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1.  Frequency and Predictors of Renal Artery Stenosis in Patients Undergoing Simultaneous Coronary and Renal Catheterization 
Background
Atherosclerotic renal artery stenosis (ARAS) remains underdiagnosed due to its nonspecific demonstrations. We aimed to both estimate the frequency of ARAS in high-risk non-selected patients undergoing simultaneous coronary and renal catheterization and possibly identify a predictive model for ARAS using baseline clinical, laboratory, and coronary angiographic variables.
Methods:
The records of 866 patients aged ≥ 21 years undergoing simultaneous coronary and renal angiography were retrieved for analysis from our computerized database. The degree of ARAS was estimated visually by experienced attending interventional cardiologists. Lesions with an estimated stenosis of ≥ 50% were considered significant. Multivariable stepwise logistic regression models were used to identify the risk factors predicting the presence and extent of ARAS.
Results:
Of a total of 866 consecutive patients undergoing renal angiography in conjunction with coronary angiography (mean age ± SD: 63.06 ± 10.32, ranging from 24 to 89 years), 454 (57%) were men. A total of 345 (39.8%) cases had significant ARAS, 77 (22.3%) of which were bilateral. Using significant ARAS as the dependent variable, six variables were identified as the independent predictors significantly associated with the presence of ARAS, namely age, female sex (male sex was found to be a protector), hypertension, history of renal failure, left anterior descending artery (LAD) stenosis > 50%, and left circumflex artery (LCX) stenosis > 50%. The Gensini score was not found to be a predictor of the presence of ARAS, but it was more likely associated with a trend towards a more extensive ARAS (adjusted OR = 1.00, 95% CI = 1.00–1.01; p value = 0.039). Other independent determinants of the ARAS extent were the same as the predictors of the ARAS presence.
Conclusion:
Although risk versus benefit was not tested in this study, it seems that clinicians could consider renal catheterization in combination with coronary angiography particularly in female patients with advanced age and with significant coronary artery stenoses in the LAD and LCX.
PMCID: PMC3466904  PMID: 23074639
Renal artery obstruction; Coronary angiography; Renal insufficiency
2.  Adipose tissue-derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis 
Stem cells (Dayton, Ohio)  2012;30(5):1030-1041.
Background
Reno-protective strategies are needed to improve renal outcomes in patients with atherosclerotic renal artery stenosis (ARAS). Adipose tissue-derived mesenchymal stem cells (MSCs) can promote renal regeneration, but their potential for attenuating cellular injury and restoring kidney repair in ARAS has not been explored. We hypothesized that replenishment of MSC as an adjunct to percutaneous transluminal renal angioplasty (PTRA) would restore renal cellular integrity and improve renal function in ARAS pigs.
Methods and Results
Four groups of pigs (n=7 each) were studied after 16 weeks of ARAS, ARAS 4 weeks after PTRA and stenting with or without adjunct intra-renal delivery of MSC (10×106 cells), and controls. Stenotic kidney blood flow (renal blood flow[RBF]) and glomerular filtration rate (GFR) were measured using multidetector computer tomography (CT). Renal microvascular architecture (micro-CT), fibrosis, inflammation, and oxidative stress were evaluated ex-vivo.
Four weeks after successful PTRA, mean arterial pressure fell to a similar level in all revascularized groups. Stenotic kidney GFR and RBF remained decreased in ARAS (p=0.01 and p=0.02) and ARAS+PTRA (p=0.02 and p=0.03) compared to normal, but rose to normal levels in ARAS+PTRA+MSC (p=0.34 and p=0.46 vs. normal). Interstitial fibrosis, inflammation, microvascular rarefaction, and oxidative stress were attenuated only in PTRA+MSC-treated pigs.
Conclusions
A single intra-renal delivery of MSC in conjunction with renal revascularization restored renal hemodynamics and function, and decreased inflammation, apoptosis, oxidative stress, microvascular loss, and fibrosis. This study suggests a unique and novel therapeutic potential for MSC in restoring renal function when combined with PTRA in chronic experimental renovascular disease.
doi:10.1002/stem.1047
PMCID: PMC3694782  PMID: 22290832
renal artery stenosis; progenitor cells; renal hypertension; revascularization
3.  Effect of spironolactone on cardiac remodeling after acute myocardial infarction 
BACKGROUND:
Few studies have reported the effect of aldosterone receptor antagonist (ARA) on myocardial remodeling after acute myocardial infarction (AMI). This study was undertaken to investigate the preventive effect of ARA on myocardial remodeling after AMI.
METHODS:
A total of 616 patients who had been admitted into the CCU of the First Affiliated Hospital of Harbin Medical University from January 2008 to January 2010 were studied prospectively. Only 528 patients were observed completely, including 266 of the control group and 262 of the treatment group. There was no statistical difference in age, gender, medical history, admission situation, and treatment between the two groups (P>0.05). The preventive effects of spironolactone on cardiac remodeling, left ventricular function, renal function and blood levels of potassium were evaluated by echocardiography, serum potassium and serum creatinine at one-month and one-year follow-up.
RESULTS:
The echocardiography indicators such as LVESD, LVEDD, LVEF, LAD-ML and LAD-SI were significantly improved in the treatment group compared with the control group at one year (P<0.05). In the treatment group, LVESD, LVEDD, LVPWT, LVEF, LAD-ML and LAD-SI were more significantly improved at one year than one month (P<0.05, P=0.007 to LVEF), and in the control group LVEF was more significantly improved at one year than one month (P=0.0277). There were no significant differences in serum potassium and serum creatinine levels between the two groups.
CONCLUSION:
On the basis of conventional treatment, the early combination of low-dose spironolactone (20 mg/d) could inhibit cardiac remodeling at late stage and prevent heart failure.
doi:10.5847/wjem.j.issn.1920-8642.2013.01.009
PMCID: PMC4129890  PMID: 25215092
Myocardial infarction; acute; Ventricular remodeling; Atrial remodeling; Aldosterone; Aldosterone blockade; Spironolactone; Cardiac function; Prognosis
4.  The Association between Atherosclerotic Renal Artery Stenosis and Acute Kidney Injury in Patients Undergoing Cardiac Surgery 
PLoS ONE  2013;8(5):e64104.
Background
Atherosclerotic renal artery stenosis (ARAS) and coronary artery disease (CAD) commonly co-exist. Some patients with unidentified ARAS may undergo cardiac surgery. While acute kidney injury (AKI) is a frequent and serious complication of cardiac surgery, we aim to evaluate the influence of ARAS on the occurrence of postoperative AKI in patients with normal or near-normal baseline renal function following cardiac surgery.
Methods
A total of 212 consecutive patients undergoing aortography after coronary angiography and cardiac surgery were retrospectively studied for their preoperative and intraoperative conditions. AKI was defined as an absolute increase in serum creatinine of more than or equal to 0.3 mg/dl (≥26.4 µmol/l) or a percentage increase in creatinine of more than or equal to 50% (1.5-fold from baseline) after cardiac surgery. A propensity score-adjusted logistic regression models was used in estimating the effect of ARAS on the risk of postoperative AKI.
Results
ARAS (≥50%) was observed in 50 (23.6%) patients, and 83 (39.2%) developed AKI after cardiac surgery. A correlation existed between renal artery patency and preoperative–to–postoperative %ΔCr in patients with ARAS (r = 0.297, P<0.0001). The propensity score-adjusted regression model showed the occurrence of postoperative AKI in patients with ARAS was significantly higher than those without ARAS (OR 2.858, 95% CI 1.260–6.480, P = 0.011).
Conclusion
ARAS is associated with postoperative AKI in patients with normal or near-normal baseline renal function after cardiac surgery.
doi:10.1371/journal.pone.0064104
PMCID: PMC3660310  PMID: 23700459
5.  Magnetic resonance elastography noninvasively detects in-vivo renal medullary fibrosis secondary to swine renal artery stenosis 
Investigative radiology  2013;48(2):61-68.
