Improvement of left ventricular function with surgical revascularization in patients eligible for implantable cardioverter-defibrillator.

INTRODUCTION: Left ventricular ejection fraction (EF) ≤ 35% is the cornerstone criterion for implantable cardioverter-defibrillator (ICD) eligibility. Improvement in EF may occur in ICD-eligible patients after coronary artery bypass graft surgery (CABG). However, the incidence, predictors, and outcomes of this process are unclear. METHODS AND RESULTS: We studied 427 patients with EF ≤ 35% who underwent CABG in the Surgical Treatment for Ischemic Heart Failure (STICH) trial and had a systematic pre- and postoperative (4 months) EF assessment using the identical cardiac imaging modality. All imaging studies were interpreted at a core laboratory. Improvement in EF was defined as postoperative EF > 35% and >5% absolute improvement from baseline. Of the 427 patients (mean age 61.8 ± 9.5 and 50 women), 125 (29.2%) had EF improvement. Their mean EF increased from 26.8% (±5.8%) to 43.3% (±6.5%) (p < .0001). EF improvement occurred in only 20% of patients with a preoperative EF < 25%. The odds of EF improvement were 1.96 times higher (95% confidence interval [CI]: 0.91-4.23, p = .09) in patients with myocardial viability. In adjusted analyses, EF improvement was associated with a significantly lower risk of all-cause mortality (hazard ratio [HR]: 0.58, 95% CI: 0.35-0.96; p = .03) and heart failure mortality (HR: 0.31, 95% CI: 0.11-0.87; p = .027). CONCLUSION: Nearly 1/3rd of ICD-eligible patients undergoing CABG had significant improvement in EF, obviating the need for primary prevention ICD implantation. These results provide patients and clinicians data on the likelihood of ICD eligibility after CABG and support the practice of reassessment of EF after revascularization.

Stress cardiomyopathy in hospitalized patients with cancer: machine learning analysis by primary malignancy type.

AIMS: Previous studies have shown that patients with stress (Takotsubo) cardiomyopathy (SC) and cancer have higher in-hospital mortality than patients with SC alone. No studies have examined outcomes in patients with active cancer and SC compared to patients with active cancer without SC. We aimed to assess the potential association between primary malignancy type and SC and their shared interaction with inpatient mortality. METHODS AND RESULTS: We analysed SC by primary malignancy type with propensity score adjusted multivariable regression and machine learning analysis using the 2016 United States National Inpatient Sample. Of 30 195 722 adult hospitalized patients, 4 719 591 had active cancer, of whom 568 239 had SC. The mean age of patients with cancer and SC was 69.1, of which 74.7% were women. Among patients with cancer, those with SC were more likely to be female and have white race, Medicare insurance, hypertension, heart failure with reduced ejection fraction, obesity, cerebrovascular disease, anaemia, and chronic obstructive pulmonary disease (P < 0.003 for all). In machine learning-augmented, propensity score multivariable regression adjusted for age, race, and income, only lung cancer [OR 1.25; 95% CI: 1.08-1.46; P = 0.003] and breast cancer [OR 1.81; 95% CI: 1.62-2.02; P < 0.001] were associated with a significantly increased likelihood of SC. Neither SC alone nor having both SC and cancer was significantly associated with in-hospital mortality. The presence of concomitant SC and breast cancer was significantly associated with reduced mortality (OR 0.48; 95% CI: 0.25-0.94; P = 0.032). CONCLUSIONS: This analysis demonstrates that primary malignancy type influences the likelihood of developing SC. Further studies will be necessary to delineate characteristics in patients with lung cancer and breast cancer which contribute to development of SC. Additional investigation should confirm lower mortality in patients with SC and breast cancer and determine possible explanations and protective factors.

Quantitative myocardial perfusion positron emission tomography and caffeine revisited with new insights on major adverse cardiovascular events and coronary flow capacity.

