freedom from death, myocardial infarction, stroke, or rehospitalization for worsening heart failure. Causes of rehospitalization during follow-up were verified by review of the discharge letters or charts of hospital stays.
All patients underwent low-dose dobutamine stress echocardiography, combined thallium single-photon-emission computed tomography and [18F]fluorodeoxyglucose positron-emission tomography, or both, as previously described.6 It was possible to analyze regional left ventricular viability in 80 patients (87%).
RESULTS
BASELINE CHARACTERISTICS OF THE PATIENTS
A total of 92 patients were enrolled in the study. Of these, 35 patients received BMC as their initial treatment (in phases 1 and 2 of the trial), 34 patients received CPC (in phases 1 and 2), and 23 patients received no intracoronary cell infusion (in phase 2, as the control group). Table 1 illustrates that the three groups of patients were well matched.
Patients with an adverse clinical event (six), subtotal stenosis of the target vessel at follow-up (three), an intraventricular thrombus precluding performance of left ventricular angiography (one), or atrial flutter or fibrillation at follow-up (one) were excluded from the exploratory analysis. In addition, of the 81 eligible patients, left ventricular angiograms could not be quantitatively analyzed in 4 because of inadequate contrast opaci-fication, in 1 because of ventricular extrasystoles, and in 4 because of the patients’ refusal to undergo invasive follow-up. Thus, a total of 72 of 81 serial paired left ventricular angiograms were available for quantitative analysis (28 in the BMC group, 26 in the CPC group, and 18 in the control group).
Table 2 summarizes the angiographic characteristics of the 75 patients included in the randomized phase of the study. At baseline, the three groups did not differ with respect to global LVEF, the extent or magnitude of regional left ventricular dysfunction, left ventricular volumes, or stroke volumes.
The absolute change in global LVEF from baseline to 3 months did significantly differ among the three groups of patients. Patients receiving BMC had a significantly larger change in LVEF than patients receiving CPC (P = 0.003) and those in the control group (P<0.001). Similar results were obtained when patients from the first two phases of the study (the pilot phase and the randomized phase) were pooled. The results did not differ when patients without evidence of viable myocardium before inclusion were analyzed separately. The change in LVEF was −0.3±3.4 percentage points in the control group (9 patients), +0.4±3.0 percentage points in the CPC group (18 patients), and +3.7±4.0 percentage points in the BMC group (18 patients) (P = 0.02 for the comparison with the control group and P = 0.02 for the comparison with the CPC group).
In the subgroup of 35 patients who underwent serial assessment of left ventricular function by MRI, MRI-derived global LVEF increased significantly, by 4.8±6.0% (P = 0.03) among those receiving BMC (11 patients) and by 2.8±5.2% (P = 0.02) among those receiving CPC (20 patients), whereas no change was observed in 4 control patients (P = 0.14). Thus, MRI-derived assessment of left ventricular function further corroborated the results obtained from the total patient population.
Analysis of regional left ventricular function revealed that BMC treatment significantly increased contractility in the center of the left ventricular target area (Table 2). Likewise, MRI-derived regional analysis of left ventricular function revealed that the number of hypocontractile segments was significantly reduced, from 10.1±3.6 to 8.7±3.6 segments (P = 0.02), and the number of normocontractile segments significantly increased, from 3.8±4.5 to 5.4±4.6 segments (P = 0.01), in the BMC group, whereas no significant changes were observed in the CPC group. MRI-derived infarct size, as measured by late enhancement volume normalized to left ventricular mass, remained constant both in the CPC group (25± 18% at baseline and 23±14% at 3 months,13 patients) and in the BMC group (20±10% at both time points, 9 patients). Thus, taken together, the data suggest that intracoronary infusion of BMC is associated with significant improvements in global and regional left ventricular contractile function among patients with persistent left ventricular dysfunction due to prior myocardial infarction.
To identify independent predictors of improved global LVEF, a stepwise multivariate regression analysis was performed; it included classic determinants of LVEF as well as various baseline characteristics of the three groups (Table 3). The multivariate analysis identified the type of progenitor cell infused and the baseline stroke volume as the only statistically significant independent predictors of LVEF recovery.
Functional Status
The functional status of the patients, as assessed by NYHA classification, improved significantly in the BMC group (from 2.23±0.6 to 1.97±0.7, P = 0.005). It did not improve significantly either in the CPC group (class, 2.16±0.8 at baseline and 1.93±0.8 at 3 months; P = 0.13) or in the control group (class, 1.91±0.7 and 2.09±0.9, respectively; P = 0.27).
RANDOMIZED CROSSOVER PHASE
Of the 24 patients who initially were randomly assigned to CPC infusion, 21 received BMC at the time of their first follow-up examination. Likewise, of the 28 patients who initially were randomly assigned to BMC infusion,
24 received CPC after 3 months.
Of the 23 patients of the control group, 10 patients received CPC and 11 received BMC at their reexamination at 3 months (Fig. 1). As illustrated in Figure 2, regardless of whether patients received BMC as initial treatment, as crossover treatment after CPC infusion, or as crossover treatment after no cell infusion,
global LVEF increased significantly after infusion of BMC. In contrast,
CPC treatment did not significantly alter LVEF when given either before or after BMC.
Thus, the intrapatient comparison of the different treatment strategies not only documents the superiority of intracoronary infusion of BMC over the infusion of CPC for improving global left ventricular function, but also corroborates our findings in the analysis of data according to initial treatment assignment. The
preserved improvement in cardiac function observed among patients who initially received BMC treatment and
then crossed over to CPC treatment demonstrates that the initially achieved differences in cardiac function persisted for at least 6 months after intracoronary infusion of BMC.
Table 1. Baseline Characteristics of the Patients.* (not copied)
Table 2. Quantitative Variables Pertaining to Left Ventricular Function, as Assessed by Left Ventricular Angiography.*
copy protected
Figure 2. Absolute Change in Quantitative Global Left Ventricular Ejection Fraction (LVEF) during the Crossover Phase of the Trial.
Data at 3 and 6 months are shown for all patients crossing over from BMC to CPC infusion (18 patients), from CPC to BMC infusion
(18 patients), and from no cell infusion to either CPC infusion (10 patients) or BMC infusion (11 patients). I bars represent standard
errors.
Table 3. Stepwise Linear Regression Analysis for Predictors of Improvement in Global Left Ventricular Ejection Fraction.*
Variable
Nonstandardized Coefficient B
95% CI for B
P Value
Treatment group
1.49
0.53 to 2.46
0.003
Baseline stroke volume
−0.13
−0.22 to –0.05
0.002
No. of cardiovascular risk factors
0.76
Time since most recent MI
0.48
Concomitant PCI
0.60
Age
0.82
Baseline ejection fraction
0.72
Baseline end-diastolic volume
0.88
* Values are shown only for significant differences. MI denotes myocardial infarction, and PCI percutaneous coronary intervention. For the overall model, the adjusted R2 was 0.29; P<0.001 by analysis of variance.
DISCUSSION
Intrapatient comparison in the crossover phase of the trial rules out the possibility that differences in the patient populations studied may have affected outcomes. However, the mechanisms involved in mediating improved contractile function after intracoronary progenitor-cell infusion are not well understood.
Experimentally, although there is no definitive proof that cardiac myocytes may be regenerated, BMC were shown to contribute to functional recovery of left ventricular contraction when injected into freshly infarcted hearts,13-15 whereas CPC profoundly stimulated ischemia-induced neovascularization.16,17 Both cell types were shown to prevent cardiomyocyte apoptosis and reduce the development of myocardial fibrosis and thereby improve cardiac function after acute myocardial infarction.18,19 Indeed, in our TOPCARE-AMI (Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction) studies,6,7,9intracoronary infusion of CPC was associated with functional improvements similar to those found with the use of BMC immediately after myocardial infarction. In the current study, however, which involved patients who had had a myocardial infarction at least 3 months before therapy,
transcoronary administration of CPC was significantly inferior to administration of BMC in altering global left ventricular function.
CPC obtained from patients with chronic ischemic heart disease show profound functional impairments,20,21 which might limit their recruitment, after intracoronary infusion, into chronically reperfused scar tissue many months or years after myocardial infarction. Thus, additional studies in which larger numbers of functionally enhanced CPC are used will be required to increase the response to intracoronary infusion of CPC.
The magnitude of the improvement after in-tracoronary infusion of BMC, with absolute increases in global LVEF of approximately 2.9 percentage points according to left ventricular angiography and 4.8 percentage points according to MRI, was modest. However, it should be noted that the improvement in LVEF occurred in the setting of full conventional pharmacologic treatment: more than 90% of the patients were receiving beta-blocker and angiotensin-convert-ing–enzyme inhibitor treatment. Moreover, results from trials of contemporary reperfusion for the treatment of acute myocardial infarction, which is regarded as the most effective treatment strategy for improving left ventricular contractile performance after ischemic injury, have reported increases in global LVEF of 2.8% (in the CADILLAC [Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications] trial) and 4.1% (in the ADMIRAL [Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up] trial).22,23
The number of patients, as well as the duration of follow-up, is not sufficient to address the question of whether the moderate improvement in LVEF associated with one-time intracoronary BMC infusion is associated with reduced mortality and morbidity among patients with heart failure secondary to previous myocardial infarction. We conclude that intracoronary infusion of BMC is associated with persistent improvements in regional and global left ventricular function and improved functional status among patients who have had a myocardial infarction at least 3 months previously. Given the reasonable short-term safety profile of this therapeutic approach, studies on a larger scale are warranted to examine its potential effects on morbidity and mortality among patients with postinfarction heart failure.
REFERENCES (1-8/23)
2001 Heart and stroke statistical update. Dallas: American Heart Association, 2000.
Braunwald E. Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360-9.
Lange RA, Hillis LD. Reperfusion therapy in acute myocardial infarction. N Engl J Med 2002;346:954-5.
Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981-8.
Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913-8.
Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 2002;106:3009-17.
Britten MB, Abolmaali ND, Assmus B, et al. Infarct remodeling after intra-coronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003;108: 2212-8.
Wollert KC, Meyer GP, Lotz J, et al. In-tracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-8.
Three-Dimensional Fibroblast Matrix Improves Left Ventricular Function post MI
Curators: Larry H. Bernstein, MD. FCAP and Aviva Lev-Ari, PhD, RN
Implantation of a Three-Dimensional Fibroblast Matrix Improves Left Ventricular Function and Blood Flow After Acute Myocardial Infarction
Hoang M. Thai*, Elizabeth Juneman*, Jordan Lancaster*, Tracy Hagerty*, Rose Do*, Lisa Castellano*, Robert Kellar†, Stuart Williams†, Gulshan Sethi*, Monika Schmelz*, Mohamed Gaballa*,†, and Steven Goldman* *Section of Cardiology, Department of Medicine and Pathology, Southern Arizona VA Health Care System, Sarver Heart Center, University of Arizona, Tucson, AZ, †Theregen Inc., San Francisco, CA
This study was designed to determine if a viable biodegradable three-dimensional fibroblast construct (3DFC) patch implanted on the left ventricle after myocardial infarction (MI) improves left ventricular (LV) function and blood flow. We ligated the left coronary artery of adult male Sprague-Dawley rats and implanted the 3DFC at the time of the infarct. Three weeks after MI, the 3DFC improved LV systolic function by increasing (p < 0.05) ejection fraction (37 ± 3% to 62 ± 5%), increasing regional systolic displacement of the infarcted wall (0.04 ± 0.02 to 0.11 ± 0.03 cm), and shifting the passive LV diastolic pressure volume relationship toward the pressure axis. The 3FDC improved LV remodeling by decreasing (p < 0.05) LV end-systolic and end-diastolic diameters with no change in LV systolic pressure. The 3DFC did not change LV end-diastolic pressure (LV EDP; 25 ± 2 vs. 23 ± 2 mmHg) but the addition of captopril (2mg/L drinking water) lowered (p < 0.05) LV EDP to 12.9 ± 2.5 mmHg and shifted the pressure–volume relationship toward the pressure axis and decreased (p < 0.05) the LV operating end-diastolic volume from 0.49 ± 0.02 to 0.34 ± 0.03 ml. The 3DFC increased myocardial blood flow to the infarcted anterior wall after MI over threefold (p < 0.05). This biodegradable 3DFC patch improves LV function and myocardial blood flow 3 weeks after MI. This is a potentially new approach to cell-based therapy for heart failure after MI.
Three-Dimensional Fibroblast Patch
Our hypothesis is that the lack of survival of new cells directly injected into the heart is related, in part, to an inadequate blood supply and inadequate matrix support for the new cells. The injected cells are fragile, resulting in cell aggregation due to lack of physical support for the cells to attach to the tissue extracellular matrix. This three-dimensional scaffold offers a potential solution to the problem of an inadequate support structure. While injection of passive materials has been proposed to improve EF potentially by decreasing wall stress (11,35), the 3DFC provides a viable cell matrix that supports new blood vessel growth (15,16). This viable cellular matrix is important because in addition to providing a new support structure for the damaged heart, we also need to create a mature blood supply such that new viable cardiac muscle can be organized in parallel forming physical and neural connections that will conduct electrical signals and create synchronized contractions. Investigators have proposed that the ideal scaffold structure for the heart would consist mainly of highly interconnected pores with a diameter of at least 200 µm, the average size of a capillary, to permit blood vessel penetration and cell interactions (5).