Objectives
Magnetic Resonance Elastography (MRE) can noninvasively sample tissue stiffness in-vivo. Renal fibrosis secondary to renal artery stenosis (RAS), which is aggravated in atherosclerotic RAS (ARAS), may increase its stiffness. An increase in cortical stiffness in-vivo can be masked by intrinsic hemodynamic determinants, while renal medullary stiffness is less dependent on renal hemodynamics. Therefore, this study tested the hypothesis that MRE-determined medullary stiffness would correspond to the histological degree of medullary fibrosis in stenotic kidneys in RAS and detect its exacerbation in ARAS.
Methods
Seventeen pigs were studied 10 weeks after induction of unilateral RAS (n=6), ARAS (n=5), or sham (n=6). Cortical and medullary stiffness was determined by 3D MRE, and renal perfusion and function using multi-detector computed-tomography. Kidney fibrosis was subsequently assessed ex-vivo using Masson’s trichrome staining.
Results
Renal stenotic cortex and medulla were significantly more fibrotic in RAS and ARAS compared to normal. However, MRE detected increased stiffness in RAS compared to normal (12.7±0.41kPa vs. 10.7±0.18kPa, p=0.004) only in the medulla, which was further increased in ARAS (16.6±1.3kPa, p=0.017 vs. RAS). MRE-derived medullary, but not cortical, stiffness significantly correlated with histological degree of fibrosis, although cortical and medullary fibrosis were correlated. Renal blood flow and function were similarly decreased in RAS and ARAS compared to normal.
Conclusion
Noninvasive 3D MRE detects increased renal medullary stiffness in RAS and ARAS in-vivo, which correlates with its fibrosis ex-vivo and may also reflect cortical fibrosis. Hence, MRE-derived medullary stiffness can potentially be useful to detect renal fibrosis and track disease progression.
doi:10.1097/RLI.0b013e31827a4990
PMCID: PMC3694773  PMID: 23262789
magnetic resonance elastography; renal artery stenosis; fibrosis
6.  Antiherpesvirus Activity in Human Sera and Urines after Administration of Adenine Arabinoside 
Journal of Clinical Investigation  1978;62(6):1142-1153.
The minimum inhibitory concentration (MIC) of adenine arabinoside (ara-A) in rabbit kidney microtiter tissue cultures (RK-13) to a prototype strain of herpes simplex virus, type 1 (E115) based upon inhibition of cytopathic effects is 1.5 μg/ml. In this system, the MIC of arabinosylhypoxanthine (ara-Hx), the major in vivo metabolic derivative of ara-A, is 75 μg/ml. Inhibition of cytopathic effects of herpes simplex virus, type 1 (HSV-1) in microtiter wells of RK-13 cells varies directly with the concentrations of ara-A or ara-Hx, and inversely with residual HSV-1. The MIC of ara-A for HSV-1 in RK-13 cells is 5-20 times lower than similar measures with vero renal, mouse embryo, or human foreskin cultures. With RK-13 tissue cultures in microtiter plates, an assay for “ara-A equivalents” in human body fluids was developed which compares in sensitivity with high pressure liquid chromatography and has the advantage of simultaneously measuring combined antiherpesvirus effects of ara-A and its major metabolic derivative, ara-Hx.
In vitro checkerboard studies in RK-13 cells confirmed that ara-A and ara-Hx in combination had antiviral effects which are synergistic. The total of the fractional MIC of ara-A plus ara-Hx in combination also varies inversely with residual HSV-1 in microtiter wells. Because virus adsorption is complete at 2 h before specimens to be tested are added in this assay, and because human interferon is not measured in rabbit cells, the antiviral assay is not affected by the presence of type-specific antiherpesvirus antibody or human interferon.
Antiviral activity (AVA) was assayed as ara-A equivalents in sera and urines from 10 patients with serious herpesvirus infections who received 2.5-20 mg/kg daily of ara-A by intramuscular or intravenous routes. When a dosage schedule of 10 mg/kg per day or more was used, sustained concentrations of AVA that ranged from 0.8 to 14.4 μg/ml were found. When an inhibitor of adenosine deaminase (covidarabine) was not added to the specimens, mean serum concentrations were ≅3.0 μg/ml (10 mg/kg per day, i.v.), and 4.1 μg/ml (20 mg/kg per day). However, in a single patient given 20 mg/kg of ara-A daily with covidarabine immediately added to the sera, the mean concentration of AVA was 12.9 μg/ml. Urines contained even higher AVA. Assays of 19 sera were performed both by microbiologic assay for AVA and by high pressure liquid chromatography for ara-A and ara-Hx. AVA was greater by microbiologic assay, and was greater than that which could be accounted for by stoichiometric chromatographic measures of ara-A and ara-Hx. These results with sera of treated patients are consistent both with the in vitro synergy of ara-A and ara-Hx found by checkerboard titrations, and with the beneficial responses to ara-A of patients with herpesvirus infections reported here and elsewhere.
Images
PMCID: PMC371878  PMID: 219024
7.  Relationship between Fibrosis and Ventricular Arrhythmias in Chagas Heart Disease Without Ventricular Dysfunction 
Arquivos Brasileiros de Cardiologia  2014;102(5):456-464.
Background
Patients with Chagas disease and segmental wall motion abnormality (SWMA) have worse prognosis independent of left ventricular ejection fraction (LVEF). Cardiac magnetic resonance (CMR) is currently the best method to detect SWMA and to assess fibrosis.
Objective
To quantify fibrosis by using late gadolinium enhancement CMR in patients with Chagas disease and preserved or minimally impaired ventricular function (> 45%), and to detect patterns of dependence between fibrosis, SWMA and LVEF in the presence of ventricular arrhythmia.
Methods
Electrocardiogram, treadmill exercise test, Holter and CMR were carried out in 61 patients, who were divided into three groups as follows: (1) normal electrocardiogram and CMR without SWMA; (2) abnormal electrocardiogram and CMR without SWMA; (3) CMR with SWMA independently of electrocardiogram.
Results
The number of patients with ventricular arrhythmia in relation to the total of patients, the percentage of fibrosis, and the LVEF were, respectively: Group 1, 4/26, 0.74% and 74.34%; Group 2, 4/16, 3.96% and 68.5%; and Group 3, 11/19, 14.07% and 55.59%. Ventricular arrhythmia was found in 31.1% of the patients. Those with and without ventricular arrhythmia had mean LVEF of 59.87% and 70.18%, respectively, and fibrosis percentage of 11.03% and 3.01%, respectively. Of the variables SWMA, groups, age, LVEF and fibrosis, only the latter was significant for the presence of ventricular arrhythmia, with a cutoff point of 11.78% for fibrosis mass (p < 0.001).
Conclusion
Even in patients with Chagas disease and preserved or minimally impaired ventricular function, electrical instability can be present. Regarding the presence of ventricular arrhythmia, fibrosis is the most important variable, its amount being proportional to the complexity of the groups.
doi:10.5935/abc.20140052
PMCID: PMC4051448  PMID: 24918912
Arrhythmias; Cardiac; Myocardial Fibrosis; Chagas Heart Disease; Ventricular Dysfunction
8.  Prevalence and distribution of late gadolinium enhancement in a large population of patients with Duchenne muscular dystrophy: effect of age and left ventricular systolic function 
Background
Duchenne muscular dystrophy (DMD), an X-linked disorder affects approximately 1 in 5000 males, is universally associated with heart disease. We previously identified myocardial disease by late gadolinium enhancement (LGE) in DMD subjects at various stages of disease, but the true prevalence is unclear. Cardiovascular magnetic resonance (CMR) is well established for both assessment of ventricular function and myocardial fibrosis by LGE. We sought to establish i) prevalence and distribution of LGE in a large DMD population and ii) relationship among LGE, age, LVEF by CMR and current living status.
Methods
Current living status, demographic and CMR data including ventricular volumes, LVEF and LGE from 314 DMD patients undergoing evaluation at a single large tertiary referral center were analyzed.