AIMS: To evaluate effects of caffeine on quantitative myocardial perfusion by positron emission tomography (PET) and associated major adverse cardiovascular events (MACE). METHODS AND RESULTS: Serum caffeine was measured for all 6087 PETs with 328 positive results (5.4%). Paired caffeine positive/negative PETs (84 patients for dipyridamole with median caffeine 1.6 mg/L, and additional 25 volunteers for regadenoson with median caffeine 7.4 mg/L) were compared for quantitative perfusion. Multivariate regression analysis for associations among caffeine, clinical/imaging variables, predicted caffeine probability was performed. MACEs were followed up to 9 years after PETs. For caffeine vs. no caffeine, respectively, stress flow was 1.74 ± 0.55 vs. 2.14 ± 0.53 for dipyridamole and 1.82 ± 0.61 vs. 2.33 ± 0.49 mL/min/g for regadenoson, and coronary flow reserve (CFR) was 2.26 ± 0.67 vs. 2.67 ± 0.72 for dipyridamole and 1.84 ± 0.33 vs. 2.31 ± 0.41 for regadenoson (all P < 0.001). Subjects were reclassified from high-risk CFR ≤2.0 with caffeine to low-risk CFR >2.0 without caffeine in 66.7% and 80% of dipyridamole and regadenoson caffeine-no-caffeine pairs, respectively. While relative images showed no differences, caffeine significantly altered coronary flow capacity (CFC) to false negative and false positive severity in 2.1% and 5.5% of the 328 caffeine positives, respectively (0.1% and 0.3% of 6087 PETs) but without change in severity guided management in most patients (92.4% of 328 caffeine or 99.6% of total 6087 PETs). CONCLUSION: Even low serum caffeine levels reduce quantitative perfusion during vasodilatory stress with false positive or false negative results minimized by empathic instruction, CFC analysis or repeat PET after strict caffeine abstention for definitive individualized risk stratification and management.

Pomegranate (Punica granatum) purified polyphenol extract inhibits influenza virus and has a synergistic effect with oseltamivir.

Influenza epidemics cause numerous deaths and millions of hospitalizations each year. Because of the alarming emergence of resistance to anti-influenza drugs, there is a need to identify new naturally occurring antiviral molecules. We tested the hypothesis that pomegranate polyphenol extract (PPE) has anti-influenza properties. Using real time PCR, plaque assay, and TCID 50% hemagglutination assay, we have shown that PPE suppresses replication of influenza A virus in MDCK cells. PPE inhibits agglutination of chicken red blood cells (cRBC) by influenza virus and is virucidal. The single-cycle growth conditions indicated that independent of the virucidal effect PPE also inhibits viral RNA replication. PPE did not alter virus ribonucleoprotein (RNP) entry into nucleus or translocation of virus RNP from nucleus to cytoplasm in MDCK cells. We evaluated four major Polyphenols in PPE (ellagic acid, caffeic acid, luteolin, and punicalagin) and demonstrated that punicalagin is the effective, anti-influenza component of PPE. Punicalagin blocked replication of the virus RNA, inhibited agglutination of chicken RBC's by the virus and had virucidal effects. Furthermore, the combination of PPE and oseltamivir synergistically increased the anti-influenza effect of oseltamivir. In conclusion, PPE inhibited the replication of human influenza A/Hong Kong (H3N2) in vitro. Pomegranate extracts should be further studied for therapeutic and prophylactic potential especially for influenza epidemics and pandemics.

Three-dimensional isotropic wavelets for post-acquisitional extraction of latent images of atherosclerotic plaque components from micro-computed tomography of human coronary arteries.