The 3DFC is a viable construct composed of a matrix embedded with human newborn dermal fibroblasts cultured in vitro onto a bioabsorbable mesh to produce living, metabolically active tissue (15,16) (see Fig. 1 and Fig 2). As the fibroblasts proliferate across the mesh, they secrete human dermal collagen, fibronectin, and glycosaminoglycans (GAGs), embedding themselves in a self-produced dermal matrix. The fibroblast cells produce angiogenic growth factors: vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and angiopoietin-1. The construct is grown in medium supplemented with serum and ascorbate; at harvest, the medium is replaced with a 10% DMSO-based cryoprotectant, the tissue is frozen and stored at −70°C. This cryopreservation and rewarming technique has been extensively studied to ensure viability of the patch. Although the mechanisms of action of the 3DFC are not completely understood, new blood vessel growth has been documented previously in SCID mice (15).
Previous work using the 3DFC as a patch for the infarcted heart in SCID mice showed histological evidence of new blood vessel growth and improvements in global LV function using a conductance catheter (16). Our data show increases in myocardial blood flow in the infarcted heart, confirming that these blood vessels are functional and that they connect to the native myocardium. We used echocardiography to document improvements in global and regional LV function. The improvements in regional LV function are important because recent work suggests that the injection of passive materials alone may be enough to reduce wall stress and increase global EF (35). In order to prove that cell-based therapy is affecting more than a passive response, the point has been made that it is necessary to be able to define regional changes in the area of the infarcted myocardium (11). We have done this using echocardiography to document that the 3DFC increases systolic displacement of the infarcted regional anterior wall (Fig. 5). Although the mechanism of action of the 3DFC has not been completely delineated, the viable fibroblasts secrete a number of growth factors, thus providing a paracrine effect to stimulate new blood vessel growth. The vicryl mesh is biodegradable such that, with dissolution, the new blood vessel growth is in the previously damaged myocardium. The most likely explanation for the improvements in regional systolic displacement of the anterior wall is that the increases in myocardial blood flow in the border zone results in recruitment of hibernating or stunned cardiac myocytes.
The fact that the 3DFC is viable with fibroblasts implanted on a mesh is important. There are data showing that inert biodegradable patches are beneficial in treating heart failure. In our laboratory we have shown that an inert biodegradable collagen patch placed on the rat heart after a nontransmural MI improves LV function and prevents adverse LV remodeling (10). There are clinical trials with a collagen type 1 matrix seeded with autologous bone marrow cells in patients undergoing coronary artery bypass surgery (4). The best known implanted mechanical constraint device is the Acorn Corp Cap device; it decreases LV size but does not cause constrictive physiology (22). There are no blood flow studies with the Acorn device. There is a recent report using an inert biodegradable polyester urethane cardiac patch applied to rats 2 weeks after coronary ligation where the LV cavity size does not change but fractional area change increases and compliance improves; there are no blood flow data in this report (6).
Application of a Patch as an Alternative to Direct Cell Injection
The use of a biodegradable patch that provides a support structure allowing new cells to attach and grow in a damaged heart is a possible alternative to the current approach of direct cell injection for cell-based therapy. Not only are the results from current clinical trials of cell-based therapy disappointing, the approach used in these trials is cumbersome, requiring harvesting bone marrow and a repeat cardiac catheterization with infarct artery reocclusion to reinject purified autologous mononuclear cells into the coronary arteries. Another problem is the recent report that intracoronary delivery of bone marrow cells results in damage to the coronary artery with luminal loss in the infarct related artery (20). These data suggest that we need new options for cell-based therapy for heart failure.
The translational aspect of this work is important; there is potential for clinical application of this 3DFC patch. At present there are two ongoing phase I clinical trials using the 3DFC; the first is a pilot trial in patients applying the 3DFC patch at the time of coronary artery bypass surgery when the surgeon cannot place a graft to a area of viable myocardium. This trial is designed to determine if the 3DFC increases myocardial perfusion to an area that the surgeon could not graft. While in this clinical study the 3DFC patch is placed with the chest open, two cases have been done with a minimally invasive approach using a modified video-assisted thorascopic surgery VATS procedure. The second trial is in patients getting a left ventricular assist device (LVAD). The 3DFC is applied at the time of LVAD placement and, upon LVAD removal, histology is done on the area of 3DFC placement in order to examine for evidence of angiogenesis.
Summary
We report improvements in myocardial blood flow, regional and global LV function, and partial reversal of LV remodeling using a viable three-dimensional fibroblast patch implanted in rats at the time of an acute MI. This patch provides a support structure that allows cells to grow into the damaged heart and creates new blood vessel growth, resulting in improved blood flow. With the limited success of direct cell injection into the heart, the 3DFC represents a new approach to cell-based therapy for heart failure.
Figures
Figure 1. Scanning electron micrograph of the 3DFC patch.
The vicryl fibers are “tube-like” structures. The fibroblasts look like irregular structures with long appendages that span from one vicryl fiber to another.
Figure 2.
(A) Three-dimensional fibroblast culture (3DFC) prior to implantation; the suture in the middle of the patch is used to attach the 3DFC to the left ventricle. (B) 3DFC at the time of implantation on the infarcted left ventricle. (C) 3DFC at 3 weeks after myocardial infarction. Note that the 3DFC is well integrated and attached to the infarcted wall. (D) 3DFC in a perfused heart preparation at 3 weeks after myocardial infarction. As note above, the 3DFC is well integrated into the infarcted wall and the suture is easily visible.
Figure 3.
Echocardiographic measured ejection fraction (EF) in sham, myocardial infarction (MI), MI + 3DFC, MI + 3DFC/Cap (captopril), and MI + 3DFC/NV (nonviable). Note that the viable 3DFC increased the EF. The EF remained increased with the addition of captopril to the viable 3DFC; the nonviable 3DFC did not improve EF. Values are mean ± SE. Sham (N = 5); MI (N = 8); MI + 3DFC/cap (N = 10); MI + 3DFC (N = 14); MI + 3DFC (nonviable) (N = 5). *p < 0.05 sham versus all groups; **p < 0.05 MI and MI + 3DFC/NV versus MI + 3DFC/cap and MI + 3DFC.
Figure 4.
Echocardiographic measured systolic displacement of the infarcted anterior wall in sham, myocardial infarction (MI), and MI + 3DFC. Note that the 3DFC improved EF back toward the normal value. Values are mean ± SE. Sham (N = 6); MI (N = 12); MI + 3DFC (N = 15); MI + NV 3DFC (N = 12). *p < 0.05 versus MI; **p < 0.05 versus MI.
Figure 5.
Echocardiographic measured LV end-diastolic and end-systolic diameters in sham, myocardial infarction (MI), and MI + 3DFC. Note that both the LV end-diastolic diameter and end-systolic diameters decrease with the 3 DFC. Values are mean ± SE. Sham (N=6); MI (N=12); MI + 3DFC (N=15); MI + NV 3DFC, (N=12). *p < 0.05 versus sham; **p < 0.05 versus MI.
Figure 6.
Pressure–volume (PV) loops in sham, myocardial infarction (MI), MI + 3DFC, and MI + 3DFC/ captopril. Note that the major shift in the PV loop was with the addition of captopril where the operating LV end-diastolic volume decreased.
Figure 7.
Anterior wall myocardial blood flow in sham (N = 11), at the time of acute myocardial infarction (MI, N = 7), MI at 3 weeks (N = 4), and MI at 3 weeks with 3DFC (N = 4). Note that the 3DFC improved blood flow in the infarcted wall. Values are mean ± SE; *p < 0.05 versus baseline and MI (3w) + 3DFC.
Figure 8
Vessel density defined by Factor VIII staining. Note the increase in vessel density in the area with the 3DFC compared to the untreated myocardial infarction (MI). MI (N = 9), MI + 3DFC (N = 8). Values are mean ± SE. *p < 0.05 versus MI.
Figure 9.
Histopathology sections of Factor VIII staining in MI + 3DFC (A–C) and MI alone (4× and 40×). Note the increased in Factor VIII staining and vessel density with the 3DFC.
Office Manager; Technical Director, Ultrasound at Line Medical
It’s impossible.
There are large variations in quality of ultrasound systems. There are also large variations in skill levels of operators. And those skill levels change over time. But the most detrimental factor is that the human body is a dynamic and unique system. Some subjects are technically difficult and LV function is basically impossible to assess, even with an excellent US system. Measurement of LVPWiD is a guess on these patients. Then there are subjects on whom you can obtain excellent images at intercostal space #2, #3, and #4. And the anatomy is bisected at a different angle and might yield three different measurements at each approach. The same can be said for a lot of the 2-D length measurements. I can probably make your RA five centimeters wide, if I try.
That said, doing about 5,000 studies will get you pretty good at recognizing your limitations, realizing the need to remeasure erroneous data, common failings of ultrasound physics and other sources of error.
Thankfully, inexperienced techs get a good education on spotting and evaluating the “exciting” stuff because these nuanced stuff takes time to develop.
Ivan,
As a former Philips employee, hello. My clinical skills included cardiac ultrasound. In response to your question, a software program with edge resolution enhancement and auto analysis would be amazing. It would remove user variability.
Clinical Coordinator of Cardiology and Cardio-Pulmonary Rehabilitation at Floyd Medical Center
I agree with Tim that it is not possible. In deference to Wayne; edge recognition software would help. But the variety of equipment skill levels, even peoples varied vision; prevent 100% agreement.
Even at the larger conferences, when you attend the “read with the experts” courses, you see that they tend to disagree looking at the same images.
unless equipment, education, and criteria for performing studies gets standardized; not going to happen.
Reproducibility and reduction (I.e. not complete removal) of variability could be achieved in several ways. For example, to cite a few: multi view imaging to remove view dependency on edge definition and occlusion; angle independent flow quantification using 3D color Doppler; image fusion and compounding with tracked probes; simultaneous (or quasi-simultaneous) multi-prove systems. All these are engineering and research challenges but we will get to them. How long it will take highly depends on how willing manufacturers are to open up to research institutions and how willing research institutions are to share and exploit results.
You’re a very brave man Ivan, asking the holy grail question of echocardiography! I’ve been doing echoes at prominent institutions for 10 years, been registered in echo since 2006, have performed probably more than 6,000 adult echoes, teach echo to technicians and sometimes residents, attended echo related conferences and read the latest Dr. Feigenbaum and Dr. Otto textbooks – so I can speak to this topic.
Here’s the deal. From what I understand, the best echo has to offer as far as EF quantification (which I think is usually the focus) is 3D volume quantification. The problem is, is that primarily due to reimbursement issues this technology has had very slow adoption and application and therefore low availability. A great application of this technology would be evaluating a patient for possible LVAD placement/treatment or heart transplant.
Given this, what most technicians are left with is 2 Dimensional echo. There are many ways we can measure Ejection Fraction with 2D Echo and they include direct 2D measurement (measuring the left ventricular internal dimension at end-diastole (LVIDd) and the left ventricular internal dimension at end-systole (LVIDs). Most modern echo systems have very specific packages that enable fairly easy measurements of these aspects of the heart and are clearly labeled. A technician can also make a similar measurement using M-Mode. The achilles-heel of M-Mode based measurement of EF is that the picture or the heart in the picture (from the parasternal long-axis window/view – PLAX) must be on-axis. If the picture is off-axis, your direct 2D measurements should be more accurate. Side note: this all goes out the window with a poorly trained or lazy echo tech who has little to no idea of what they’re doing – and unfortunately there’s too many of these out there (read more on this later). So, as far as 2D left ventricular dimension measurements of EF go, direct 2D (on screen) measurements are preferable.
According to a Wake Forest Cardiology conference which I attended several years ago in Orlando, “The Beat Goes On” the best or most accurate measurement of EF with 2D echo (assuming there’s a good, well-trained, knowledgeable and hard working echo tech performing the test) is with Simpson’s Bi-plane method/Quantification. This measurement is based on volume of blood in the heart at end-diastole and end-systole (see the pattern). Once this is calculated a technician can then calculate the stroke volume (which most packages calculate automatically once the proper measurements are calculated and entered) and the cardiac output (Stroke volume (SV) X heart rate (HR)). As a reference the heart wants to push around 5 liters of blood per minute to sustain life and normal body function. Of course this can greatly increase with exercise or decrease slightly with rest as can your respiratory function.
The way the Biplane Simpsons’ method is performed is that a technician calculates the following from both the apical-4-chamber view and the apical-2-chamber view (again most modern systems have these measurements built into the package and labeled and they can also be exported directly to the preliminary report through DICOM specs.):
1. Left ventricular volume at End-Diastole (LVVED) – A4C
1. Left ventricular volume at End-Systole (LVVES) – A4C
1. Left ventricular volume at End-Diastole (LVVED) – A2C
1. Left ventricular volume at End-Systole (LVVED) – A2C
Yes, you can imagine this is very time consuming. It can be done later once the scan is done however once the patient leaves, you can not go back and adjust your view if you think your picture is foreshortened or off-axis, etc.
cont’d–
The bottom line is that quantification in echo, particularly in calculating EF depends on the situation. Simpsons’ method is not performed routinely in most labs because if the EF visually looks normal (around 55% – 70%) from the long-axis, short-axis and apical 4 chamber and apical 2 chamber views then there’s usually not a huge need for it; little additional benefit. I try to do it as much as possible because I like to do as best an echo I can and also it’s good to practice and a little fun when you have very clear/great quality pictures (ironically these are the people who you know their EF is probably normal the minute they walk through your door!).
There are many tools and techniques one can employ to optimize their 2D/Simpsons’ EF measurements. Here are a few:
* the patient into the proper position (left lateral decubitus) — I use a wedge to keep them on their left side and keep their head well supported with a rolled up pillow or rolled up blankets
* the proper echo settings/frequency. Use penetration setting if you have to, but if they have good pictures, use the best resolution setting you can without sacrificing endocardial border definition — otherwise you’re defeating the purpose
* the proper breathing techniques (I find from parasternal window it’s best to have the patient inhale, exhale all the way and then hold their breath for loop acquisition and best to have them inhale and hold for apical acquisitions – but just play around with it until you get the picture you want).