Results
113 of 314 (36%) of DMD subjects showed LGE positivity with prevalence increasing from 17% of patients <10 years to 34% of those aged 10–15 years and 59% of those >15 years-old. Patients with LVEF ≥55% were LGE positive in 30% of cases; this increased to 84% for LVEF <55%. LGE was more prevalent in the free wall (531/1243, 42.7%) vs. septal segments (30/565, 5.3%). Patients with septal involvement were significantly older and had lower LVEF than those with isolated free wall LGE. Ten percent (11/113) patients who had LGE died 10.8 months after CMR. Only one patient from the LGE negative group died. Patients who died had higher heart rate, larger left ventricular volume and mass, greater number of positive LGE segment and increase incident of septal LGE compared to those who remained alive.
Conclusion
In DMD patients, LGE occurs early, is progressive and increases with both age and decreasing LVEF. Segmentally, the incidence of the number of positive LGE segments increase with age and lower LVEF. Older patients and those who died during the study period had more septal LGE involvement. The current studies suggest that the time course and distribution of LGE-positivity may be an important clinical biomarker to aid in the management of DMD-associated cardiac disease.
doi:10.1186/1532-429X-15-107
PMCID: PMC3896985  PMID: 24359596
Cardiovascular magnetic resonance; Duchenne muscular dystrophy; Late gadolinium enhancement; Ejection fraction; Myocardial fibrosis
9.  Screening for significant atherosclerotic renal artery stenosis with a regression model in patients undergoing transradial coronary angiography/intervention 
Objective: Early detection of atherosclerotic renal artery stenosis (ARAS) is clinically important with respect to blood pressure control, prevention of renal insufficiency, and even improving survival. We investigated whether the presence of significant ARAS (luminal diameter narrowing ≥70%) could be predicted using a logistic regression model before coronary angiography/intervention. Methods: Initially, we developed a logistic regression model for detecting significant ARAS based upon clinical and angiographic features and biochemical measurements in a cohort of 1 813 patients undergoing transfemoral coronary and renal angiography. This model was then prospectively applied to an additional 495 patients who received transradial renal angiography to ascertain its predictive accuracy for the presence of significant ARAS. Results: Multivariate regression analysis revealed that older age (≥65 years), resistant hypertension, type 2 diabetes, creatinine clearance (Ccr) ≤60 ml/min, and multivessel coronary disease were independent predictors for significant ARAS. A logistic regression model for detecting ARAS by incorporating conventional risk factors and multivessel coronary disease was generated as: P/(1−P)=exp(−2.618+1.112[age≥65 years]+1.891[resistant hypertension]+0.453[type 2 diabetes]+0.587[Ccr≤60 ml/min]+2.254[multivessel coronary disease]). When this regression model was prospectively applied to the additional 495 patients undergoing transradial coronary and renal angiography, significant ARAS could be detected with a sensitivity of 81.2%, specificity of 88.9%, and positive and negative predictive accuracies of 53.8% and 96.7%, respectively. Conclusions: The logistic regression model generated in this study may be useful for screening for significant ARAS in patients undergoing transradial coronary angiography/intervention.
doi:10.1631/jzus.B1201003
PMCID: PMC3411096  PMID: 22843183
Renal artery stenosis; Transradial coronary angiography; Resistant hypertension
10.  Left Ventricular Geometric Remodeling in Relation to Non-Ischemic Scar Pattern on Cardiac Magnetic Resonance Imaging 
Purpose
Left ventricular (LV) remodeling and myocardial fibrosis have been linked to adverse heart failure outcomes. Mid wall late gadolinium enhancement (MW-LGE) on cardiac magnetic resonance (CMR) imaging is well-associated with non-ischemic cardiomyopathy (NICM), but prevalence in ischemic cardiomyopathy (ICM) and association with remodeling are unknown.
Methods
The population comprised patients with systolic dysfunction (LVEF≤40%). CMR was used to identify MW-LGE, conventionally defined as fibrosis of the mid-myocardial or epicardial aspect of the LV septum.
Results
285 patients were studied. MW-LGE was present in 12%, and was 10-fold more common with NICM (32%) vs. ICM (3%, p<0.001). However, owing to higher prevalence of ICM, 15% of patients with MW-LGE had ICM. LV wall stress was higher (p=0.02) among patients with, vs. those without, MW-LGE despite similar systolic blood pressure (p=0.24). In multivariate analysis, MW-LGE was associated with CMR-quantified LV end-diastolic volume (p=0.03) independent of LVEF and mass. Incorporation of clinical and imaging variables demonstrated MW-LGE to be associated with higher LV end-diastolic volume (OR=1.13 [CI 1.004–1.27] per 10 ml/m2, p=0.04) after controlling for presence of NICM (OR=16.0 [CI 5.8–44.1], p<0.001).
Conclusions
While more common in NICM, MW-LGE can occur in ICM and is a marker of LV chamber dilation irrespective of cardiomyopathic etiology.
doi:10.1007/s10554-014-0487-8
PMCID: PMC4233172  PMID: 25008088
cardiomyopathy; cardiovascular magnetic resonance; myocardial fibrosis; remodeling
11.  Unrecognized Non-Q-Wave Myocardial Infarction: Prevalence and Prognostic Significance in Patients with Suspected Coronary Disease 
PLoS Medicine  2009;6(4):e1000057.
Using delayed-enhancement cardiovascular magnetic resonance, Han Kim and colleagues show that in patients with suspected coronary disease the prevalence of unrecognized myocardial infarction without Q-waves is more than 3-fold higher than that with Q-waves and predicts subsequent mortality.
Background
Unrecognized myocardial infarction (UMI) is known to constitute a substantial portion of potentially lethal coronary heart disease. However, the diagnosis of UMI is based on the appearance of incidental Q-waves on 12-lead electrocardiography. Thus, the syndrome of non-Q-wave UMI has not been investigated. Delayed-enhancement cardiovascular magnetic resonance (DE-CMR) can identify MI, even when small, subendocardial, or without associated Q-waves. The aim of this study was to investigate the prevalence and prognosis associated with non-Q-wave UMI identified by DE-CMR.
Methods and Findings
We conducted a prospective study of 185 patients with suspected coronary disease and without history of clinical myocardial infarction who were scheduled for invasive coronary angiography. Q-wave UMI was determined by electrocardiography (Minnesota Code). Non-Q-wave UMI was identified by DE-CMR in the absence of electrocardiographic Q-waves. Patients were followed to determine the prognostic significance of non-Q-wave UMI. The primary endpoint was all-cause mortality. The prevalence of non-Q-wave UMI was 27% (50/185), compared with 8% (15/185) for Q-wave UMI. Patients with non-Q-wave UMI were older, were more likely to have diabetes, and had higher Framingham risk than those without MI, but were similar to those with Q-wave UMI. Infarct size in non-Q-wave UMI was modest (8%±7% of left ventricular mass), and left ventricular ejection fraction (LVEF) by cine-CMR was usually preserved (52%±18%). The prevalence of non-Q-wave UMI increased with the extent and severity of coronary disease on angiography (p<0.0001 for both). Over 2.2 y (interquartile range 1.8–2.7), 16 deaths occurred: 13 in non-Q-wave UMI patients (26%), one in Q-wave UMI (7%), and two in patients without MI (2%). Multivariable analysis including New York Heart Association class and LVEF demonstrated that non-Q-wave UMI was an independent predictor of all-cause mortality (hazard ratio [HR] 11.4, 95% confidence interval [CI] 2.5–51.1) and cardiac mortality (HR 17.4, 95% CI 2.2–137.4).
Conclusions
In patients with suspected coronary disease, the prevalence of non-Q-wave UMI is more than 3-fold higher than Q-wave UMI. The presence of non-Q-wave UMI predicts subsequent mortality, and is incremental to LVEF.