RATIONALE AND OBJECTIVES: The capability of wavelet transforms to separate signals into frequency bands is the basis for its use in image compression and storage, data management and transmission, and, recently, extraction of latent images of tissue components from noisy medical images. Analysis of temporal variations of radiofrequency backscatter of intravascular ultrasound with one-dimensional wavelets can detect lipid-laden plaque in coronary arteries with a sensitivity and specificity of >80%. In this study we evaluate the capability of a novel, 3-dimensional isotropic wavelet analysis to perform high resolution, non-directionally biased, statistically reliable, non-invasive discrimination between components of human coronary atherosclerotic plaques in micro-CT. MATERIALS AND METHODS: Coronary artery segments (5-15 mm) were excised at necropsy from 18 individuals with advanced coronary atherosclerosis. Specimens were imaged using a GE Locus SP ex vivo micro-CT scanner and processed for histological correlation (833 sections). The isotropic wavelet constructs were applied to the entire volume of CT data of each arterial segment to distinguish tissue textures of varying scales and intensities. Voxels were classified and plaque characterization achieved by comparing the relative magnitudes of these wavelet constituents to that of several reference plaque tissue components. RESULTS: Processing of micro-CT images via these isotropic wavelet algorithms permitted 3-D, color-coded, high resolution, digital discrimination between lumen, calcific deposits, lipid-rich deposits, and fibromuscular tissue providing detail not possible with conventional thresholding based on Hounsfield intensity units. Using the isotropic wavelets (with histology as the gold standard), lipid-rich pools approaching the size of the filter for the isotropic wavelet algorithm (0.25 mm [250 microns] in length) were identified with 81% sensitivity and 86% specificity. Calcific deposits, fibromuscular tissue, and lumen equal to or larger than the wavelet filter size were detected without error (100% sensitivity and specificity). CONCLUSION: Isotropic wavelet analysis permits high resolution, multi-dimensional identification of coronary atherosclerotic plaque components in micro-CT with sensitivity and specificity similar to that achieved with data obtained invasively (from IVUS in vivo) using one-dimensional wavelets. Further studies are necessary to test the applicability of this technology to clinical, multi-detector scanners.

Quantification of roughness of calcific deposits in computed tomography scans of human coronary arteries.

OBJECTIVES: The incidence of coronary artery disease has been shown to be greater in patients with calcific deposits than in those without. It has been suggested that the pattern of distribution of coronary calcific deposits within coronary arteries is of greater predictive value for acute coronary events than the overall quantity. Whether roughness of calcific deposits is a predictor of acute coronary events is not known. We derived and tested an algorithm, Voxel-Based Bosselation (VBB), for noninvasive quantification of roughness of calcific deposits in human coronary arteries imaged by computed tomography (CT). METHODS AND RESULTS: VBB was tested on 213 coronary calcific deposits from electron beam CT scans of 27 patients. This algorithm evaluates the 3-dimensional connectedness of surface voxels of each deposit: smooth masses have low VBB and rough masses high VBB. The algorithm was calibrated with artificially generated phantoms as well as background noise mimicking calcific deposits and surrounding heart tissue. The VBB algorithm is applicable to calcific deposits of all scales and gradations. The VBB values of the deposits in this study did not correlate with deposit size further supporting its validity as a measurement of roughness. The VBB index corresponded directly with visual reconstruction using Phong-shaded algorithms. CONCLUSIONS: The VBB index, derived here, is a noninvasive method of quantifying the roughness of calcific deposits in CT scan data which can now be used in future clinical studies to determine possible correlations with increased plaque vulnerability and major acute coronary events.

Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes.

Systemic infections can trigger heart attacks. We conducted an autopsy study to investigate the pathologic effect of systemic infections on coronary artery inflammation. We studied 14 atherosclerotic patients diagnosed with an acute systemic infection. Our control group (n=13) had atherosclerosis without infection. The groups were similar in luminal stenosis and age. Coronary artery sections were stained with H&E and markers for macrophages (CD68), T cells (CD3), and dendritic cells (S100). On pathologic examination, 5 infected patients had acute myocardial infarction with thrombosis. Macrophage density in plaques and in periadventitial fat was higher in the infected group (NS). The infected patients' adventitia had significantly more macrophages (1,577 +/- 1,872 vs 265 +/- 185 per mm(2); P=0.047). The macrophage density, similar in the control group's adventitia and plaque, was significantly greater in the infected group's adventitia than in the plaque. The adventitia and periadventitial fat of the infected group had more T cells than did samples from the control group (48.4 +/- 45.0 vs 14.1 +/- 6.3 per mm(2); P=0.002). The groups exhibited similar plaque T-cell density. The infected patients' plaques, but not the adventitia and periadventitial fat, had more dendritic cells than did the controls' (3.2 +/- 2.5 vs 0.3 +/- 0.5 per mm(2); P=0.022). To our knowledge, this is the 1st report to establish a connection between acute systemic infections and significant increases in inflammatory cells in the atherosclerotic coronary arteries of human beings. This offers a new therapeutic target for preventing heart attacks in high-risk patients.

Is it time to prescribe statins to patients with calcified aortic stenosis?