* the picture on axis and avoid foreshortening — this is very key for the Simpsons’ method of discs
Now, you’ve tried all this, you’re sweating, your hand and shoulder are about to fall off, you see stars or angels or both and the patient and their family think you are completely clueless and think you’re torturing their Wife/Husband/Daughter/Friend/etc. and you’re wondering if you’ll have a job tomorrow. So what do you do?
Definity Echo contrast (Perflutren Lipid Microsphere) – http://www.definityimaging.com/ – you say? Yes, possibly. You need to A. Get the patient’s consent (although this is beginning to change) B. Establish IV access for the injection of the Definity solution C. Activate the Definity and use it within a certain period D. Utilize it correctly.
Basically Definity contrast is little gas bubbles that reflect the ultrasound beams (for which 2D pictures are generated from pulsed-wave doppler) very well or strongly and allow for a stronger, clearer/better resolution image. The heart walls/endocardial borders are one color and the contrast is the other (the contrast is usually the white-milky substance you see inside the left ventricle while it’s filling and contracting. Most people think it’s pretty “cool” when they see it and it can make a dramatic difference in how you visually estimate or calculate the EF. As I mentioned, Simpsons’ method (the preferred 2D EF calc. method) is highly dependent on operator skill and effort and hence picture quality. And Definity contrast can greatly enhance the picture quality. Last week I had a patient where you could barely see any endocardial border without Definity and visually estimating his EF would be a total shot in the dark. Well, we administered Definity, and I’m not lying it was still a tough scan, but once the Definity was injected and began to appear in the right ventricle and then left, I could see immediately that his EF was completely normal (55-60%). This was important to assess clinically because the patient was in the CCU at the time and he was s/p CABG. Judging whether the EF is normal or not can have a big play in clinical decision making for other conditions.
Ironically getting an accurate EF has to do more with having the right technician perform your test than it has to do with technology or anything else. And unfortunately there’s no lack of pitfalls there.
State of Cardiology on Wall Stress, Ventricular Workload and Myocardial Contractile Reserve: Aspects of Translational Medicine (TM)
Updated on 2/17/2023
The training statement was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, Society of Thoracic Surgeons, and Society for Vascular Medicine.
Bass TA, et al “2023 ACC/AHA/SCAI advanced training statement on interventional cardiology (coronary, peripheral vascular, and structural heart interventions): A report of the ACC Competency Management Committee”J Am Coll Cardiol 2023; DOI: 10.1016/j.jacc.2022.11.002.
Dong H, Mosca H, Gao E, Akins RE, Gidding SS and Tsuda T
Journal of Translational Medicine 2013, 11:183 (7 August 2013)
In this article we expose the e-Reader to
A. The State of Cardiology on
wall stress
ventricular workload and
myocardial contractile reserve
B. Innovations in a Case Study in Cardiology Physiological Research on above subjects
C. Prevailing Models in Translational Medicine
D. Mapping of One Case Study in Cardiology Physiological Research onto Weber’s Triangle of Biomedicine.
The mapping facilitate e-Reader’s effort to capture the complexity of aspects of Translational Medicine and visualization of the distance on this Triangle between where the results of this case study are and the Human Corner — the Roadmap of the “bench-to-bedside” research, or the “translation” of physiological and basic science research into practical clinical applications.
This article has the following sections:
Introduction
Author: Justin Pearlman, MD, PhD, FACC
Translational medicine aims to fast track the pathway from scientific discovery to clinical applications and assessment of benefits. Cardiovascular examples include novel biomarkers of disease, new heart assist devices, new technologies for catheter intervention, and new medications. The Institute of Medicine’s Clinical Research Roundtable describes translation medicine in two fundamental blocks: “…the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention [with] first testing in humans…”, and “…the translation of results from clinical studies into everyday clinical practice and health decision making…” [2].
Identifying where contributions are achieving translation has been addressed by the biometric tool called the triangle of biomedine [3].
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Jiang F, Zhang J, Wang X, Shen X: Important steps to improve translation from medical research to health policy.J Trans Med 2013, 11:33. BioMed Central Full Text
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Chiappelli F: From translational research to translational effectiveness: the “patient-centered dental home” model.Dental Hypotheses 2011, 2:105-112. Publisher Full Text
Maida C: Building communities of practice in comparative effectiveness research.In Comparative effectiveness and efficacy research and analysis for practice (CEERAP): applications for treatment options in health care. Edited by Chiappelli F, Brant X, Cajulis C. Heidelberg: Springer–Verlag; 2012.
Westfall JM, Mold J, Fagnan L: Practice-based research—“blue highways” on the NIH roadmap.JAMA 2007, 297:403-406. PubMed Abstract | Publisher Full Text
Chiappelli F, Brant X, Cajulis C: Comparative effectiveness and efficacy research and analysis for practice (CEERAP) applications for treatment options in health care. Heidelberg: Springer–Verlag; 2012.
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This article has the following EIGHT Sections:
I. Key Explanation Models for the Translational Process in BioMedicine, aka Translational Medicine (TM)
II. TM Model selection in this article, for mapping the fit of a Case Study in Cardiology Physiological Research, within the TM Model selected
III. Limitations of the TM Model to explain the Translational Process in BioMedicine
IV. Mapping the fit of a Case Study in Cardiology Physiological Research, within the TM Model selected
V. Clinical Implications of the Case Study in Cardiology Physiological Research
VI. Limitations of the Case Study in Cardiology Physiological Research
VII. The State of Cardiology on
wall stress
ventricular workload and
myocardial contractile reserve
VIII. What are the Innovations of the Case Study in Cardiology Physiological Research
I. Key Explanation Models for the Translational Process in BioMedicine, aka Translational Medicine (TM)
The National Institutes of Health (NIH) Roadmap places special emphasis on “bench-to-bedside” research, or the “translation” of basic science research into practical clinical applications. The Clinical and Translational Science Awards (CTSA) Consortium is one example of the large investments being made to develop a national infrastructure to support translational science, which involves reducing regulatory burdens, launching new educational initiatives, and forming partnerships between academia and industry. However, while numerous definitions have been suggested for translational science, including the qualitative T1-T4 classification, a consensus has not yet been reached. This makes it challenging to measure the impact of these major policy changes.
BASIC DISCOVERY -T1-> CLINICAL INSIGHTS -T2-> IMPLICATIONS FOR PRACTICE -T3-> IMPLICATIONS FOR POPULATION HEALTH -T4-> IMPLICATIONS FOR GLOBAL HEALTH
Model A: QUALTITATIVE T1-T4 CLASSIFICATION [(7) & (8-10) in Weber’s list of Reference, below]
In biomedicine, translational science is research that has gone from “bench” to “bedside”, resulting in applications such as drug discoverythat can benefit human health [1–6]. However, this is an imprecise description. Numerous definitions have been suggested, including the qualitative T1-T4 classification [7].
Several bibliometric techniques have been developed to quantitatively place publications in the translational spectrum. Narin assigned journals to fields, and then grouped these fields into either “Basic Research” or “Clinical Medicine” [8-10]. Narin also developed another classification called research levels, in which journals are assigned to “Clinical Observation” (Level 1), “Clinical Mix” (Level 2), “Clinical Investigation” (Level 3), or “Basic Research” (Level 4) [8]. He combines Levels 1 and 2 into “Clinical Medicine” and Levels 3 and 4 to “Biomedical Research”.
Model B: Average research level of a collection of articles as the mean of the research levels of those articles
Lewison developed methods to score the translational research level of individual articles from keywords within the articles’ titles and addresses. He defines the average research level of a collection of articles as the mean of the research levels of those articles [11–13] . For validity, one must assume that the keywords reflect content fairly and without bias. If the government adapts such a scoring system to influence funding in order to promote translational research, that will create a bias.
Model C: “Translatability” of drug development projects
A multidimensional scoring system has been developed to assess the “translatability” of drug development projects [29,30]. This requires manual review of the literature which poses difficulties for scalability and consistency across reviewers and over time.
Model D: Fontelo’s 59 words and phrases suggesting that the article is Translational
Fontelo identified 59 words and phrases, which when present in the titles or abstracts of articles, suggest that the article is translational [31]. It is an interesting sampling method, but it may present a bias to particular styles of presentation.
Model E: The triangle of biomedicine by Griffin M Weber – This Model is the main focus of this article
The Triangle of Biomedicine uses a bibliometric approach to map PubMed articles onto a graph. The corners of the triangle represent research related to animals, to cells and molecules. The position of a publication on the graph is based on its topics, as determined by its Medical Subject Headings (MeSH). Translation is defined as movement of a collection of articles, or the articles that cite those articles, towards the human corner.
Results
The Triangle of Biomedicine provides a quantitative way of determining if an individual scientist, research organization, funding agency, or scientific field is producing results that are relevant to clinical medicine. Validation of the method examined examples that have been previously described in the literature, comparing it to other methods of measuring translational science.
Conclusions
The Triangle of Biomedicine is a novel way to identify translational science and track changes over time. This is important to policy makers in evaluating the impact of the large investments being made to accelerate translation. The Triangle of Biomedicine also provides a simple visual way of depicting this impact, which can be far more powerful than numbers alone. As with any metric, its limitations and potential biases should always be kept in mind. As a result, it should be used to supplement rather than replace alternative methods of measuring or defining translational science. What is unique, though, to the Triangle of Biomedicine, is its simple visual way of depicting translation, which can be far more powerful to policy makers than numbers alone.
Keywords:
Translational science; Bibliometric analysis; Medical subject headings; Data visualization; Citation analysis
II. TM Model selection in this article, for mapping the fit of a Case Study in Cardiology Physiological Research, within the TM Model selected
Model E: The triangle of biomedicine by Griffin M Weber
In this study, we analyze the 20 million publications in the National Library of Medicine’s PubMed database by extending these bibliometric approaches in three ways: (1) We divide basic science into two subcategories, research done on animals or other complex organisms and research done on the cellular or molecular level. We believe it is important to make this distinction due to the rapid increase in “-omics” research and related fields in recent years. (2) We classify articles using their Medical Subject Headings (MeSH), which are assigned based on the content of the articles. Journal fields, title keywords, and addresses only approximate an article’s content. (3) We map the classification scheme onto a graphical diagram, which we call the Triangle of Biomedicine, which makes it possible to visualize patterns and identify trends over time.
Article classification technique
Using a simple algorithm based on an article’s MeSH descriptors, we determined whether each article in PubMed contained research related to three broad topic areas—animals and other complex organisms (A), cells and molecules (C), or humans (H). An article can have more than one topic area. Articles about both animals and cells are classified as AC, articles about both animals and humans are AH, articles about cells and humans are CH, and articles about all three are ACH. Articles that have none of these topic areas are unclassified by this method.
In order to identify translational research, we constructed a trilinear graph [21], where the three topic areas are placed at the corners of an equilateral triangle, with A on the lower-left, C on the top, and H on the lower-right. The midpoints of the edges correspond to AC, AH, and CH articles, and the center of the triangle corresponds to ACH articles.
An article can be plotted on the Triangle of Biomedicine according to the MeSH descriptors that have been assigned to it. For example, if only human descriptors, and no animal or cell descriptors have been assigned to an article, then it is classified as an H article and placed at the H corner. An article with both animal and cell descriptors, and no human descriptors, is classified as an AC article and placed at the AC point. A collection of articles is represented by the average position of its articles. Although an individual article can only be mapped to one of seven points, a collection of articles can be plotted anywhere in the triangle.
An imaginary line, the Translational Axis, can be drawn from the AC point to the H corner. The position of one or more articles when projected onto this axis is the Translational Index (TI). By distorting the Triangle of Biomedicine by bringing the A and C corners together at the AC point, the entire triangle can be collapsed down along the Translational Axis to the more traditional depiction of translational science being a linear path from basic to clinical research. In other words, the Triangle of Biomedicine does not replace the traditional linear view, but rather provides additional clarity into the path research takes towards translation.
Summary of categories
Mapping A-C-H categories to Narin’s basic-clinical classification scheme
The National Library of Medicine (NLM) classifies journals into different disciplines, such as microbiology, pharmacology, or neurology, with the use of Broad Journal Headings. We used Narin’s mappings to group these disciplines into basic research or clinical medicine. Individual articles were given a “basic research” score of 1 if they were in a basic research journal and 0 if they were in a “clinical medicine” journal. For each A-C-H category, a weighted average of its articles’ scores was calculated, with the weights being the inverse of the total number of basic research (4,316,495) and clinical medicine (11,689,341) articles in PubMed. That gives a numeric value for the fraction of articles within a category that are basic research, which is corrected for the fact that PubMed as a whole has a greater number of clinical medicine articles.
Mapping A-C-H categories to Narin’s four-level classification scheme
For each of his four research levels, Narin selected a prototype journal to conduct his analyses:The Journal of the American Medical Association (JAMA, Level 1), The New England Journal of Medicine (NEJM, Level 2), The Journal of Clinical Investigation (JCI, Level 3), and The Journal of Biological Chemistry (JBC, Level 4). Each is widely considered a leading journal and has over 25,000 articles spanning more than 50 years. For each A-C-H category, we determined the number of articles from each of these four journals and calculated a weighted average of their research levels, with the weights being the inverse of the total number of articles each journal has in PubMed.