Trial Registration
Clinicaltrials.gov NCT00493168
Editors' Summary
Background
Coronary artery disease (CAD; also called coronary heart disease) is the leading cause of death among adults in developed countries. In the USA alone, it kills nearly half a million people every year. CAD is caused by narrowing of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. With age, fatty deposits (atherosclerotic plaques) coat the walls of these arteries and restrict the heart's blood supply, which causes the characteristic symptoms of CAD—angina (chest pains that are usually relieved by rest) and shortness of breath. In addition, if a plaque breaks off the wall of a coronary artery, it can completely block that artery and kill part of the heart, which causes a potentially fatal heart attack (doctors call this a myocardial infarction or MI). Heart attacks are often characterized by long-lasting chest pain that is not relieved by rest. Risk factors for CAD include smoking, high blood pressure, high blood levels of cholesterol (a type of fat), and being overweight. Treatments for the condition include lifestyle changes (for example, losing weight), and medications that lower blood pressure and blood cholesterol. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Not everyone who has a heart attack has chest pain. In fact, some studies suggest that 40–60% of MIs have no obvious symptoms. It is important, however, that these “unrecognized” MIs (UMIs) are diagnosed because they have death rates similar to those of MIs with clinical symptoms and need to be treated in a similar way. Traditionally, UMIs have been diagnosed using an electrocardiogram (ECG). When the heart beats, it generates small electric waves that can be picked up by electrodes attached to the skin. The pattern of these waves (the ECG) provides information about the heart's health. Alterations in the ECG, leading to so-called Q-waves, indicate that a UMI has occurred some time previously. However, not all UMIs result in Q-waves. In this study, the researchers use a recently developed technique—delayed enhancement cardiovascular magnetic resonance (DE-CMR), which can detect heart damage even in patients whose Q-waves are absent—to measure the prevalence (the fraction of a population that has a disorder) of non-Q-wave UMI. The researchers also investigate whether non-Q-wave UMI increases the risk of death.
What Did the Researchers Do and Find?
The researchers used electrocardiography and DE-CMR to look for Q-wave and non-Q-wave UMI, respectively, in 185 patients with suspected CAD but no history of MI. They then followed the patients for 2 years to discover whether a diagnosis of non-Q-wave UMI predicted their likelihood of dying from any cause or from a heart problem. 27% of the patients had evidence of non-Q-wave UMI whereas only 8% had evidence of Q-wave UMI. Patients with non-Q-wave UMI tended to have only a small area of heart damage and, consistent with this limited damage, their hearts pumped near-normal volumes of blood. Examination of the patients' arteries with a technique called coronary angiography indicated that the patients with widespread and/or severe CAD had a higher prevalence of non-Q-wave UMI than those with limited CAD. Finally, patients with non-Q-wave UMI had an 11-fold higher risk of death from any cause and a 17-fold higher risk of death from a heart problem than patients without UMI.
What Do These Findings Mean?
These findings indicate that non-Q-wave UMI occurs more than 3-times as often in patients with suspected CAD than Q-wave UMI and that patients with non-Q-wave UMI have a much greater risk of dying than patients without MI. Thus, if all cases of UMI—both Q-wave and non-Q-wave UMI—could be identified, it might be possible to reduce the number of deaths among people with CAD. However, before any recommendations are made to include DE-CMR in the routine examination of people with suspected CAD to achieve this aim, additional studies must be undertaken to confirm that non-Q-wave UMI is a common feature of CAD and to test whether the early diagnosis of non-Q-wave UMI does extend the life expectancy of people with CAD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000057.
This study is further discussed in a PLoS Medicine Perspective by Clara Chow
The MedlinePlus encyclopedia has pages on coronary heart disease, heart attacks, and electrocardiograms (in English and Spanish). MedlinePlus also provides links to further information on all aspects of heart disease (in English and Spanish)
Information is available from the US National Heart Lung and Blood Institute on coronary heart disease
The UK National Health Service Choices website also provides information about coronary heart disease (in several languages).
The Nobel Foundation provides an interactive electrocardiogram game
doi:10.1371/journal.pmed.1000057
PMCID: PMC2661255  PMID: 19381280
12.  Low prevalence of fibrosis in thalassemia major assessed by late gadolinium enhancement cardiovascular magnetic resonance 
Background
Heart failure remains a major cause of mortality in thalassaemia major. The possible role of cardiac fibrosis in thalassemia major in the genesis of heart failure is not clear. It is also unclear whether cardiac fibrosis might arise as a result of heart failure.
Methods
We studied 45 patients with thalassaemia major who had a wide range of current cardiac iron loading and included patients with prior and current heart failure. Myocardial iron was measured using T2* cardiovascular magnetic resonance (CMR), and following this, late gadolinium enhancement (LGE) was used to determine the presence of macroscopic myocardial fibrosis.
Results
The median myocardial T2* in all patients was 22.6 ms (range 5.3-58.8 ms). Fibrosis was detected in only one patient, whose myocardial T2* was 20.1 ms and left ventricular ejection fraction 57%. No fibrosis was identified in 5 patients with a history of heart failure with full recovery, in 3 patients with current left ventricular dysfunction undergoing treatment, or in 18 patients with myocardial iron loading with cardiacT2* < 20 ms at the time of scan.
Conclusion
This study shows that macroscopic myocardial fibrosis is uncommon in thalassemia major across a broad spectrum of myocardial iron loading. Importantly, there was no macroscopic fibrosis in patients with current or prior heart failure, or in patients with myocardial iron loading without heart failure. Therefore if myocardial fibrosis indeed contributes to myocardial dysfunction in thalassemia, our data combined with the knowledge that the myocardial dysfunction of iron overload can be reversed, indicates that any such fibrosis would need to be both microscopic and reversible.
doi:10.1186/1532-429X-13-8
PMCID: PMC3025880  PMID: 21241474
13.  Atherosclerotic Renal Artery Stenosis—Diagnosis and Treatment 
Mayo Clinic Proceedings  2011;86(7):649-657.
Renal artery stenosis (RAS) is characterized by a heterogeneous group of pathophysiologic entities, of which fibromuscular dysplasia and atherosclerotic RAS (ARAS) are the most common. Whether and which patients should undergo revascularization for ARAS is controversial. The general consensus is that all patients with ARAS should receive intensive medical treatment. The latest randomized clinical trials have increased confusion regarding recommendations for revascularization for ARAS. Although revascularization is not indicated in all patients with ARAS, experts agree that it should be considered in some patients, especially those with unstable angina, unexplained pulmonary edema, and hemodynamically significant ARAS with either worsening renal function or with difficult to control hypertension. A search of the literature was performed using PubMed and entering the search terms renal artery stenosis, atherosclerotic renal artery stenosis, and renal artery stenosis AND hypertension to retrieve the most recent publications on diagnosis and treatment of ARAS. In this review, we analyze the pathways related to hypertension in ARAS, the optimal invasive and noninvasive modalities for evaluating the renal arteries, and the available therapies for ARAS and assess future tools and algorithms that may prove useful in evaluating patients for renal revascularization therapy.
doi:10.4065/mcp.2011.0181
PMCID: PMC3127560  PMID: 21719621
14.  Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphism and Left Ventricular Function in Early Chronic Kidney Disease 
PLoS ONE  2015;10(1):e0116160.
Background
Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated.
Methods
140 non-dialysis CKD patients, who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of two clinical trials, were genotyped for eNOS Glu298Asp SNP retrospectively.
Results
The median estimated glomerular filtration rate (eGFR) was 50mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction in this cohort. There were significant differences in LVEF across eNOS genotypes with GG genotype being associated with a worse LVEF compared to other genotypes (LVEF: GG 71%, TG 76%, TT 73%, p = 0.006). After multivariate analysis, (adjusting for age, eGFR, baseline mean arterial pressure, contemporary CMR heart rate, total cholesterol, high sensitive C-reactive protein, body mass index and gender) GG genotype was associated with a worse LVEF, and increased LV end-diastolic and systolic index (p = 0.004, 0.049 and 0.009 respectively).
Conclusions
eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses.
doi:10.1371/journal.pone.0116160
PMCID: PMC4303420  PMID: 25612295
15.  Insights from magnetic resonance imaging of left ventricular non-compaction in adults of North African descent 
Background
Left ventricular non-compaction (LVNC) is a recently recognized rare disorder. Magnetic resonance imaging (MRI) may help to clarify the uncertainties related to this genetic cardiomyopathy. Despite the fact that many articles have been published concerning the use of MRI in the study of LVNC, there is a lack of data describing the disease in the North African population. The aim of our study is to clarify MRI findings of LVNC in North African patients.