Aortic stenosis (AS) is a common disease especially in the older population. It is associated with high mortality and morbidity. Recent data suggest that coronary artery disease and AS share common risk factors. Retrospective studies suggest that statins might slow the progression of AS but there are no randomized clinical trial data available. It would seem that statins can be considered for medical treatment of AS; however, this needs to be investigated in future randomized clinical trials.

Leukocyte count and coronary heart disease: implications for risk assessment.

Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count is a marker of inflammation that is widely available in clinical practice. This paper reviews the available epidemiologic evidence for a relationship between the leukocyte count and coronary heart disease (CHD). Numerous epidemiologic and clinical studies have shown leukocytosis to be an independent predictor of future cardiovascular events, both in healthy individuals free of CHD at baseline and in patients with stable angina, unstable angina, or a history of myocardial infarction. This relationship has been observed in prospective and retrospective cohort studies, as well as in case-control studies. It is strong, consistent, temporal, dose-dependent, and biologically plausible. The relationship persists after adjustment for multiple CHD risk factors, including smoking. Elevated differential cell counts, including eosinophil, neutrophil, and monocyte counts, also predict the future incidence of CHD. Leukocytosis affects CHD through multiple pathologic mechanisms that mediate inflammation, cause proteolytic and oxidative damage to the endothelial cells, plug the microvasculature, induce hypercoagulability, and promote infarct expansion. In summary, leukocytosis has been consistently shown to be an independent risk factor and prognostic indicator of future cardiovascular outcomes, regardless of disease status. The leukocyte count is inexpensive, reliable, easy to interpret, and ordered routinely in inpatient and outpatient settings. However, its diagnostic and prognostic utility in CHD is widely unappreciated. Further studies are needed to assess the true impact of leukocytosis on CHD, compare it with other inflammatory markers such as C-reactive protein and lipoprotein phospholipase A(2) levels, and promote its use in CHD prediction.

Blood pressure measures and electrocardiogram-defined myocardial infarction in an Iranian population: Tehran Lipid and Glucose study.

The purpose of this study was to describe blood pressure values in Iranian adults with electrocardiogram (ECG) evidence of a myocardial infarction (MI). High blood pressure is a risk factor, and an ECG can be diagnostic of coronary artery disease. In recent studies the role of pulse pressure in predicting coronary artery disease has been suggested to be more important than that of blood pressure. From among participants of the Tehran Lipid and Glucose study, data for 2479 men and 3060 women aged > or =30 years not currently using any antihypertensive medication were collected. The study used the mean of two separate blood pressure measurements for each individual. ECG findings of all subjects were coded according to Minnesota ECG coding criteria, and they were categorized into probable/possible MI or no MI. ECG evidence of probable or possible MI was found in 1.2% of subjects (1.8% in men vs. 0.8% in women, p<0.001). Prevalence of ECG-defined MI in hypertensive persons was two-fold higher than in normotensives. Adjusted for age, sex, and body mass index, mean diastolic blood pressure was significantly lower in cases with ECG-defined MI than in subjects without MI (p<0.03). There was a strong positive correlation between pulse pressure and systolic blood pressure in both hypertensive/normotensive and MI/no MI groups at the p<0.001 level. There was a weak inverse correlation between diastolic blood pressure and pulse pressure in hypertensive/normotensive/no MI groups (-0.32 and -0.14, both p<0.001). Diastolic blood pressure was not correlated with pulse pressure in cases with MI. Prevalence of ECG-defined MI in hypertensive cases was higher than in normotensives. Systolic blood pressure is a better predictor for pulse pressure than diastolic blood pressure in both normotensive and hypertensive populations with or without ECG-defined MI.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

Plaque blush, branch location, and calcification are angiographic predictors of progression of mild to moderate coronary stenoses.