III. Limitations of the TM Model to explain the Translational Process in BioMedicine: The triangle of biomedicine by Griffin M Weber
This work is limited in several ways. It takes at least a year for most articles to be assigned MeSH descriptors. During that time the articles cannot be classified using the method described in this paper. Also, our classification method is based on a somewhat arbitrary set of MeSH descriptors—different descriptors could have been used to map articles to A-C-H categories. However, the ones we used seemed intuitive and they produced results that were consistent with Narin’s classification schemes. Finally, any metric based on citation analysis is dependent on the particular citation database used, and there are significant differences among the leading databases [22]. In this study, we used citations in PubMed that are derived from PubMed Central because they are freely available in their entirety, and therefore our method can be used without subscriptions to commercial citation databases, such as Scopus and Web of Science, which are cost-prohibitive to most people. However, because these commercial databases have a greater number of citations and index different journals than PubMed, they might show shorter or alternative paths towards translation (i.e., fewer citation generations or less time). Though, as described in our Methods, there is evidence that suggests these differences might be relatively small. Selecting the best citation database for identifying translational research is a topic for future research.
Another area of future research could attempt to identify a subset of H articles that truly reflect changes in health practice and create a separate category P for these articles. This might be possible, for example, by using Khoury’s approach of using PubMed’s “publication type” categorization of each article to select for those that are clinical trials or practice guidelines [7]. This could be visualized in the Triangle of Biomedicine by moving H articles to the center of the triangle and placing P articles in the lower-right corner, thereby highlighting research that has translated beyond H into health practice.
IV. Mapping the fit of a Case Study in Cardiology Physiological Research, within the TM Model selected
The triangle of biomedicine by Griffin M Weber
Figure 1.Disciplines mapped onto the Triangle of Biomedicine.The corners of the triangle correspond to animal (A), cellular or molecular (C), and human (H) research. The dashed blue line indicates the Translational Axis from basic research to clinical medicine. The position of each circle represents the average location of the articles in a discipline. The size of the circle is proportional to the number of articles in that discipline. The color of the circle indicates the Translational Distance (TD)—the average number of citation generations needed to reach an H article. The position of the light blue box connected to each discipline represents the average location of articles citing publications in that discipline. To provide clarity, not all disciplines are shown. Note however, that if authors knew this measurement would be applied and could affect their funding, then they might increase human study citation of basic research to game the “translational distance.”
For this article we selected A Case Study in Cardiology Physiological Research
Integrated wall stress: a new methodological approach to assess ventricular workload and myocardial contractile reserve
Hailong Dong124, Heather Mosca1, Erhe Gao3, Robert E Akins1, Samuel S Gidding2and Takeshi Tsuda12*
This study appeared in 2013 in the Journal of Translational Medicine. It studied mice, creating heart attacks in order to evaluate the physiologic significance of “integrated wall stress” (IWS) as a marker of total ventricular workload. The measure IWS was obtained by integrating continuous wall stress curve by accumulating wall stress values at millisecond sampling intervals over one minute, in order to include in wall stress effects of heart rate and contractility (inotropic status of the myocardium). As an example of translational medicine, it raises numerous issues. As a mouse study, it qualifies as basic science. It examines the impact of heart attack on changes inducible by the inotropic agent dobutamine. If the concept were to influence clinical care and outcomes, it would qualify as translational. All of the tools applied to the mice are applicable to patients: heart attacks (albeit not purposefully induced), the echocardiography measurements, and the dobutamine impact. That enables citation of human studies in the references, and ready application to human studies in the future. Mice however have much faster heart rates, so the choice of one minute for the integral may have different significance for humans. Gene expression was also measured. The authors conclude IWS represents a balance between external ventricular workload and intrinsic myocardial contractile reserve. The fact that the Journal has the word “translational” may represent a bias. Many of the links between animal and human focused references occur electively in the discussion section. The authors propose the measurement might help identify pre-clinical borderline failing of contractility. If so, the full axis of translational value will require that IWS can improve outcomes. Currently, blood levels of brain naturetic peptide are used as a marker of myocardial strain that may help identify early failing contractility. Presumably, early recognition could identify a population that might benefit from early intervention to forestall progression. Evidence based medicine will have difficulties. First, it is biased by the “Will Roger’s Effect” whereby early recognition of a disease subdivides the lowest class, inherently shifting the apparent status of each half of the subdivision (Will Roger’s made a joke that when Oklahoma residents moved to California for the gold rush, they improved the average intelligence of both groups, an observation adapted to explain a redefinition bias). Second, the actual basis for a change in clinical application will be complex, with political as well as scientific influences. Third, it will be even more difficult to discern its impact on outcomes, even if targeted therapy for patients with distinctive IWS is associated with an apparent improvement in outcomes. Convincing documentation would require extensive comparisons and controlled studies, but once a method is clinically adapted, it is commonly considered unethical to perform a controlled study in which the “preferred method” is not applied to a group.
V. Clinical Implications of the Case Study in Cardiology Physiological Research
Background
Wall stress is a useful concept to understand the progression of ventricular remodeling. We measured cumulative LV wall stress throughout the cardiac cycle over unit time and tested whether this “integrated wall stress (IWS)” would provide a reliable marker of total ventricular workload.
Methods and results
We applied IWS to mice after experimental myocardial infarction (MI) and sham-operated mice, both at rest and under dobutamine stimulation. Small infarcts were created so as not to cause subsequent overt hemodynamic decompensation. IWS was calculated over one minute through simultaneous measurement of LV internal diameter and wall thickness by echocardiography and LV pressure by LV catheterization. At rest, the MI group showed concentric LV hypertrophy pattern with preserved LV cavity size, LV systolic function, and IWS comparable with the sham group. Dobutamine stimulation induced a dose-dependent increase in IWS in MI mice, but not in sham mice; MI mice mainly increased heart rate, whereas sham mice increased LV systolic and diastolic function. IWS showed good correlation with a product of peak-systolic wall stress and heart rate. We postulate that this increase in IWS in post–MI mice represents limited myocardial contractile reserve.
Conclusion
We hereby propose that IWS provides a useful estimate of total ventricular workload in the mouse model and that increased IWS indicates limited LV myocardial contractile reserve.
IWS can be estimated by obtaining IWS index, which is calculated non-invasively by simultaneous M-mode echocardiogram and cuff blood pressure measurement, i.e., PS-WS instead of ES-WS and heart rate. This will provide a sensitive way to detect subclinical borderline failing myocardium in which the decline in LV myocardial contractile reserve precedes apparent LV dysfunction. This method may be clinically useful to address LV myocardial reserve in those patients who are not amenable to perform on exercise stress test, such as immediate post-operative patients under mechanical ventilation, critically ill patients with questionable LV dysfunction, and patients with primary muscular disorders and general muscular weakness (i.e., Duchenne muscular dystrophy).
VI. Limitations of the Case Study in Cardiology Physiological Research
There are certain limitations in this study.
First, wall stress measurement is reliable when there is an equal wall thickness with symmetrical structure. Obviously, with the creation of small MI, there is an asymmetry of LV myocardium in both structure and consistency (myocardium vs. scar tissue). However, the scar tissue is small and restricted to the LV apex (approximately 14% of entire LV myocardium [5]). In fact, most of LV wall was thickened after induction of this small experimental MI. Nevertheless, we acknowledge that this is our major limitation.
Secondly, there is an individual variability in response to dobutamine stimulation even in sham mice. Although the average sham mice (n = 5) showed only a modest increase in HR, PS-WS, and IWS during dobutamine stimulation, one mouse presented in Figure 1 showed a notable increase in HR and PS-WS in response to dobutamine. Nevertheless, even with increased HR and PS-WS, the calculated IWS remained relatively unchanged in the sham-operated mice.
Lastly, the reliability of IWS index is based upon the stipulation that ED-WS is significantly low compared with the systolic wall stress. Thus, IWS index may not be accurate in obvious volume overload cases and/or dilated hearts with LV dysfunction where ED-WS is significantly higher than that in normal condition. Of note, ED-WS in human is higher than that in mice in relation to PS-WS, probably around 15 to 20% of PS-WS [12].
VII. State of Cardiology on
wall stress
ventricular workload and
myocardial contractile reserve
Ventricular remodeling is a chronic progressive pathological process that results in heart failure after myocardial infarction (MI) or persistent unrelieved biomechanical overload [1,2]. Persistent and unrelieved biomechanical overload in combination with activation of inflammatory mediators and neurohormones is thought to be responsible for progressive ventricular remodeling after MI [3,4], but studies to investigate specific mechanisms in animals are hampered by the difficulty involved in quantifying biomechanical workload in vivo. The magnitude of ventricular remodeling advances in line with progressive ventricular geometric changes including myocardial hypertrophy and chamber dilatation with accompanying functional deterioration [1,2]. Previously, we proposed that post-ischemic ventricular remodeling is a pathological spectrum ranging from benign myocardial hypertrophy to progressive heart failure in the mouse model in which the prognosis is primarily determined by the magnitude of residual hemodynamic effects [5]. However, there has been no optimum quantitative measurement of ventricular workload as a contributory indicator of ventricular remodeling other than wall stress theory to explain how ventricular dilatation and hypertrophy develop after loss of viable working myocardium [6,7].
The concept of ventricular wall stress was introduced by Strauer et al. as a primary determinant of myocardial oxygen demand [8]. They indicated that overall myocardial energy demand depends upon intramyocardial wall tension, inotropic state of the myocardium, and heart rate. Wall stress theory is commonly introduced to explain development of concentric hypertrophy in chronic pressure overload and progressive ventricular dilatation in the failing heart. One study argued that peak-systolic wall stress increased as LV function worsened in a chronic volume overloaded status [9], and another suggested that peak-systolic wall stress closely reflected LV functional reserve during exercise [10]. However, the effect of heart rate or myocardial contractility was not considered in either study. Heart rate has been shown to be one of several important factors contributing to myocardial oxygen consumption [11].
Herein, we introduce a novel concept of “integrated wall stress (IWS)” to assess its significance as a marker of total ventricular workload and to validate its physiological relevance in the mouse model. The concept of continuous LV wall stress measurement was reported previously, but authors did not address the overall effects of changing wall stress during the cardiac cycle on the working myocardium [12]. We have defined IWS as cumulative wall stress over unit time: IWS was obtained by integrating continuous wall stress curve by accumulating wall stress values at millisecond sampling intervals over 1 min. By calculating IWS, we were able to incorporate the effects of not only systolic wall stress, but also of heart rate and inotropic status of the myocardium. These data were analyzed against conventional hemodynamic parameters in animals with and without MI in conjunction with incremental dobutamine stress. We hypothesize that unchanged IWS represents stable ventricular myocardial contractile reserve and that increase in IWS implies an early sign of mismatch between myocardial reserve and workload imposed on ventricular myocardium.
VIII. What are the Innovations of the Case Study in Cardiology Physiological Research
IWS measures total wall stress throughout the cardiac cycle over a unit time (= 1 min) including the effect of heart rate and inotropic state of the ventricular myocardium, whereas one-spot measurement of PS-WS and ED-WS only reflects maximum and minimum wall stress during a cardiac cycle, respectively. We hypothesized that increase in IWS indicates failure of myocardium to counteract increased ventricular workload. We have measured IWS in the mouse model in various physiological and pathological conditions to validate this hypothesis. Unchanged IWS observed in sham operated mice may imply that the contractile reserve of ventricular myocardium can absorb the increased cardiac output, whereas increased IWS after MI suggests that ventricular workloads exceeds intrinsic myocardial contractile reserve. Thus, we postulate that IWS is a reliable physiological marker in indicating a balance between external ventricular workload and intrinsic myocardial contractile reserve.
#1
IWS and myocardial reserve
“Wall stress theory” is an important concept in understanding the process of cardiac hypertrophy in response to increased hemodynamic loading [16]. When the LV myocardium encounters biomechanical overload, either pressure overload or volume overload, cardiac hypertrophy is naturally induced to normalize the wall stress so that myocardium can minimize the increase in myocardial oxygen demand; myocardial oxygen consumption depends mainly on systolic wall stress, heart rate, and contractility [8,17]. A question arises whether this hypertrophic response is a compensatory physiological adaptation to stabilize the wall stress or a pathological process leading to ventricular remodeling and heart failure. Physiological hypertrophy as seen in trained athletes reveals increased contractile reserve, whereas pathological hypertrophy shows a decrease in contractile reserve in addition to molecular expression of ventricular remodeling [18–20]. However, what regulates the transition from compensatory adaptation to maladaptive process is not well understood.
Systolic wall stress has been studied extensively as a clinical marker for myocardial reserve. Systolic wall stress reflects the major determinants of the degree of LV hypertrophy and plays a predominant role in LV function and myocardial energy balance [17]. It has been shown that increased systolic wall stress inversely correlates with systolic function and myocardial reserve in patients with chronic volume overload [9,10,21], chronic pressure overload [22,23], and dilated cardiomyopathy [24]. However, one-point measurement of systolic wall stress does not encompass the effect of heart rate and contractile status, the other critical factors that affect myocardial oxygen demand [11]. The idea of IWS has been proposed to incorporate wall stress throughout the cardiac cycle and reflects the effects of heart rate and contractile status.
Myocardial oxygen consumption is determined mainly by ventricular wall stress, heart rate and contractility [17], which are all incorporated in IWS measurement. Continuous measurement of LV wall stress was previously reported in humans [12,15] and dogs [11] with a similar method, but not in mice. By integrating the continuous WS over one minute, we estimated the balance between myocardial contractile reserve and total external ventricular workload and examined its trend in relation to inotropic stimulation in the mouse heart in vivo. In this study, we have proposed unchanged IWS as a marker of sufficient myocardial contractile reserve, since increased wall stress demands higher myocardial oxygen consumption. Indeed, systolic wall stress does not increase with strenuous isometric exercise in healthy young athletes [25]. Thus, we propose that increase in IWS indicates diminished myocardial contractile reserve.