Methods
In our retrospective cohort, twelve patients (7 male, mean age 53 ± 8 years) underwent MRI for suspected LVNC. Correlations were investigated between the number of non-compacted segments per patient and left ventricular ejection fraction (LVEF), then between the number of non-compacted segments and left ventricular end diastolic diameter. The presence or absence of late gadolinium enhancement (LGE) was qualitatively determined for each left ventricular myocardial segment.
Results
Non-compaction was more commonly observed at the apex, the anterior and the lateral walls, especially on their apical and mid-cavity segments. 83% of patients had impaired LVEF. There was no correlation between the number of non-compacted segments per patient and LVEF (r = -0.361; p = 0.263), nor between the number of non-compacted segments per patient and left ventricular end diastolic diameter (r = 0.280; p = 0.377). LGE was observed in 22 left ventricular segments. No association was found between the pattern of fibrosis and non-compaction distribution (OR = 2.2, CI [0.91-5.55], p = 0.076).
Conclusion
The distribution of LVNC in North African patients does not differ from other populations. Ventricular dysfunction is independent from the number of non-compacted segments. Myocardial fibrosis is not limited to non-compacted areas but can extend to compacted segments.
doi:10.1186/1755-7682-5-10
PMCID: PMC3327641  PMID: 22405292
16.  Epicardial adipose tissue in patients with heart failure 
Purpose
The aim of this study was to evaluate the extent of epicardial adipose tissue (EAT) and its relationship with left ventricular (LV) parameters assessed by cardiovascular magnetic resonance (CMR) in patients with congestive heart failure (CHF) and healthy controls.
Background
EAT is the true visceral fat deposited around the heart which generates various bioactive molecules. Previous studies found that EAT is related to left ventricular mass (LVM) in healthy subjects. Further studies showed a constant EAT to myocardial mass ratio in normal, ischemic and hypertrophied hearts.
Methods
CMR was performed in 66 patients with CHF due to ischemic cardiomyopathy (ICM), or dilated cardiomyopathy (DCM) and 32 healthy controls. Ventricular volumes, dimensions and LV function were assessed. The amount of EAT was determined volumetrically and expressed as mass indexed to body surface area. Additionally, the EAT/LVM and the EAT/left ventricular remodelling index (LVRI) ratios were calculated.
Results
Patients with CHF had less indexed EAT mass than controls (22 ± 5 g/m2 versus 34 ± 4 g/m2, p < 0.0001). In the subgroup analysis there were no significant differences in indexed EAT mass between patients with ICM and DCM (21 ± 4 g/m2 versus 23 ± 6 g/m2, p = 0.14). Linear regression analysis showed that with increasing LV end-diastolic diameter (LV-EDD) (r = 0.42, p = 0.0004) and LV end-diastolic mass (LV-EDM) (r = 0.59, p < 0.0001), there was a significantly increased amount of EAT in patients with CHF. However, the ratio of EAT mass/LV-EDM was significantly reduced in patients with CHF compared to healthy controls (0.54 ± 0.1 versus 0.21 ± 0.1, p < 0.0001). In CHF patients higher indexed EAT/LVRI-ratios in CHF patients correlated best with a reduced LV-EF (r = 0.49, p < 0.0001).
Conclusion
Patients with CHF revealed significantly reduced amounts of EAT. An increase in LVM is significantly related to an increase in EAT in both patients with CHF and controls. However, different from previous reports the EAT/LVEDM-ratio in patients with CHF was significantly reduced compared to healthy controls. Furthermore, the LV function correlated best with the indexed EAT/LVRI ratio in CHF patients. Metabolic abnormalities and/or anatomic alterations due to disturbed cardiac function and geometry seem to play a key role and are a possible explanation for these findings.
doi:10.1186/1532-429X-12-40
PMCID: PMC2914772  PMID: 20624277
17.  Acute and chronic effects of continuous positive airway pressure therapy on left ventricular systolic and diastolic function in patients with obstructive sleep apnea and congestive heart failure 
BACKGROUND:
Obstructive sleep apnea (OSA) may contribute to the pathogenesis of congestive heart failure (CHF). Nocturnal continuous positive airway pressure (CPAP) therapy can alleviate OSA and may have a role in the treatment of CHF patients.
OBJECTIVES:
To investigate the acute and chronic effects of CPAP therapy on left ventricular systolic function, diastolic function and filling pressures in CHF patients with OSA.
METHODS:
Twelve patients with stable CHF (New York Heart Association II or III, radionuclide ejection fraction lower than 40%) underwent overnight polysomnography to detect OSA. In patients with OSA (n=7), echocardiography was performed at baseline (awake, before and during acute CPAP administration) and after 6.9±3.3 weeks of nocturnal CPAP therapy. Patients without OSA (n=5) did not receive CPAP therapy, but underwent a baseline and follow-up echocardiogram.
RESULTS:
In CHF patients with OSA, acute CPAP administration resulted in a decrease in stroke volume (44±15 mL versus 50±14 mL, P=0.002) and left ventricular ejection fraction ([LVEF] 34.8±5.0% versus 38.4±3.3%, P=0.006) compared with baseline, but no change in diastolic function or filling pressures (peak early diastolic mitral annular velocity [Ea]: 6.0±1.6 cm/s versus 6.3±1.6 cm/s, P not significant; peak early filling velocity to peak late filling velocity [E/A] ratio: 1.05±0.74 versus 1.00±0.67, P not significant; E/Ea ratio: 10.9±4.1 versus 11.3±4.1, P not significant). In contrast, chronic CPAP therapy resulted in a trend to an increase in stroke volume (59±19 mL versus 50±14 mL, P=0.07) and a significant increase in LVEF (43.4±4.8% versus 38.4±3.3%, P=0.01) compared with baseline, but no change in diastolic function or filling pressures (Ea: 6.2±1.2 cm/s versus 6.3±1.6 cm/s, P not significant; E/A ratio: 1.13±0.61 versus 1.00±0.67, P not significant; E/Ea ratio: 12.1±2.7 versus 11.3±4.1, P not significant). There was no change in left ventricular systolic function, diastolic function or filling pressures at follow-up in CHF patients without OSA.
CONCLUSIONS:
Acute CPAP administration decreased stroke volume and LVEF in stable CHF patients with OSA. In contrast, chronic CPAP therapy for seven weeks improved left ventricular systolic function, but did not affect diastolic function or filling pressures. The potential clinical implications of the discrepant effects of CPAP therapy on left ventricular systolic and diastolic function in CHF patients with OSA warrant further study.
PMCID: PMC2643175  PMID: 18787720
Congestive heart failure; Continuous positive airway pressure therapy; Echocardiography; Left ventricular function; Obstructive sleep apnea
18.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.
A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.
The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Objective
The objective of this analysis is to assess the effectiveness and safety of positron emission tomography (PET) imaging using F-18-fluorodeoxyglucose (FDG) for the assessment of myocardial viability. To evaluate the effectiveness of FDG PET viability imaging, the following outcomes are examined:
the diagnostic accuracy of FDG PET for predicting functional recovery;
the impact of PET viability imaging on prognosis (mortality and other patient outcomes); and
the contribution of PET viability imaging to treatment decision making and subsequent patient outcomes.
Clinical Need: Condition and Target Population
Left Ventricular Systolic Dysfunction and Heart Failure
Heart failure is a complex syndrome characterized by the heart’s inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality.
In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD)1 is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997.
Treatment Options
In general, there are three options for the treatment of heart failure: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure.
Myocardial Viability
Left ventricular dysfunction may be permanent if a myocardial scar is formed, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically:
dobutamine echocardiography (echo),
stress echo with contrast,
SPECT using either technetium or thallium,
cardiac magnetic resonance imaging (cardiac MRI), and
positron emission tomography (PET).
Dobutamine Echocardiography
Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 – 10 μg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability.
Stress Echocardiography with Contrast
Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium.
SPECT
SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images.
The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%.
There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery.
Cardiac Positron Emission Tomography
Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG).
During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of PET for detecting myocardial viability?
What is the prognostic value of PET viability imaging (mortality and other clinical outcomes)?
What is the contribution of PET viability imaging to treatment decision making?
What is the safety of PET viability imaging?