BACKGROUND: Angiographic predictors of plaque progression are weak and few: length, irregular surface, turbulence, low shear, and (in some studies) eccentricity and calcification. Having noted plaques that briefly retained dye after angiography, we interpreted these as plaques with a fissured surface or neovascularization and hypothesized that progression would be predicted by "plaque blush." METHODS: Plaques (<50% diameter stenosis) in 68 pairs of angiograms, 5.6 +/- 4.8 months apart, were reviewed by 2 blinded observers. The presence of plaque blush, calcification, clot (mobile defect), eccentricity, and a branch point location were compared between progressing (> or =20% stenosis increase) and nonprogressing plaques. RESULTS: Sixteen lesions in 15 patients progressed from 29% +/- 13% to 68% +/- 14% over a period of 8.1 +/- 7.9 months. Patients with and without progression were similar in sex, age, congestive heart disease risk factors, medications, interval between angiograms, clinical presentation, and initial stenosis severity. By logistic regression, plaque blush (BL) (P =.002), calcification (CA) (P =.024), and a branch (BR) point location (P =.001) predicted plaque progression. The odds ratio for plaque progression (ORp) was calculated as ORp = e(2.5 x BL + 1.8 x CA + 2.6 x BR). Using an ORp of 1/3, the model has 81% sensitivity and 77% specificity. A second analysis in which each progressive lesion was compared with proximal and distal lesions and with one in a different coronary artery yielded similar results. CONCLUSIONS: In mild to moderate coronary stenoses, studied retrospectively, plaque blush (a new sign) and a branch point location were strong predictors of plaque progression, whereas calcification was a weak predictor of progression.

Superparamagnetic iron oxide-based method for quantifying recruitment of monocytes to mouse atherosclerotic lesions in vivo: enhancement by tissue necrosis factor-alpha, interleukin-1beta, and interferon-gamma.

BACKGROUND: It has been found recently that the MRI contrast agent superparamagnetic iron oxide (SPIO) localizes to aortic atherosclerotic plaques. We therefore asked whether SPIO might be used to monitor monocyte recruitment into aortic atherosclerotic plaques. METHODS AND RESULTS: Eleven female apo E knockout (K/O) mice, each 11 months old, were divided into 2 groups. Six mice received tissue necrosis factor-alpha (0.2 microg IP once), interleukin-1beta (0.2 micro g IP once), and interferon-gamma (100 U/g per day IP for 5 days); 5 received 0.5 mL saline containing 1% BSA and served as sham-treated atherosclerotic controls. Two wild-type C57BL/6 mice served as sham-treated nonatherosclerotic controls. Three hours after initial cytokine or sham treatment, all mice received SPIO by intravenous injection (1 mmol/kg iron). Six days later, all mice were euthanized, the hearts and aortas were perfused under physiological pressure, and the entire aortas were studied histologically. Atherosclerotic plaques in cytokine-treated mice contained more iron-positive macrophages per cross section than did those in sham-treated apo E K/O control mice (42+/-11.8 versus 11.6+/-5.9) (P<0.0001). Iron-laden macrophages were present either in subendothelial plaque surfaces or in thin layers overlying the internal elastic lamina, often at the edges of atherosclerotic plaques. No iron deposition was seen in aortas of the wild-type nonatherosclerotic control mice. Immunocytochemistry showed mostly macrophages and few T lymphocytes in atherosclerotic plaques of cytokine-treated mice. CONCLUSIONS: SPIO allows detection of iron-laden macrophages in the aortic subendothelium of apo E-deficient mice under basal conditions and monitoring of monocyte recruitment after cytokine injection.

Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice.

BACKGROUND: The role of infection in the development and complications of atherosclerosis has been the focus of much attention. We reported previously that influenza vaccination was associated with reduced risk of recurrent myocardial infarction. Here, we report the effect of influenza A virus on the apolipoprotein E-deficient (apoE(-/-)) mouse, an animal model of atherosclerosis. METHODS AND RESULTS: Twenty-four apoE(-/-) mice >24 months old were injected with 1 LD(50) (lethal dose 50) of influenza A virus. Ten wild-type C57BL/6 infected mice and 11 noninfected age-matched apoE(-/-) mice served as controls. Multiple aortic sections were studied histologically 3, 5, and 10 days later. The infected mice showed markedly increased intimal cellularity compared with the noninfected apoE(-/-) mice. No aortic abnormalities were seen in infected wild-type mice. Ten infected apoE(-/-) mice had a significant subendothelial infiltrate composed of a heterogeneous group of cells that stained positively for smooth muscle cell actin, F4/80 (macrophages), and CD3 (T lymphocytes). One case of subocclusive platelet and fibrin-rich thrombus was seen. CONCLUSIONS: This study shows that influenza infection promotes inflammation, smooth muscle cell proliferation, and fibrin deposition in atherosclerotic plaques.