#2
Small MI model as a unique model to study early phase of progressive ventricular remodeling
A complex series of protective and damaging events takes place after MI, resulting in increased ventricular workload [26]. Initial ventricular geometric change is considered as a primary compensatory response to counteract an abrupt loss of contractile tissue. In classical theories of wall stress, which rely on the law of Laplace, the mechanisms of progressive ventricular dilatation and functional deterioration of the LV are attributed to the increased wall stress that is not compensated by the intrinsic compensatory mechanisms [2,16]. Although this theory is obvious in advanced stage of heart failure, the subclinical ventricular remodeling following borderline cases such as following small MI with initial full compensatory response is not well explained.
Study shown that our small MI model induced concentric hypertrophy without LV dilatation as if initial myocardial damage was completely compensated (Figure 2) [5]. Although LV hypertrophy is induced initially to normalize the wall stress and to prevent ventricular dilatation, this hypertrophy is not altogether a physiological one because of decreased inotrophic and lusitropic reserve when stimulated with dobutamine (Figure 4) and because of simultaneous molecular and histological evidence of remodeling in the remote nonischemic LV myocardium (Figure 3). IWS and PS-WS become normalized in small MI at rest under anesthesia as a result of reactive hypertrophy accompanied by increased ANP and BNP mRNA level. Borderline maladaptive LVH is characterized by maintained LV performance at the expense of limited myocardial contractile reserve, and this abnormality can be unmasked by inotropic stimulation [18]. The trend of IWS at rest and with dobutamine stimulation suggests that MI mice were likely exposed to higher IWS during usual awake and active condition than sham-operated mice. In contrast, systolic wall stress in the pressure overload-induced LV hypertrophy showed a level comparable to that of sham both at rest and under stimulation by β1 adrenergic agonist, prenalterol, with comparable heart rate changes [27]. For this reason, IWS assessment by measuring cumulative WS in a unit time with and without inotropic stimuation should serve as a sensitive marker to assess whether induced LV hypertrophy is a compensatory physiological adaptation process or a pathological maladaptation process. Increased IWS that indicates imposed workload surpassing myocardial contractile reserve is likely to become a major driving factor in inducing progressive ventricular remodeling or initiating deleterious maladaptive processes after MI.
#3
IWS represents myocardial oxygen demand that can be estimated non-invasively
Study demonstrated a very good correlation between IWS and the product of PS-WS and HR (“IWS index”) in both MI and sham-operated hearts (Figure 6). This formula appears physiologically acceptable provided that ED-WS is sufficiently low compared with the PS-WS (approximately 10%, as is shown in Figures 4B and C). ES-WS was previously introduced as a useful tool for assessing myocardial loading status and myocardial oxygen consumption, but its measurement requires complicated preparation [28,29]. Because there is an excellent correlation between PS-WS and ES-WS, it has been demonstrated that ES-WS can be substituted by PS-WS [28], which can be easily obtained non-invasively [30]. ES-WS was previously determined as a useful marker to quantify LV afterload and contractility that can be simply and accurately measured non-invasively [15]. As myocardial oxygen consumption is mainly dependent upon systolic wall stress, contractility, and heart rate, it seems reasonable to propose that IWS and IWS index represent the status of myocardial contractile reserve.
Conclusions & Next Phases in Translational Medicine and Cardiology Physiological Research
Author: Justin Pearlman, MD, PhD, FACC
Visual and numeric scores that assess the commitment to translation of basic discoveries to measured impact on human outcomes followed by increased prevalence of the benefits is of course desirable, but fraught with challenges. Metrics of translational medicine may lead to rewards that can “game” the system by promoting choices of MeSH codes that augment the score for individual articles and/or clusters of work from a center of research without correlation to the actual impact of the body of work. The fairness of a metric also must account for division of labor whereby one group of researchers achieves major basic discoveries that ferment useful applications to improved outcomes in patient care, while others focus on applications or application assessments that may have widely disparate degrees of impact on the reduction to practice, validation and dissemination of improved care.
Thus in order to promote useful metrics of translational medicine progress, we propose a set of metrics on the metrics:
1. impact of reviewer skill/bias
2. impact of author coding/bias
3. ability to assess an impact factor independent of author word choices
4. ability to credit basic research for its downstream impact on other researchers culminating in clinical applications, validation, and dissemination of human benefits
5. ability to discern pioneering advances from “me too” duplications of effort and minor variations on work of the same group or others
6. ability to assess cost effectiveness, including the occurrences of subsequent re-investigations to clarify issues that could have been addressed in the instance study
7. ability to compute contribution to quality life year gain per dollar of added care
Journal of Translational Medicine 2013, 11:126 (24 May 2013)
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Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
and
Article Curator: Aviva Lev-Ari, PhD, RN
The clinical motivations for coronary artery imaging include identifying and characterizing obstructive lesions, analyzing suitability for various feasible interventions, and assessing comparative risk with and without interventions. With improvements in non-invasive detection of fixed obstructions in the coronary arteries, it should not be surprising that half of the lesions that cause heart attacks (myocardial infarction) among those who had recent imaging consisted of unstable plaques that were less than 50% obstructive. Therefore there is growing interest not only in more reliable detection of lesions that exceed 50% obstruction, but also improved characterization of lesions that are not obstructive but may be unstable.
By way of analogy, think of impaired blood supply to the heart as a traffic jam in a roadway. The best time to check for a traffic jam is during rush hour. The corresponding clinical scenario is stress testing. There are three major roadways in the heart: left anterior, left circumflex, and right, each with branches (forks). The two left major vessels stem from a short but treacherous left main (“widow maker”). A temporary traffic jam results in symptoms of impaired delivery (angina, from hunger due to late delivery of food). Alternatively, a prolonged traffic disruption can result in suicidal tissue destruction (starvation). A fixed obstruction consists of potholes and landslides resulting in a persisting shutdown of half or more of the lanes in the highway. An unstable plaque consists of a less severe abnormality that can cause accidents (plaque rupture, local hemorrhage, sudden occlusion). A road may shutdown not only from progressive road damage, but also a truck can flip over and shutdown a relatively clean roadway.
Among patients who had recent coronary imaging prior to the onset of a heart attack, half do not have occlusive lesions. Instead of slow progressive reduction in vessel diameter leading to a critically severe flow reduction, the mechanism in the cases of no severe narrowing is attributed to unstable plaque, meaning plaque with thin fibrous caps that rupture, causing sudden thrombosis. Stress tests focus on detection of fixed obstructions and do not warn who has unstable plaque. Thus the next great frontier for coronary imaging is not just to identify flow reducing lesions, but also to identify unstable plaque even if it is not currently flow limiting. This article presents candidate imaging methods and their current capabilities.
Coronary imaging methods include:
intra-coronary ultrasound (IVUS)
optical coherence imaging (fiberoptic)
computed tomographic xray angiography (CTA)
magnetic resonance angiography (MRA)
near infra-red spectroscopic imaging (NIRS)
NIRS-IVUS Imaging To Characterize the Composition and Structure of Coronary Plaques
authored by highly experienced interventional cardiologists expert in the field of coronary plaque characterization, contains a detailed description of the new NIRS-IVUS combination catheter, and the clinical information obtained during its use in over 90 hospitals in over 10 countries. Case vignettes, cohort outcomes, reviews, and plans for future studies are also presented. It is our hope that this information will be useful in the near term to those seeking to improve PCI. For the longer term, we believe that the NIRS-IVUS system is an excellent candidate for evaluation as a detector of vulnerable plaque. Success in the prospective studies that are planned will make it possible to detect vulnerable plaques and thereby enhance efforts to prevent coronary events.
Imaging Methods for Detection of Intravascular Plaque – Direct, Robust and/or Validated
Comparative Intravascular Imaging for Lipid Core Plaque: VH-IVUS vs OCT vs NIRS
Eric Fuh, MD and Emmanouil S. Brilakis, MD, PhD
VA North Texas Healthcare System, Dallas, TX and Division of Cardiology, Dept of Medicine, UT Southwestern Medical Center, Dallas, TX
Conclusions
VH-IVUS, OCT, and NIRS can assist in the detection and evaluation of lipid core plaque. Comparative studies have shown important differences between modalities, but are all limited from lack of comparison with the gold standard of histology. Given the different strengths and weaknesses of each modality, combination imaging will likely provide the best results.41 Further refinement of the clinical implications of LCP detection and its impact on optimizing treatment strategy selection will stimulate advances in LCP detection imaging.
OCT and NIRS can image through calcified lesions, whereas IVUS cannot. LCPs are often accompanied by neovascularization, which can only be visualized by OCT. VH-IVUS may classify stents, which usually appear white (misclassified as “calcium”) surrounded by red (misclassified as “necrotic core”), although this does not appear to be a limitation for NIRS and OCT.54
Reference 41:
Bourantas CV, Gracia-Gracia HM, Naka KK, et al. Hybrid intravascular imaging: current applications and prospective potential in the study of coronary atherosclerosis, JACC 2013;61:1369-1378
Abstract
The miniaturization of medical devices and the progress in image processing have allowed the development of a multitude of intravascular imaging modalities that permit more meticulous examination of coronary pathology. However, these techniques have significant inherent limitations that do not allow a complete and thorough assessment of coronary anatomy. To overcome these drawbacks, fusion of different invasive and noninvasive imaging modalities has been proposed. This integration has provided models that give a more detailed understanding of coronary artery pathology and have proved useful in the study of the atherosclerotic process. In this review, the authors describe the currently available hybrid imaging approaches, discuss the technological innovations and efficient algorithms that have been developed to integrate information provided by different invasive techniques, and stress the advantages of the obtained models and their potential in the study of coronary atherosclerosis.
Kim SW, Mintz GS, Hong YJ, et al. The virtual histology intravascular ultrasound appearance of newly placed drug-eluting stents. Am J Cardiol. 2008;102:1182-1186.
American Journal of Cardiology Volume 102, Issue 9 , Pages 1182-1186, 1 November 2008
Intravascular ultrasound (IVUS) is used before and after intervention and at follow-up to assess the quality of the acute result as well as the long-term effects of stent implantation. Virtual histology (VH) IVUS classifies tissue into fibrous and fibrofatty plaque, dense calcium, and necrotic core. Although most interventional procedures include stent implantation, VH IVUS classification of stent metal has not been validated. In this study, the VH IVUS appearance of acutely implanted stents was assessed in 27 patients (30 lesions). Most stent struts (80%) appeared white (misclassified as “calcium”) surrounded by red (misclassified as “necrotic core”); 2% appeared just white, and 17% were not detectable (compared with grayscale IVUS because of the software-imposed gray medial stripe). The rate of “white surrounded by red” was similar over the lengths of the stents; however, undetectable struts were mostly at the distal edges (31%). Quantitatively, including the struts within the regions of interest increased the amount of “calcium” from 0.23 ± 0.35 to 1.07 ± 0.66 mm2 (p <0.0001) and the amount of “necrotic core” from 0.59 ± 0.65 to 1.31 ± 0.87 mm2 (p <0.0001). Most important, because this appearance occurs acutely, it is an artifact, and the red appearance should not be interpreted as peristrut inflammation or necrotic core when it is seen at follow-up. In conclusion, acutely implanted stents have an appearance that can be misclassified by VH IVUS as “calcium with or without necrotic core.” It is important not to overinterpret VH IVUS studies of chronically implanted stents when this appearance is observed at follow-up. A separate classification for stent struts is necessary to avoid these misconceptions and misclassifications.
The Search for Vulnerable Plaque — The Pace Quickens
Ryan D. Madder, MD1, Gregg W. Stone, MD2, David Erlinge, MD3, James E. Muller, MD4
Affiliations
1Frederik Meijer Heart & Vascular Institute, Spectrum Health, Grand Rapids, Michigan;
2New York Presbyterian Hospital, Columbia University and Car-diovascular Research Foundation, New York, New York;
3Department of Cardiology, Lund University, Lund, Sweden;
4Infraredx, Inc., Burlington, Massachusetts
Disclosure: Drs. Madder and Erlinge report no financial relationships or conflicts of interest regarding the content herein.
Dr. Stone is a consultant for Infraredx, Inc., Volcano Corp., Medtronic, and Boston Scientific, and is a member of the scientific advisory boards for Boston Scientific and Abbott Vascular.
Dr. Muller is a full-time employee of Infraredx, Inc from which he receives salary and equity.
Address for Correspondence: Email: ryan.madder@spectrumhealth.org
The search for the vulnerable plaque has been a lengthy endeavor requiring the work of multiple individuals and institutions over many years. It is disappointing that in more than 2 decades since the “vulnerable plaque” concept was formulated, over 40 million coronary events have occurred. However, it is encouraging that positive answers are now available for most of the questions related to a vulnerable plaque detection and treatment strategy. As shown in Table 1, most of the essential preconditions of a successful vulnerable plaque strategy are present. This positive information has accelerated the pace of work in this area. The pathophysiology of coronary events is well-understood; powerful imaging methods are available; and therapies, both existing and novel, may well be effective (although appropriately powered randomized trials are required to demonstrate their safety and effectiveness). The time is approaching for the conduct of prospective outcome trials to determine the value of a vulnerable plaque strategy for more effective prevention of coronary events.
Table 1. Essential Components of a Strategy to Prevent Coronary Events by the Detection and Treatment of Vulnerable Plaques
Essential Components
Evidencefrom Published Research
Pathophysiology of Coronary Events
• Are the causes of coronary events known?
Yes
Constantinides and others have shown that most coronary events are caused by rupture of a thin-capped LRP with subsequent formation of an occlusive thrombus.1-5
• Are LRPs focal?
Yes
Cheruvu et al demonstrated that ruptures and TCFA occupy less than 4% of the length of arteries studied at autopsy.8
• Are LRPs stable over time?