Literature Search
A literature search was performed on July 17, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 to July 16, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In addition, published systematic reviews and health technology assessments were reviewed for relevant studies published before 2004. Reference lists of included studies were also examined for any additional relevant studies not already identified. The quality of the body of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
English language full-reports
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known CAD
PET imaging using FDG for the purpose of detecting viable myocardium
Criteria applying to diagnostic accuracy studies:
Assessment of functional recovery ≥3 months after revascularization
Raw data available to calculate sensitivity and specificity
Gold standard: prediction of global or regional functional recovery
Criteria applying to prognosis studies:
Mortality studies that compare revascularized patients with non-revascularized patients and patients with viable and non-viable myocardium
Exclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
PET perfusion imaging
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Animal or phantom studies
Studies focusing on the technical aspects of PET
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Duplicate publications
Criteria applying to diagnostic accuracy studies
Gold standard other than functional recovery (e.g., PET or cardiac MRI)
Assessment of functional recovery occurs before patients are revascularized
Outcomes of Interest
Diagnostic accuracy studies
Sensitivity and specificity
Positive and negative predictive values (PPV and NPV)
Positive and negative likelihood ratios
Diagnostic accuracy
Adverse events
Prognosis studies
Mortality rate
Functional status
Exercise capacity
Quality of Life
Influence on PET viability imaging on physician decision making
Statistical Methods
Pooled estimates of sensitivity and specificity were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced. The area under the sROC curve was estimated by numerical integration with a cubic spline (default option). Finally, pooled estimates of mortality rates were calculated using weighted means.
Quality of Evidence
The quality of evidence assigned to individual diagnostic studies was determined using the QUADAS tool, a list of 14 questions that address internal and external validity, bias, and generalizibility of diagnostic accuracy studies. Each question is scored as “yes”, “no”, or “unclear”. The quality of the body of evidence was then assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
A total of 40 studies met the inclusion criteria and were included in this review: one health technology assessment, two systematic reviews, 22 observational diagnostic accuracy studies, and 16 prognosis studies. The available PET viability imaging literature addresses two questions: 1) what is the diagnostic accuracy of PET imaging for the assessment; and 2) what is the prognostic value of PET viability imaging. The diagnostic accuracy studies use regional or global functional recovery as the reference standard to determine the sensitivity and specificity of the technology. While regional functional recovery was most commonly used in the studies, global functional recovery is more important clinically. Due to differences in reporting and thresholds, however, it was not possible to pool global functional recovery.
Functional recovery, however, is a surrogate reference standard for viability and consequently, the diagnostic accuracy results may underestimate the specificity of PET viability imaging. For example, regional functional recovery may take up to a year after revascularization depending on whether it is stunned or hibernating tissue, while many of the studies looked at regional functional recovery 3 to 6 months after revascularization. In addition, viable tissue may not recover function after revascularization due to graft patency or re-stenosis. Both issues may lead to false positives and underestimate specificity. Given these limitations, the prognostic value of PET viability imaging provides the most direct and clinically useful information. This body of literature provides evidence on the comparative effectiveness of revascularization and medical therapy in patients with viable myocardium and patients without viable myocardium. In addition, the literature compares the impact of PET-guided treatment decision making with SPECT-guided or standard care treatment decision making on survival and cardiac events (including cardiac mortality, MI, hospital stays, unintended revascularization, etc).
The main findings from the diagnostic accuracy and prognosis evidence are:
Based on the available very low quality evidence, PET is a useful imaging modality for the detection of viable myocardium. The pooled estimates of sensitivity and specificity for the prediction of regional functional recovery as a surrogate for viable myocardium are 91.5% (95% CI, 88.2% – 94.9%) and 67.8% (95% CI, 55.8% – 79.7%), respectively.
Based the available very low quality of evidence, an indirect comparison of pooled estimates of sensitivity and specificity showed no statistically significant difference in the diagnostic accuracy of PET viability imaging for regional functional recovery using perfusion/metabolism mismatch with FDG PET plus either a PET or SPECT perfusion tracer compared with metabolism imaging with FDG PET alone.
FDG PET + PET perfusion metabolism mismatch: sensitivity, 89.9% (83.5% – 96.4%); specificity, 78.3% (66.3% – 90.2%);
FDG PET + SPECT perfusion metabolism mismatch: sensitivity, 87.2% (78.0% – 96.4%); specificity, 67.1% (48.3% – 85.9%);
FDG PET metabolism: sensitivity, 94.5% (91.0% – 98.0%); specificity, 66.8% (53.2% – 80.3%).
Given these findings, further higher quality studies are required to determine the comparative effectiveness and clinical utility of metabolism and perfusion/metabolism mismatch viability imaging with PET.
Based on very low quality of evidence, patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy. Given the quality of evidence, however, this estimate of effect is uncertain so further higher quality studies in this area should be undertaken to determine the presence and magnitude of the effect.
While revascularization may reduce mortality in patients with viable myocardium, current moderate quality RCT evidence suggests that PET-guided treatment decisions do not result in statistically significant reductions in mortality compared with treatment decisions based on SPECT or standard care protocols. The PARR II trial by Beanlands et al. found a significant reduction in cardiac events (a composite outcome that includes cardiac deaths, MI, or hospital stay for cardiac cause) between the adherence to PET recommendations subgroup and the standard care group (hazard ratio, .62; 95% confidence intervals, 0.42 – 0.93; P = .019); however, this post-hoc sub-group analysis is hypothesis generating and higher quality studies are required to substantiate these findings.
The use of FDG PET plus SPECT to determine perfusion/metabolism mismatch to assess myocardial viability increases the radiation exposure compared with FDG PET imaging alone or FDG PET combined with PET perfusion imaging (total-body effective dose: FDG PET, 7 mSv; FDG PET plus PET perfusion tracer, 7.6 – 7.7 mSV; FDG PET plus SPECT perfusion tracer, 16 – 25 mSv). While the precise risk attributed to this increased exposure is unknown, there is increasing concern regarding lifetime multiple exposures to radiation-based imaging modalities, although the incremental lifetime risk for patients who are older or have a poor prognosis may not be as great as for healthy individuals.
PMCID: PMC3377573  PMID: 23074393
19.  Management of congestive heart failure: a gender gap may still exist. Observations from a contemporary cohort 
Background
Unlike other cardiovascular diseases the incidence and prevalence of congestive heart failure (CHF) continues to increase. While gender differences in coronary artery disease have been well described, to date, there has been a relative paucity of similar data in patients with CHF. We conducted a pilot study to evaluate the profile and management of patients with CHF at a tertiary care centre to determine if a gender difference exists.
Methods
A chart review was performed at a tertiary care centre on consecutive patients admitted with a primary diagnosis of CHF between June 1997 and 1998. Co-morbidity, diagnostic investigations, and management of CHF were recorded. Comparisons between male and female patients were conducted.
Results
One hundred and forty five patients were reviewed. There were 80 male (M) and 65 female (F) patients of similar age [71.6 vs. 71.3 (M vs. F), p = NS]. Male patients were more likely to have had a previous myocardial infarction (66% vs. 35%, p < 0.01) and revascularization (41% vs. 20%, p < 0.05), and had worse left ventricular ejection fraction (LVEF) than women, [median LVEF 3 vs. 2 (M vs. F), p < 0.01]. Male patients were more likely to have a non-invasive assessment of left ventricular (LV) function [85% vs. 69%, (M vs. F), p < 0.05]. A logistic regression analysis suggests that amongst those without coronary disease, males were more likely to receive non-invasive testing. There were no differences in the use of prescribed medications, in this cohort.
Conclusions
This pilot study demonstrated that there seem to be important gender differences in the profile and management of patients with CHF. Importantly women were less likely to have an evaluation of LV function. As assessment of LV function has significant implications on patient management, this data justifies the need for larger studies to assess gender differences in CHF profile and treatment.
doi:10.1186/1471-2261-3-1
PMCID: PMC149453  PMID: 12590653
20.  Treatment with atorvastatin is associated with a better prognosis in chronic heart failure with systolic dysfunction: results from The Daunia Heart Failure Registry 
Netherlands Heart Journal  2013;21(9):408-416.