Yes
Kubo et al demonstrated that most fibroatheromas by radiofrequency IVUS remain fibroatheromas over time.39
Detection of Suspected Vulnerable Plaque by Invasive Imaging (For Secondary Prevention)
• Can invasive imaging safely detect LRP?
Yes
Waxman et al, Ino et al, and many others have demonstrated the safety of detecting LRP in patients.40
• Do cross-sectional studies show increased LRP concentrated at culprit sites?
Yes
Madder et al, Erlinge et al, Ino et al have shown LRP concentrated at the culprit site across the spectrum of ACS.14,16,41
• Do prospective studies show that suspected vulnerable plaque can be detected in advance?
Yes
PROSPECT, VIVA, PREDICTION established the principle by proving that increased plaque burden predicted events but prediction lacked specificity.23-25
• Is more specific detection of vulnerable plaque possible?
?
NIRS-IVUS and OCT may provide more specific detection of VP, but have not yet been tested in a prospective study.
Can Vulnerable Plaques be Treated?
• Is systemic treatment of LRPs possible with current agents?
Yes
YELLOW study showed a reduction in LRP with rosuvastatin.33
• Is focal treatment of LRPs possible with current methods?
Yes
Ruptured LRPs are routinely stented in ACS in clinical practice with good outcomes.
• Can systemic treatment be enhanced with new agents?
?
PCSK9 inhibitors, Apo A1 Milano, other agents in development may be more effective than statins, but more costly.35,36
• Can focal treatments be enhanced with new methods?
?
Bioresorbable vascular scaffolds and/or drug-coated balloons may be useful for VP.
Primary Prevention
• Can demographic and serum biomarkers be used as a first step in a screening strategy?
Yes
Framingham Risk Score, improved serum biomarkers, and genetic markers can identify individuals at increased risk.
• Can non-invasive imaging with CTA detect LRP and increased risk?
Yes
Motoyama et al have identified CTA markers associated with future events.26
Cost-Effectiveness
• Will a strategy of detection and treatment of vulnerable plaque, if proven to be successful, be cost-effective for secondary prevention?
Probably
Bosch et al demonstrated that for patients already undergoing invasive imaging, the added costs of detection and treatment of VP are likely to be less than the cost of second events, leading to a cost-saving approach that also improves health.38
• Will a strategy of detection and treatment of vulnerable plaque, if proven to be successful, be cost-effective for primary prevention?
?
Bosch et al: For primary prevention the cost of screening would be greater than for secondary prevention. Cost-effectiveness would depend upon cost, the accuracy of detection, and effectiveness of therapy.38
1. Constantinides P. Plaque fissures in human coronary thrombosis. J Atheroscler Res. 1966;6:1-17.
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3. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276-1282.
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6. Waksman R, Serruys PW. Handbook of the Vulnerable Plaque. Martin Dunitz: London, England, 2004.
7. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317-325.
8. Cheruvu P, Finn A, Gardner C, et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries – a pathologic study. J Am Coll Cardiol. 2007;50:940-949.
9. Hong M, Mintz GS, Lee CW, et al. Comparison of coronary plaque rupture between stable angina and acute myocardial infarction: a three-vessel intravascular ultrasound study in 235 patients. Circulation. 2004;110:928-933.
10. Fujii K, Kobayashi Y, Mintz GS, et al. Intravascular ultrasound assessment of ulcerated ruptured plaques. A comparison of culprit and non-culprit lesions of patients with acute coronary syndromes and lesions in patients without acute coronary syndromes. Circulation. 2003;108:2473-2478.
11. Ehara S, Kobayashi Y, Yoshiyama M, et al. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction. An intravascular ultrasound study. Circulation. 2004;110:3424-3429.
12. Lee SY, Mintz GS, Kim SY, et al. Attenuated plaque detected by intravascular ultrasound: clinical, angiographic, and morphologic features and post-percutaneous coronary intervention complications in patients with acute coronary syndromes. J Am Coll Cardiol Intv. 2009;2:65-72.
13. Asakura M, Ueda Y, Yamaguchi O, et al. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol. 2001;37:1284-1288.
14. Ino Y, Kubo T, Tanaka A, et al. Difference of culprit lesion morphologies between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol Intv. 2011;4:76-82.
15. Madder RD, Smith JL, Dixon SR, Goldstein JA. Composition of target lesions by near-infrared spectroscopy in patients with acute coronary syndrome versus stable angina. Circ Cardiovasc Interv. 2012;5:55-61.
16. Madder RD, Goldstein JA, Madden SP, et al. Detection by near-infrared spectroscopy of large lipid core plaques at culprit sites in patients with acute ST-segment elevation myocardial infarction. J Am Coll Cardiol Intv. In press, 2013.
17. Hoffmann U, Moselewski F, Nieman K, et al. Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by mulitdetector computed tomography. J Am Coll Cardiol. 2006;47:1655-1662.
18. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol. 2007;50:319-326.
19. Madder RD, Chinnaiyan KM, Marandici AM, Goldstein JA. Features of disrupted plaques by coronary computed tomographic angiography: correlates with invasively proven complex lesions. Circ Cardiovasc Imaging. 2011;4:105-113.
20. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79;733-743.
21. Kolodgie FD, Burke AP, Farb A, et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol. 2001;16:285-292.
22. Yamagishi M, Terashima M, Awano K, et al. Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. J Am Coll Cardiol. 2000;35:106-111.
23. Stone GW, Maehara A, Lansky A, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226-235.
24. Calvert PA, Obaid DR, O’Sullivan M, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) study. J Am Coll Cardiol Imaging. 2011;4:894-901.
25. Stone PH, Saito S, Takahashi S, et al. Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics: the PREDICTION study. Circulation. 2012;126:172-181.
26. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. 2009;54:49-57.
27. Stone GW, Maehara A, Mintz GS. The reality of vulnerable plaque detection. J Am Coll Cardiol Imaging. 2011;4:902-904.
28. Madder RD, Steinberg DH, Anderson RD. Multimodality direct coronary imaging with combined near-infrared spectroscopy and intravascular ultrasound: Initial US experience. Catheter Cardiovasc Interv. 2013;81:551-7.
29. Kume T, Akasaka T, Kawamoto T, et al. Measurement of the thickness of the fibrous cap by optical coherence tomography. Am Heart J. 2006;152:755.e1-4.
30. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.
31. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.
32. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078-2087.
33. Kini AS, Baber U, Kovacic JC, et al. Changes in plaque lipid content after short-term, intensive versus standard statin therapy: the YELLOW trial. J Am Coll Cardiol. 2013 (In press).
34. Takarada S, Imanishi T, Kubo T, et al. Effect of statin therapy on coronary fibrous-cap thickness in patients with acute coronary syndrome: assessment by optical coherence tomography study. Atherosclerosis. 2009;202:491-497.
35. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380:29-36.
36. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292-2300.
37. Braunwald, E. Epilogue: What do clinicians expect from imagers? J Am Coll Cardiol. 2006;47:C101-C103.
38. Bosch JL, Beinfeld MT, Muller JE, Brady T, Gazelle GS. A cost-effectiveness analysis of a hypothetical catheter-based strategy for the detection and treatment of vulnerable coronary plaques with drug-eluting stents. J Interv Cardiol. 2005;18:339-349.
39. Kubo T, Maehara A, Mintz GS, et al. The dynamic nature of coronary artery lesion morphology assessed by serial virtual histology intravascular ultrasound tissue characterization. J Am Coll Cardiol. 2010;55:1590-1597.
40. Waxman S, Dixon SR, L’Allier P, et al. In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results and exploratory analysis of the SPECTroscopic Assessment of Coronary Lipid (SPECTACL) multicenter study. J Am Coll Cardiol Imaging. 2009;2:858-868.
41. Erlinge D, Muller JE, Puri R, et al. Validation of a near-infrared spectroscopic signature of lipid located at culprit lesions in ST-segment elevation myocardial infarction. European Atherosclerosis Society. June 2013 (abstract).
Christos V. Bourantas, MD, PhD1, Hector M. Garcia, MD, PhD1, Roberto Diletti, MD1, Carlos A.M. Campos, MD1, Yaojun Zhang, MD, PhD1, Scot Garg, MRCP, PhD2, Patrick W. Serruys, MD, PhD1
1Department of Interventional Cardiology, Erasmus University Medical Centre, Thoraxcenter, Rotterdam, The Netherlands and 2Department of Cardiology, East Lancashire NHS Trust, Haslingden Road, Blackburn, Lancashire, United Kingdom.
Disclosures: The authors report no financial relationships or conflicts of interest regarding the content herein.
Address for correspondence: Email: p.w.j.c.serruys@erasmusmc.nl
The advent of intravascular imaging in the 1980s allowed us to studyin vivo plaque morphology and its prognostic implications.
Angioscopy and intravascular ultrasound (IVUS) were the first imaging techniques that provided information about the composition of plaque and allowed detection of its lipid component.7,8
However, the first applications of these modalities in the clinical setting not only underscored their potential value in the study of atherosclerosis but also highlighted their limitations in characterizing atheroma.9-11 Therefore an effort was made over the last few years to develop advanced techniques that would allow more reliable assessment of a plaque’s composition. Today several modalities are available for this purpose including:
the radiofrequency analysis of the IVUS backscatter signal (RF-IVUS),
near-infrared spectroscopy (NIRS),
optical coherence tomography (OCT),
magnetic resonance spectroscopy,
intravascular magnetic resonance imaging,
Raman spectroscopy,
photoacoustic imaging, and
time resolved spectroscopic imaging (Figure 1).
Some of these modalities are still in their infancy, while others have already been used in the clinical setting providing robust evidence about the prognostic implications of the differing compositions of the plaque. The aim of this review article is to present the most recent evidence about the long-term consequences of the atheroma’s phenotype.
Current Evidence from NIRS-based Clinical Studies
NIRS relies on the principle that different organic molecules absorb and scatter NIRS light to different degrees and wavelengths. Recent advances in device technology enabled the development of a catheter suitable for assessing the plaque in human coronaries that is able to emit NIR light and acquire the scattered signal. Spectral analysis of the obtained signal provides a color-coded display, called a chemogram (Figure 1C), which provides the probability that lipid core is present in the superficial plaque (studied depth approximately: 1 mm). Several studies have examined the reliability of this technique using histology as the gold standard and demonstrated a high overall accuracy in detecting lipid-rich plaques while others demonstrated its feasibility in the clinical setting.19-20
The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis (NCT01789411) – NIRS sub-study was the first prospective trial designed to evaluate the prognostic implications of an increased lipid component, as detected by NIRS, in coronary plaques. Two hundred three patients that underwent X-ray angiography, and PCI if it was indicated, had NIRS in a non-culprit coronary segment and were followed-up for 1 year. Twenty-eight patients sustained a MACE during the follow-up period; 21 of these events were non-culprit lesion related. Lipid plaque burden index appeared to be an independent predictor of MACE (hazard ratio: 4.04, 95% confidence interval: 1.33-12.29; P=0.01).
Currently, the Chemometric Observation of Lipid Rich Plaque of Interest in Native Coronary Arteries (COLOR, NCT00831116) registry is recruiting patients. This study is planning to recruit 2000 patients that will be investigated with NIRS imaging, and aims to examine the association between the presence of a necrotic core in the atheroma and subsequent coronary events. Preliminary results indicate that the absence of lipid-rich plaques is related with better outcomes (www.infraredx.com/the-color-registry).
Current Evidence From OCT-based Clinical Studies
OCT imaging with its high resolution appears able to provide detailed assessment of the superficial plaque and visualize structures that are unseen by other techniques such as the presence of micro calculations of thin-capped fibroatheroma (TCFA). However, a significant limitation of this technique is its poor penetration (1-2 mm), which does not permit through visualization of plaque burden, as well as its low capacity in differentiating lipid from calcific tissue when these are deeply embedded in the vessel wall.21
In this analysis, 53 patients who underwent PCI had OCT imaging in non-obstructive lesion sat baseline and repeat angiography at 7 months follow-up. They found that plaques with a TCFA phenotype, exhibiting vessel walldiscontinuities, macrophages, neo-vessels, and thrombi were morelikely to progress and cause significant angiographic obstructions.22
Future Perspective in Plaque Imaging – Conclusions
Cumulative data derived from intravascular imaging studies have provided robust evidence about the prognostic implications of plaque’s composition and burden, and demonstrated a strong association between the presence of lipid-rich plaques and future cardiovascular events. Plaque pathology and quantification of lipid components is done by hybrid catheters able to acquire different intravascular imaging data.23
1.Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysis of the composition ofatherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarctionand in sudden coronary death. Circulation. 1989;80:1747-1756.
3.Clark E, Graef I, Chasis H. Thrombosis of the aorta and coronary arteries. Archives of Pathology.1936;22:183-212.
4.Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death:a comprehensive morphological classification scheme for atherosclerotic lesions. ArteriosclerThromb Vasc Biol. 2000;20:1262-1275.
5.Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediatelesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council onArteriosclerosis, American Heart Association. Circulation. 1994;89:2462-2478.
6.ﾭrotic lesions and a histological classification of atherosclerosis. A report from the Committee onVascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation.1995;92:1355-1374.
7.Di Mario C, The SH, Madretsma S, et al. Detection and characterization of vascular lesionsby intravascular ultrasound: an in vitro study correlated with histology. J Am Soc Echocardiogr. 1992;5:135-146.
8.ﾭdation by histomorphologic analysis and association with stable and unstable coronary syndromes.J Am Coll Cardiol. 1996;28:1-6.
9.Hiro T, Leung CY, Russo RJ, et al. Variability in tissue characterization of atherosclerotic plaqueby intravascular ultrasound: a comparison of four intravascular ultrasound systems. Am J CardImaging. 1996;10:209-218.
10.ﾭdial infarction: ability of optical coherence tomography compared with intravascular ultrasoundand coronary angioscopy. J Am Coll Cardiol. 2007;50:933-939.
11.ﾭated with future risk of acute coronary syndrome: detection of vulnerable patients by angioscopy.J Am Coll Cardiol. 2006;47:2194-2200.
12.ﾭnary syndrome using integrated backscatter intravascular ultrasound. J Am Coll Cardiol.2006;47:734-741.
13.Amano T, Matsubara T, Uetani T, et al. Lipid-rich plaques predict non-target-lesion ischemicevents in patients undergoing percutaneous coronary intervention. Circ J. 2011;75:157-166.
14.ﾭsclerosis. N Engl J Med. 2011;364:226-235.
15.Calvert PA, Obaid DR, O’Sullivan M, et al. Association between IVUS findings and adverseﾭsclerosis) Study. JACC Cardiovasc Imaging. 2011;4:894-901.
16.Granada JF, Wallace-Bradley D, Win HK, et al. In vivo plaque characterization using intravascularultrasound-virtual histology in a porcine model of complex coronary lesions. Arterioscler ThrombVasc Biol. 2007;27:387-393.
17.Sales FJ, Falcao BA, Falcao JL, et al. Evaluation of plaque composition by intravascular ultrasound“virtual histology”: the impact of dense calcium on the measurement of necrotic tissue. ﾭvention. 2010;6:394-399.
19.ﾭmens with a novel catheter-based near-infrared spectroscopy system. JACC Cardiovasc Imaging. 2008;1:638-648.
20.Waxman S, Dixon SR, L’Allier P, et al. In vivo validation of a catheter-based near-infrared spectrosﾭcopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study.JACC Cardiovasc Imaging. 2009;2:858-868.
21.Manfrini O, Mont E, Leone O, et al. Sources of error and interpretation of plaque morphology byoptical coherence tomography. Am J Cardiol. 2006;98:156-159.
22.Uemura S, Ishigami K, Soeda T, et al. Thin-cap fibroatheroma and microchannel findings inoptical coherence tomography correlate with subsequent progression of coronary atheromatousplaques. Eur Heart J. 2012;33:78-85.
23.ﾭplications and prospective potential in the study of coronary atherosclerosis. J Am Coll Cardiol.2013;61:1369-378.
24.ﾭtroscopy and intra-vascular ultrasound catheter to identify composition and structure of coronaryplaque. EuroIntervention. 2010;5:755-756.
25.ﾭﾭgrated Biomarker and Imaging Study-3 (IBIS-3). EuroIntervention. 2012;8:235-241.
NIRS-IVUS Imaging Identifies Lesions at High Risk of Peri-Procedural Myocardial Infarction
James A. Goldstein, MD, Simon R. Dixon, MBChB*, Gregg W. Stone, MD
From the Department of Cardiovascular Medicine, William Beaumont Hospital, Royal Oak, MI.
Address for correspondence: James A. Goldstein, MD, FACC, Department of Cardiovascular Medicine, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073. Email: jgoldstein@beaumont.edu
Disclosures: Dr. Goldstein is a consultant for and owns equity in Infraredx, Inc. Dr. Stone is a consultant for Infraredx, Inc., Volcano Corp., Medtronic, and Boston Scientific, and is a member of the scientific advisory boards for Boston Scientific and Abbott Vascular. Dr. Dixon reports no financial relationships or conflicts
Abstract:
Percutaneous coronary intervention (PCI) is associated with distal embolization complications, including peri-procedural myocardial infarction (PPMI), including no-reflow, in 3%-15% of cases. These complications are predominantly related to distal embolization of lipid core plaque (LCP) components. Catheter-based near-infrared spectroscopy (NIRS) provides rapid, automated detection of LCPs, the magnitude of which appears associated with a high-risk of PPMI. Employing this technique may facilitate development of preventive measures such as embolic protection devices (EPDs).
Figures 1. A 62-year-old man with stable angina underwent coronary angiography, which demonstrated a complex hazy ulcerated culprit lesion in the mid-right coronary artery (Figure 1A, solid arrow). Neither the angiogram nor an intravascular ultrasound image indicated the presence of thrombus. NIRS demonstrated a large yellow signal spanning the circumference of the culprit site (Figure 1B, white rectangle), indicating the presence of a napkin-ring LCP; a smaller LCP was evident distally (Figure 1, open arrow).
Figure 2. Balloon angioplasty was performed (Figure 2A, arrow), which led to prompt no-reflow (Figure 2B, arrow) associated with severe bradyarrhythmia and profound hypotension (Figure 2C). After brief cardiopulmonary resuscitation and pharmacological support with atropine and dopamine, physiologic rhythm and blood pressure were restored and stenting resulted in excellent angiographic outcome. However, the patient developed a peri-stenting non-transmural infarction (peak creatine kinase of 512 ng/mL) and required an additional day of hospital care in an intensive care unit. (Goldstein JA, et al. JACC Cardiovasc Imaging. 2009;2(12):1420-1424. Reproduced with permission.)
Jason C. Kovacic, MD, PhD, Annpoorna Kini, MD, MRCP
From The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York.
Address for correspondence: Dr. Annapoorna Kini, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY, 10029. Email: annapoorna.kini@mountsinai.org
Disclosures: Dr. Kovacic is supported by National Institutes of Health Grant K08HL111330 and has received research support from AstraZeneca. Dr. Kini acknowledges honoraria from Medscape and has received research grant support from InfraReDx.
A new group of terms is slowly creeping in to the atherosclerotic disease lexicon: “Lipid Arc,” “Lipid Core Plaque,” “Lipid-Rich Plaque,” “Lipid Core Burden Index” and other similar phrases. While clinicians and researchers have long been aware of the central importance of lipid in the biology of atherosclerosis, the growing use of these terms is driven by the recent widespread use of novel imaging modalities that provide accurate detection, and even quantification, of the extent of lipid that is contained within the core of an atherosclerotic plaque. Our ability to detect and quantify lipid in plaques is opening up new therapeutic opportunities for modifying the atherosclerotic disease process, which may ultimately be of benefit to patients.
At the present time there are 3 methods that are commonly used to measure the extent of lipid in atherosclerotic plaques. Perhaps most familiar of these is coronary computer tomographic (CT) scanning. While more commonly used to quantitate calcification or luminal stenosis, CT scanning is readily able to quantitate the extent of lipid associated with an atherosclerotic lesion. However, while several studies have reported various Hounsfield Unit (HU)-based criteria to distinguish lipid-rich from fibrous plaques, the HU cut-off points have so far been inconsistent. The use of CT for detecting lipid-rich plaque is further limited by its relatively low spatial resolution and the fact that the HU values for distinguishing between fibrous and lipid-rich plaques are overlapping.1 In contrast, optical coherence tomography (OCT) offers perhaps the greatest spatial resolution of all clinically available coronary imaging devices. OCT can offer exquisite detail of abluminal coronary artery anatomy, including detection of lipid core plaque. However, while automated systems are being developed, at the present time the quantitation of lipid by OCT is a somewhat specialized process that typically involves detailed off-line analysis.
A specific intra-coronary imaging catheter for the quantitation of coronary artery lipid content is now available and FDA approved: diffuse reflectance near-infrared spectroscopy (NIRS). The application of NIRS to identify lipid deposition within coronary arteries has been validated ex vivo2-5 and in vivo.6,7 Although NIRS itself is essentially only able to detect and quantitate lipid, design changes and technological advances to this catheter have now made it possible to combine intravascular ultrasound (IVUS) and NIRS technology on a single instrument. In one of the few clinical studies published to date using this device, NIRS has already shown that a high lipid burden in a target lesion undergoing percutaneous coronary intervention (PCI) is associated with an increased likelihood of peri-procedural myocardial infarction.7
It is well known that the reduction of cholesterol levels by statin therapy is associated with significant decreases in plaque burden. REVERSAL,8 ASTEROID,9 and more recently the SATURN II10 trial showed that in patients with coronary artery disease (CAD), lipid lowering with high-dose statin therapy reduced progression of plaque atheroma burden, even causing plaque regression of some lesions. However, while reduction in atheroma burden and plaque size are important anatomical endpoints, a major unresolved question had been the mechanism of action of statins and the unanswered question of whether they reduce plaque lipid content. Indeed, a high burden of plaque lipid is one of the cardinal features of a rupture-prone vulnerable lesion.11 Therefore, the ability to reduce plaque lipid content may have important effects on lesion stability and therefore, might impact clinical endpoints.
The advent of sensitive imaging tools for the evaluation of plaque lipid content has paved the way for the investigation of potential pharmacological therapies for lipid core plaque. In particular, the ability of NIRS to provide an automated quantitation of plaque lipid provides a ready-made platform for this task. We recently completed the YELLOW study of high-dose statin therapy for the potential reduction of coronary artery lipid content as assessed by NIRS. We randomized 87 patients with multivessel CAD undergoing elective PCI to rosuvastatin 40 mg daily vs conventional statin therapy. Following PCI of the culprit lesion, non-culprit lesions with a fractional flow reserve (FFR) <0.8 were interrogated using IVUS and NIRS. Changes in plaque composition were assessed after 6-12 weeks during follow-up angiography. The core finding of this study was that high-dose statin therapy was associated with significant reductions in the lipid content of coronary atherosclerotic plaques. Interestingly, despite reduced plaque lipid content, in this relatively short time period concordant changes in gross lesion characteristics such as total atheroma volume or % plaque burden were not observed.12 In short, the YELLOW study identified that even before gross atheroma regression occurs, lipid removal from plaques is an early event upon initiation of high-dose statin therapy. Furthermore, the results of the YELLOW study are concordant with the known acute benefits of statin therapy in patients presenting with acute coronary syndromes, where the early introduction of these agents is known to be of clinical benefit.13 While the YELLOW study was the first of this nature and the results remain to be replicated in a larger trial, these findings have revived interest in the concept of the “vulnerable plaque” because it appears possible that by causing lipid core reduction over a just few weeks, high-dose statin therapy may have rapid plaque stabilizing effects. We are now embarking on the YELLOW II study, where we will further explore the utility of high-dose rosuvastatin for the early reduction of plaque lipid content and potential mechanistic pathways.
What other agents might have therapeutic efficacy for lipid core reduction? This question is perhaps more complex than it might first appear, because at the present time we do not know the specific mechanism whereby high-dose rosuvastatin causes lipid reduction in plaques. Theoretically it may be due to reduced LDL, increased HDL, other mechanisms or a combination of these effects. Potentially, other agents that are already available such as bile acid sequestrants, ezetimibe, and fibrates may have a weak lipid core reducing effect. However, we would underscore the fact that at the present time the utility of these agents is speculative, and no other agent (apart from high-dose rosuvastatin in the YELLOW study) has been shown to reduce lipid content in vivo in human plaques. Furthermore, given the fact that these other agents are far less potent in their overall effect than rosuvastatin 40 mg/day, it may be clinically challenging to determine if they have efficacy for lipid core reduction beyond that of statins.
In addition to pharmacotherapy, it must be remembered that we have several non-pharmacological treatments in our armamentarium that may impact lipid core reduction. For example, exercise is known to be associated with reduced plaque lipid content,14 and proper adherence to current guidelines with respect to lifestyle and diet are of paramount importance in any patient in whom it is considered desirable to reduce plaque lipid content.
Looking ahead, there are several emerging and investigational agents that may hold promise for lipid core reduction. Microsomal triglyceride transfer protein (MTP) is expressed in the liver, intestine, and the heart and is required for the proper assembly of VLDL and chylomicrons. In animals, treatment with an MTP inhibitor leads to a rapid reduction in plasma lipid levels, with a significant decrease in lipid content and monocyte-derived (CD68+) cells in atherosclerotic plaques.15 On December 21, 2012, the first of the MTP inhibitors was approved for clinical use. Lomitapide (marketed as Juxtapid) was approved by the FDA as an adjunct to a low fat diet and other lipid-lowering treatments for patients with homozygous familial hypercholesterolemia. However, concerns have been raised due to hepatic side effects and liver toxicity. As a result, lomitapide will carry a boxed warning and will only be available through a restricted program.16 Another new drug that was recently given restricted approval in the US for homozygous familial hypercholesterolemia is mipomersen. This agent is an antisense therapeutic that targets messenger RNA for apolipoprotein B, leading to reduced apoB protein and LDL levels. While showing efficacy for lowering LDL,17 safety concerns have thus far prohibited this agent from gaining approval for use in Europe. PCSK9 inhibitors are yet another novel class of agents that may hold promise for reducing lipid core plaque. PCSK9 is involved in the degradation of the LDL receptor (LDLR), and by inhibiting PCSK9 it is believed that this permits more LDL receptors to remain active and participate in LDL removal from the blood, thereby reducing plasma LDL and cholesterol levels. Denis et al18 recently demonstrated that gene inactivation of PCSK9 in mice reduced aortic cholesterol accumulation and atherosclerotic lesion development in atherosclerosis-prone mice. Based on their powerful LDL lowering effect, intense efforts are currently underway to develop clinically efficacious PCSK9 inhibitors with several agents already moving to phase II/III human studies.19 While all of these new and emerging therapies are cause for optimism, the recent experience with CETP-inhibitors and the overall failure of this class so far to stand up to rigorous testing as HDL raising agents in phase III studies20,21 serves to remind us that not all “promising future therapies” survive through the arduous clinical testing pipeline.