Background
Few works have evaluated the effect of statins on left ventricular dysfunction in patients with chronic heart failure (CHF), by using tissue Doppler imaging (TDI). We therefore aimed to investigate whether atorvastatin treatment may influence prognosis and myocardial performance evaluated by TDI in subjects with CHF.
Methods
Five hundred thirty-two consecutive CHF outpatients enrolled in a local registry, the Daunia Heart Failure Registry, were prospectively analysed. 195 patients with CHF and left ventricular ejection fraction (LVEF) ≤40 %, either in treatment with atorvastatin (N: 114) or without statins (N: 81), underwent TDI examination. Adverse events were evaluated during follow-up.
Results
The atorvastatin group showed a lower incidence of adverse events (cardiac death: 0 % vs 7 %, p < 0.01), and better TDI performance (E/E’ 15 ± 5.7 vs 18 ± 8.3, p < 001) than controls. Ischaemic CHF patients in treatment with atorvastatin also showed a lower incidence of adverse events (death: 10 % vs 26 %, p < 0.05; sustained ventricular arrhythmias: 5 % vs 19 %, p < 0.05, cardiac death: 0 vs 8 %, p < 0.05) and better TDI performance (E/E’ ratio: 15.00 ± 5.68 vs 19.72 ± 9.14, p < 0.01; St: 353.70 ± 48.96 vs 303.33 ± 68.52 msec, p < 0.01) than controls. The association between atorvastatin and lower rates of cardiac death remained statistically significant even after correction in a multivariable analysis (RR 0.83, 95 % CI 0.71–0.96, p < 0.05 in CHF with LVEF ≤40 %; RR 0.77, 95 % CI 0.62–0.95, p < 0.05 in ischaemic CHF with LVEF ≤40 %).
Conclusions
Treatment with atorvastatin in outpatients with systolic CHF is associated with fewer cardiac deaths, and a better left ventricular performance, as assessed by TDI.
doi:10.1007/s12471-013-0430-y
PMCID: PMC3751026  PMID: 23712465
Chronic heart failure; Atorvastatin; Echocardiography; Tissue Doppler imaging
21.  ENDOTHELIAL PROGENITOR CELLS HOMING AND RENAL REPAIR IN EXPERIMENTAL RENOVASCULAR DISEASE 
Stem cells (Dayton, Ohio)  2010;28(6):1039-1047.
Background
Tissue injury triggers reparative processes that often involve endothelial progenitor cells (EPC) recruitment. We hypothesized that atherosclerotic renal artery stenosis (ARAS) activates homing signals that would be detectable in both the kidney and endothelial progenitor cells (EPC), and attenuated upon renal repair using selective cell-based therapy.
Methods
Pigs were treated with intra-renal autologous EPC after 6 weeks of ARAS. Four weeks later, expression of homing-related signals in EPC and kidney, single-kidney function, microvascular density, and morphology were compared to untreated ARAS and normal control pigs (n=7 each).
Results
Compared to normal EPC, EPC from ARAS pigs showed increased stromal cell-derived factor (SDF)-1, angiopoietin-1, Tie-2, and ckit expression, but downregulation of erythropoietin and its receptor. The ARAS kidney released the ckit-ligand stem-cell factor (SCF), uric acid, and erythropoietin, and upregulated integrin β2, suggesting activation of corresponding homing signaling. However, angiopoietin-1 and SDF-1/CXCR4 were not elevated. Administration of EPC into the stenotic kidney restored angiogenic activity, improved microvascular density, renal hemodynamics and function, decreased fibrosis and oxidative stress, and attenuated endogenous injury signals.
Conclusion
The ARAS kidney releases specific homing signals corresponding to cognate receptors expressed by EPC. EPC show plasticity for organ-specific recruitment strategies, which are upregulated in early atherosclerosis. EPC are renoprotective as they attenuated renal dysfunction and damage in chronic ARAS, and consequently decreased the injury signals. Importantly, manipulation of homing signals may potentially allow therapeutic opportunities to increase endogenous EPC recruitment.
doi:10.1002/stem.426
PMCID: PMC2958683  PMID: 20506499
endothelial progenitor cells; renal artery stenosis; homing factors
22.  LATE GADOLINIUM ENHANCEMENT BY CARDIOVASCULAR MAGNETIC RESONANCE HERALDS AN ADVERSE PROGNOSIS IN NONISCHEMIC CARDIOMYOPATHY 
Structured Abstract
Objectives
We examined whether the presence and extent of late gadolinium enhancement (LGE) by CMR predict adverse outcomes in nonischemic cardiomyopathy (NICM) patients.
Background
Morbidity and mortality is high in NICM patients. However, the clinical course of an individual patient is unpredictable and current risk stratification approaches are limited. Cardiovascular magnetic resonance (CMR) detects myocardial fibrosis, which appears as LGE after contrast administration and may convey prognostic importance.
Methods
In a prospective cohort study, 65 NICM patients with LVEF ≤35% underwent CMR before placement of an internal cardioverter defibrillator (ICD) for primary prevention of sudden cardiac death. CMRs were analyzed for the presence and extent of LGE, and for LV function, volumes, and mass. Patients were followed for an index composite endpoint of three cardiac events: hospitalization for heart failure, appropriate ICD firing, and cardiac death.
Results
42% (n=27) of patients had CMR LGE, averaging 10±13% of LV mass. During a 17 month median follow-up, 44% (n=12) of patients with LGE had an index composite outcome event, versus only 8% (n=3) of those without LGE (p<0.001 for Kaplan-Meier survival curves). After adjustment for LV volume index and functional class, patients with LGE had an eight-fold higher risk of experiencing the primary outcome (hazard ratio 8.2, 95% CI 2.2–30.9, p=0.002).
Conclusions
CMR LGE in NICM patients strongly predicts adverse cardiac outcomes. CMR LGE may represent the end-organ consequences of sustained adrenergic activation and adverse LV remodeling, and its identification may significantly improve risk stratification strategies in this high risk population.
Condensed Abstract
Predicting prognosis in nonischemic cardiomyopathy patients is challenging and current risk stratification approaches are limited. Cardiovascular magnetic resonance (CMR) detects myocardial fibrosis, which appears as late gadolinium enhancement (LGE). The presence of LGE predicts an eight-fold increased risk of an adverse cardiac outcome (HR 8.1, 95% CI 1.9–33.7, p=0.004), after controlling for baseline variables. CMR LGE may reflect the transition from compensated to decompensated state resulting from long-term stressors such as sustained adrenergic activation and/or the mechanical disadvantages caused by LV remodeling leading to increasing fibrosis. Identifying CMR LGE may significantly improve risk stratification strategies in this high risk population.
doi:10.1016/j.jacc.2008.03.018
PMCID: PMC2459322  PMID: 18565399
cardiomyopathy; prognosis; magnetic resonance imaging
23.  Early detection of subclinical ventricular deterioration in aortic stenosis with cardiovascular magnetic resonance and echocardiography 
Background
Severe aortic stenosis (AS) patients with late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) or left ventricular (LV) systolic dysfunction are known to have worse outcome. We aimed to investigate whether LGE on CMR would be useful in early detection of subclinical LV structural and functional derangements in AS patients.
Methods
118 patients with moderate to severe AS were prospectively enrolled. Echocardiography and CMR images were taken and the patients were divided into groups according to the presence/absence of LGE and of LV systolic dysfunction (LV ejection fraction (EF) <50%). The stiffness of LV was calculated based on Doppler and CMR measurements.
Results
Patients were grouped into either group 1, no LGE and normal LVEF, group 2, LGE but normal LVEF and group 3, LGE with depressed LVEF. There was a significant trend towards increasing LV volumes, worsening of LV diastolic function (E/e’, diastolic elastance), systolic function (end-systolic elastance) and LV hypertrophy between the three groups, which coincided with worsening functional capacity (all p-value < 0.001 for trend). Also, significant differences in the above parameters were noted between group 1 and 2 (E/e’, 14.6 ± 4.3 (mean ± standard deviation) in group 1 vs. 18.2 ± 9.4 in group 2; end-systolic elastance, 3.24 ± 2.31 in group 1 vs. 2.38 ± 1.16 in group 2, all p-value < 0.05). The amount of myocardial fibrosis on CMR correlated with parameters of diastolic (diastolic elastance, Spearman’s ρ = 0.256, p-value = 0.005) and systolic function (end-systolic elastance, Spearman’s ρ = -0.359, p-value < 0.001).