In conclusion, there is renewed interest in the concept of “plaque regression” and pharmacological therapy for “lipid core reduction.” This has been driven by our increasing ability to image and quantify these phenomena, and more recently by the provocative findings that high-dose statin therapy may achieve both of these clinical endpoints. Further studies are now required to evaluate novel agents, define mechanisms of action and, most importantly, to confirm that atherosclerotic lipid core reduction is associated with plaque stabilization and fewer clinical endpoints.
References, pp. 27A-28A in the Supplement
1. Kristanto W, van Ooijen PM, Greuter MJ, et al. Non-calcified coronary atherosclerotic plaque visualization on CT: effects of contrast-enhancement and lipid-content fractions. Int J Cardiovasc Imaging. 2013; online ahead of print.
2. Cassis LA, Lodder RA. Near-IR imaging of atheromas in living arterial tissue. Anal Chem. 1993;65:1247-1256.
3. Jaross W, Neumeister V, Lattke P, et al. Determination of cholesterol in atherosclerotic plaques using near infrared diffuse reflection spectroscopy. Atherosclerosis. 1999;147:327-337.
4. Moreno PR, Lodder RA, Purushothaman KR, et al. Detection of lipid pool, thin fibrous cap, and inflammatory cells in human aortic atherosclerotic plaques by near-infrared spectroscopy. Circulation. 2002;105:923-927.
5. Wang J, Geng YJ, Guo B, et al. Near-infrared spectroscopic characterization of human advanced atherosclerotic plaques. J Am Coll Cardiol. 2002;39:1305-1313.
6. Waxman S, Dixon SR, L’Allier P, et al. In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study. JACC Cardiovasc Imaging. 2009;2:858-868.
7. Goldstein JA, Maini B, Dixon SR, et al. Detection of lipid-core plaques by intracoronary near-infrared spectroscopy identifies high risk of periprocedural myocardial infarction. Circ Cardiovasc Interv. 2011;4:429-437.
8. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29-38.
9. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.
10. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078-2087.
11. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation. 2002;105:939-943.
12. Kini AS, Baber U, Kovacic JC, et al. Changes in plaque lipid content after short-term, intensive versus standard statin therapy: The YELLOW Trial. J Am Coll Cardiol. 2013;62:21-29.
13. Hulten E, Jackson JL, Douglas K, et al. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166:1814-1821.
14. Yoshikawa D, Ishii H, Kurebayashi N, et al. Association of cardiorespiratory fitness with characteristics of coronary plaque: assessment using integrated backscatter intravascular ultrasound and optical coherence tomography. Int J Cardiol. 2013;162:123-128.
15. Hewing B, Parathath S, Mai CK, et al. Rapid regression of atherosclerosis with MTP inhibitor treatment. Atherosclerosis. 2013;227:125-129.
16. Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356:148-156.
17. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:998-1006.
18. Denis M, Marcinkiewicz J, Zaid A, et al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation. 2012;125:894-901.
19. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891-1900.
20. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089-2099.
21. Kovacic JC, Fuster V. From Treating Complex Coronary Artery Disease to Promoting Cardiovascular Health: Therapeutic Transitions and Challenges, 2010-2020. Clin Pharmacol Ther. 2011;90:509-518.
KOVACIC and KINI
28A
The Journal of Invasive Cardiology®
KEY SOURCE for this Article
Journal of Invasive Cardiology, August 2013, Vol 25/Supplement A
Print ISSN 1042-3931 / Electronic ISSN 1557-2501
Introduction
NIRS-IVUS Imaging To Characterize the Composition and Structure of Coronary Plaques
D. RIZIK AND J.A. GOLDSTEIN……………………………………..2A
Background
Imaging of Plaque Composition and Structure with the TVC Imaging System™ and TVC Insight™ Catheter
B. SHYDO, ET AL…………………………………………………………5A
Comparative Intravascular Imaging for Lipid Core Plaque: NIRS vs VH-IVUS vs OCT
E. FUH AND E.S. BRILAKIS……………………………………………9A
Plaque Characterization and PCI Procedural Outcomes
NIRS-IVUS Imaging Identifies Lesions at High Risk of
Since the Affordable Care Act became law in 2010, cardiologists have been mired in a fog of uncertainty, leading to delays in making important practice management decisions.
“When I get together with colleagues at national meetings, I get the sense that nobody really understands the future,” said Cam Patterson, MD, MBA, chief of the division of cardiology at the University of North Carolina at Chapel Hill.
That uncertainty “throws a wrench into the planning process,” including recruitment and benchmark setting, he told MedPage Today.
“It’s a major sea change,” added Thomas Tu, MD, director of the cardiac catheterization lab for the Louisville Cardiology Group in Louisville, Ky., who notes that physicians are “struggling” to find ways they can be influential in the new environment.
Patterson noted the plight of young cardiologists seeking jobs in a healthcare market unsure of how or when to make its next move.
“It’s challenging to hire new recruits when budgetary and human resources decisions are essentially on hold until there is a better understanding of what the ACA will bring,” he commented.
Regarding setting benchmarks, Patterson said the days of merely imagining your quality is as good as the next practice or hospital are gone.
Cold, hard data are the new norm, but which data and how best to collect and analyze them, as well as apply the results in a robust and meaningful way, are being worked out slowly.
“As with everyone else, we are scrambling to get a grip on what our quality measures are,” Patterson said.
Education and Prevention Will Be Key
Hospitalists, as well as advanced nurse practitioners and physician assistants, can help ease the workload due to the shortage of primary care providers, a shortage that is particularly acute in California, according to C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles.
“If the reform happens the way it is intended, we should have an integrated healthcare system where primary prevention — management of hypertension, dyslipidemia, diabetes, smoking cessation counseling, and therapeutic lifestyle changes — is handled at the primary care level,” she said.
The truth of the matter, however, is that it takes twice as long to train the average general physician as it does an average nurse practitioner, and four times as long as the average physician assistant.
“It’s a lot to expect of physician extenders to practice primary care medicine,” Merz toldMedPage Today.
“A better system is the medical home model, with physician team leaders and physician extenders who work on protocols. The physician extenders would be licensed and would be able to work autonomously within a protocol,” she said.
Five years ago, the cardiology department at Geisinger Health Center in Danville, Pa., employed four nurse practitioners or clinical nurse specialists. Today, there are 12 and the department is seeking three more, according to James Blankenship, MD, vice president of the Society for Cardiovascular Angiography and Interventions, as well as an interventional cardiologist at Geisinger.
Blankenship also said that acknowledging the need for more primary care providers is to miss half of the equation. “We will need more specialists, as well.”
Given the newly insured patients coming into the system, as well as the aging Medicare population, cardiologists will be stretched pretty thin. But the field of cardiology has been instrumental in advocating teamwork among the different specialties for years, he said. “That’s a train that’s already on the tracks.”
Merz noted an expectation to see more cardiovascular care teams in response to the ACA. Such teams typically consist of a physician leader, nurse practitioners, pharmacists, behavioral experts, rehab professionals, and others.
These teams are vital for the care of high-risk patients such as survivors of angioplasty, bypass surgery, and heart failure, she said, especially since there aren’t enough cardiologists to do it all.
Echoing Blankenship, Merz said that cardiologists will probably be busier than ever as heart disease remains the leading killer among men and women as the population ages. She noted a decline in the most severe type of heart attack — ST-segment elevation MI, or STEMI — in the Medicare population, a decline that is likely multifactorial, but two reasons stand out as attributable to the decline — the use of low-dose aspirin and statin therapy for primary and secondary prevention, she said.
“At whatever level these medications are prescribed and managed — primary care physician, nurse practitioner, cardiologist — one thing is clear: they work and they should continue to be utilized at the front line of heart disease management,” Merz said.
Patients with chronic diseases already consume a great deal of healthcare resources. The other side of that coin is prevention, noted Kathy Berra, MSN, ANP, president of the Preventive Cardiovascular Nurses Association and a nurse at Stanford Prevention Research Center in Stanford, Calif.
“Prevention is a family affair. It’s been shown that when women take care of themselves, the health of the family improves.”
Emerging as one of the more important gatekeepers for women’s health — including cardiovascular health — are ob/gyns, Berra said.
Gynecologists have increased their efforts to quiz women about heart disease risk factors such as hypertension, high cholesterol, and diabetes. If red flags are apparent, patients can be referred to primary care providers, internal medicine physicians, or cardiologists.
“Ob/gyns are on the front line of women’s health. Perhaps under the ACA model, these specialists will have a closer relationship with cardiologists,” Berra told MedPage Today.
Regarding nurses and other care providers in hospitals, they need to be able to educate patients about how to take care of themselves post-discharge, how to understand the importance of their medications, and how to best re-connect with their nonhospital environment.
Readmission is at epidemic proportions and it can be reined in by patient education at the hospital level. Even pharmacists are getting more involved in patient education.
Scott & White Hospital in Temple, Texas, has a program that encourages adherence by waiving drug copays following an education session, according to James Rohack, MD, director of the Center for Healthcare Policy at Scott & White.
Patients on Seniorcare who are on five medications or more are asked if they want to participate in the program. If they agree, they meet with a pharmacist once a month for 15 to 30 minutes. The pharmacist goes over everything about the patient’s medication, listens to any concerns, and sends him or her home with new medications, waiving the copay.
“Having no copay is a great benefit for patients on fixed incomes, but it goes beyond that. A little bit of education goes a long way and if patients can be reminded once a month about the importance of taking their medications, we will have fewer hospitalizations,” Rohack said.
Accountable Care Organizations
The development of ACOs is probably one of the biggest challenges under the ACA, said Geisinger’s Blankenship.
The promise of ACOs is to have better integrated care, less fragmented care among various providers. Part of this integrated care involves incentives to minimize procedures that are either unnecessary or could be replaced with a less costly treatment.
“Having been under a fee-for-service model for a long time, some in cardiology might find the new paradigm challenging,” Blankenship suggested.
ACOs are supposed to help take the sting out of moving away from the fee-for-service model by providing the opportunity for better coordinated care — which should translate into a higher quality of care.
However, ACOs can be difficult to set up, especially from scratch, as they have a large startup cost, he said.
One of the most important aspects of an ACO is to have a solid network of primary care doctors. Patterson, at UNC Chapel Hill, said the uncertainty of whether his state will expand Medicaid has led to the “very aggressive acquisition of primary care practices.”
“The goal is to have enough physicians and patients so that we will have a low-cost ACO when we are ready to implement that model. We are going to need about 1 million patients to have an efficient ACO,” he said.
But there are also fears that the ACA will deluge cardiologists with paperwork.
“In the clinic, I spend as much time with paperwork as I do with patients — particularly with Medicare and Medicaid patients,” noted John Day, MD, director of Heart Rhythm Services at Intermountain Medical Center in Salt Lake City, Utah. “Many of us are worried we haven’t even seen the beginning of the deluge.”
The intrusion of paperwork and other government regulations tends to erode the time physicians get to spend with patients — “one of the primary reasons I wanted to be a doctor,” Day said.
In addition, Day said that he and many of his colleagues are disappointed that the ACA did not address malpractice concerns. “Perhaps it’s not so much what’s in the bill as what is not in the bill,” he said.
“Malpractice concerns are real; they scare me every day; it affects how you practice medicine. I don’t see how you can rein in costs without addressing the malpractice quagmire,” Day told MedPage Today.
Shifting Sands
“For those of us working in the trenches, we have a vague concept of the changes coming down the road,” said James A. de Lemos, MD, director of the coronary care unit at Parkland Memorial Hospital in Dallas.
“We seem to be too busy to think about the changes, which leads to one of my biggest worries — that I won’t have prepared my troops well enough,” he said.
From a clinical perspective, it’s business as usual, with de Lemos and colleagues focused on growth and the development of referrals and procedure services.
“We are concerned, however, that the entire paradigm is going to shift and what we’re building today might not be financially sound in the ACO model,” de Lemos told MedPage Today.
De Lemos, who is active in cardiovascular biomarker research, suggested that biomarkers will become more important in the ACA era of healthcare.
“It will no longer be prudent to send everyone with a complaint to a cardiologist,” he commented. “Biomarker screening may play a role as a triage method to separate out those who merit a trip to the cardiologist from those who can be treated by primary care doctors.”
Rohack made these suggestions for getting ready for the changes associated with the ACA:
Make sure you are actively aware of your quality measures, your individual quality measures.
When caring for uninsured adults, make sure you are aware of the potential benefits with health insurance exchanges, because they may qualify.
Make sure you are aware of impending deadlines regarding the implementation of certain aspects associated with electronic medical records because penalties can be assessed for missing deadlines.
Who Takes the Lead?
There are a lot of moving pieces that will contribute to finding success in the new era of healthcare and leaders must emerge to help forge pathways that others can follow. Hospitalists will be among those leaders, says Jeffrey H. Barsuk, MD, MS, a hospitalist and director of Simulation and Patient Safety for Graduate Medical Education at Northwestern University Feinberg School of Medicine in Chicago.
“At our hospital, we are probably the largest group of physicians involved in healthcare safety, quality, and reform,” he said.
The ACA, he told MedPage Today, is starting to have more of an impact on how he and his colleagues position themselves for the future.
In particular, the new bundled payment and fee-per-encounter models are ideal scenarios where hospitalists can make a difference by bridging gaps in the continuity of care and helping to shorten the length of stay without compromising quality.
Hospitalists can, for example, provide smoking cessation counseling for heart patients, discuss the importance of medication adherence, and check to ensure there are no contraindications to the medications or no potential for drug-drug adverse interactions.
Ultimately, though, clinicians at all levels, primary care practitioners and specialists, will need to work closely together because, as interventionalist Tu noted, government intervention that is not well thought out can backfire. The ACA might save money in the short run, Tu said, but in the long term, there is a great potential “to damage the care of patients and harm the profession of medicine. Already many good people don’t want to be in the field anymore.”
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