Conclusions
These findings demonstrate the usefulness of CMR for early detection of subclinical LV structural and functional deterioration in AS patients.
doi:10.1186/1532-429X-15-72
PMCID: PMC3766067  PMID: 23984681
Aortic stenosis; Cardiovascular magnetic resonance; Echocardiography; Heart function; Ventricular remodeling; Magnetic resonance imaging; Myocardial function; Myocardial fibrosis
24.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Background
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
Conclusion
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
doi:10.1371/journal.pmed.1001680
PMCID: PMC4106719  PMID: 25050550
25.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
Objective
The objective was to update the 2001 systematic review conducted by the Institute For Clinical Evaluative Sciences (ICES) on the use of positron emission tomography (PET) in assessing myocardial viability. The update consisted of a review and analysis of the research evidence published since the 2001 ICES review to determine the effectiveness and cost-effectiveness of PET in detecting left ventricular (LV) viability and predicting patient outcomes after revascularization in comparison with other noninvasive techniques.
Background
Left Ventricular Viability
Heart failure is a complex syndrome that impairs the contractile ability of the heart to maintain adequate blood circulation, resulting in poor functional capacity and increased risk of morbidity and mortality. It is the leading cause of hospitalization in elderly Canadians. In more than two-thirds of cases, heart failure is secondary to coronary heart disease. It has been shown that dysfunctional myocardium resulting from coronary heart disease (CAD) may recover contractile function (i.e. considered viable). Dysfunctional but viable myocardium may have been stunned by a brief episode of ischemia, followed by restoration of perfusion, and may regain function spontaneously. It is believed that repetitive stunning results in hibernating myocardium that will only regain contractile function upon revascularization.
For people with CAD and severe LV dysfunction (left ventricular ejection fraction [LVEF] <35%) refractory to medical therapy, coronary artery bypass and heart transplantation are the only treatment options. The opportunity for a heart transplant is limited by scarcityof donor hearts. Coronary artery bypass in these patients is associated with high perioperative complications; however, there is evidence that revascularization in the presence of dysfunctional but viable myocardium is associated with survival benefits and lower rates of cardiac events. The assessment of left ventricular (LV) viability is, therefore, critical in deciding whether a patient with coronary artery disease and severe LV dysfunction should undergo revascularization, receive a heart transplant, or remain on medical therapy.
Assessment of Left Ventricular Viability
Techniques for assessing myocardial viability depend on the measurement of a specific characteristic of viable myocytes such as cell membrane integrity, preserved metabolism, mitochondria integrity, and preserved contractile reserve. In Ontario, single photon emission computed tomography (SPECT) using radioactive 201thallium is the most commonly used technique followed by dobutamine echocardiography. Newer techniques include SPECT using technetium tracers, cardiac magnetic resonance imaging, and PET, the subject of this review.
Positron Emission Tomography
PET is a nuclear imaging technique based on the metabolism of radioactive analogs of normal substrates such as glucose and water. The radiopharmaceutical used most frequently in myocardial viability assessment is F18 fluorodeoxyglucose (FDG), a glucose analog. The procedure involves the intravenous administration of FDG under controlled glycemic conditions, and imaging with a PET scanner. The images are reconstructed using computer software and analyzed visually or semi-quantitatively, often in conjunction with perfusion images. Dysfunctional but stunned myocardium is characterized by normal perfusion and normal FDG uptake; hibernating myocardium exhibits reduced perfusion and normal/enhanced FDG uptake (perfusion/metabolism mismatch), whereas scar tissue is characterized by reduction in both perfusion and FDG uptake (perfusion/metabolism match).
Review Strategy
The Medical Advisory Secretariat used a search strategy similar to that used in the 2001 ICES review to identify English language reports of health technology assessments and primary studies in selected databases, published from January 1, 2001 to April 20, 2005. Patients of interest were those with CAD and severe ventricular dysfunction being considered for revascularization that had undergone viability assessment using either PET and/or other noninvasive techniques. The outcomes of interest were diagnostic and predictive accuracy with respect to recovery of regional or global LV function, long-term survival and cardiac events, and quality of life. Other outcomes of interest were impact on treatment decision, adverse events, and cost-effectiveness ratios.
Of 456 citations, 8 systematic reviews/meta-analyses and 37 reports on primary studies met the selection criteria. The reports were categorized using the Medical Advisory Secretariat levels of evidence system, and the quality of the reports was assessed using the criteria of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) developed by the Centre for Dissemination of Research (National Health Service, United Kingdom). Analysis of sensitivity, specificity, predictive values and likelihood ratios were conducted for all data as well as stratified by mean left ventricular ejection fraction (LVEF). There were no randomized controlled trials. The included studies compared PET with one or more other noninvasive viability tests on the same group of patients or examined the long-term outcomes of PET viability assessments. The quality assessment showed that about 50% or more of the studies had selection bias, interpreted tests without blinding, excluded uninterpretable segments in the analysis, or did not have clearly stated selection criteria. Data from the above studies were integrated with data from the 2001 ICES review for analysis and interpretation.
Summary of Findings
The evidence was derived from populations with moderate to severe ischemic LV dysfunction with an overall quality that ranges from moderate to low.
PET appears to be a safe technique for assessing myocardial viability.
CAD patients with moderate to severe ischemic LV dysfunction and residual viable myocardium had significantly lower 2-year mortality rate (3.2%) and higher event-free survival rates (92% at 3 years) when treated with revascularization than those who were not revascularized but were treated medically (16% mortality at 2-years and 48% 3-year event-free survival).
A large meta-analysis and moderate quality studies of diagnostic accuracy consistently showed that compared to other noninvasive diagnostic tests such as thallium SPECT and echocardiography, FDG PET has:
Higher sensitivity (median 90%, range 71%–100%) and better negative likelihood ratio (median 0.16, range 0–0.38; ideal <0.1) for predicting regional myocardial function recovery after revascularization.
Specificity (median 73%, range 33%–91%) that is similar to other radionuclide imaging but lower than that of dobutamine echocardiography
Less useful positive likelihood ratio (median 3.1, range 1.4 –9.2; ideal>10) for predicting segmental function recovery.
Taking positive and negative likelihood ratios together suggests that FDG PET and dobutamine echocardiography may produce small but sometimes important changes in the probability of recovering regional wall motion after revascularization.
Given its higher sensitivity, PET is less likely to produce false positive results in myocardial viability. PET, therefore, has the potential to identify some patients who might benefit from revascularization, but who would not have been identified as suitable candidates for revascularization using thallium SPECT or dobutamine echocardiography.
PET appears to be superior to other nuclear imaging techniques including SPECT with 201thallium or technetium labelled tracers, although recent studies suggest that FDG SPECT may have comparable diagnostic accuracy as FDG PET for predicting regional and global LV function recovery.
No firm conclusion can be reached about the incremental value of PET over other noninvasive techniques for predicting global function improvement or long-term outcomes in the most important target population (patients with severe ischemic LV dysfunction) due to lack of direct comparison.
An Ontario-based economic analysis showed that in people with CAD and severe LV dysfunction and who were found to have no viable myocardium or indeterminate results by thallium SPECT, the use of PET as a follow-up assessment would likely result in lower cost and better 5-year survival compared to the use of thallium SPECT alone. The projected annual budget impact of adding PET under the above scenario was estimated to range from $1.5 million to $2.3 million.
Conclusion
In patients with severe LV dysfunction, that are deemed to have no viable myocardium or indeterminate results in assessments using other noninvasive tests, PET may have a role in further identifying patients who may benefit from revascularization. No firm conclusion can be drawn on the impact of PET viability assessment on long-term clinical outcomes in the most important target population (i.e. patients with severe LV dysfunction).
PMCID: PMC3385418  PMID: 23074467

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