The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness ...study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD.
A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ≤0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88-0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69-0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65-0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001).
In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively.
http://www.clinicaltrials.gov. Unique identifier: NCT00979199.
Hybrid imaging provides a non-invasive assessment of coronary anatomy and myocardial perfusion. We sought to evaluate the added clinical value of hybrid imaging in a multi-centre multi-vendor ...setting.
Fourteen centres enrolled 252 patients with stable angina and intermediate (20-90%) pre-test likelihood of coronary artery disease (CAD) who underwent myocardial perfusion scintigraphy (MPS), CT coronary angiography (CTCA), and quantitative coronary angiography (QCA) with fractional flow reserve (FFR). Hybrid MPS/CTCA images were obtained by 3D image fusion. Blinded core-lab analyses were performed for CTCA, MPS, QCA and hybrid datasets. Hemodynamically significant CAD was ruled-in non-invasively in the presence of a matched finding (myocardial perfusion defect co-localized with stenosed coronary artery) and ruled-out with normal findings (both CTCA and MPS normal). Overall prevalence of significant CAD on QCA (>70% stenosis or 30-70% with FFR≤0.80) was 37%. Of 1004 pathological myocardial segments on MPS, 246 (25%) were reclassified from their standard coronary distribution to another territory by hybrid imaging. In this respect, in 45/252 (18%) patients, hybrid imaging reassigned an entire perfusion defect to another coronary territory, changing the final diagnosis in 42% of the cases. Hybrid imaging allowed non-invasive CAD rule-out in 41%, and rule-in in 24% of patients, with a negative and positive predictive value of 88% and 87%, respectively.
In patients at intermediate risk of CAD, hybrid imaging allows non-invasive co-localization of myocardial perfusion defects and subtending coronary arteries, impacting clinical decision-making in almost one every five subjects.
Obesity is a complex pathology with interacting and confounding causes due to the environment, hormonal signaling patterns, and genetic predisposition. At present, the Zucker rat is an eligible ...genetic model for research on obesity and metabolic syndrome, allowing scrutiny of gene expression profiles. Real-time PCR is the benchmark method for measuring mRNA expressions, but the accuracy and reproducibility of its data greatly depend on appropriate normalization strategies. In the Zucker rat model, no specific reference genes have been identified in myocardium, kidney, and lung, the main organs involved in this syndrome. The aim of this study was to select among ten candidates (Actb, Gapdh, Polr2a, Ywhag, Rpl13a, Sdha, Ppia, Tbp, Hprt1 and Tfrc) a set of reference genes that can be used for the normalization of mRNA expression data obtained by real-time PCR in obese and lean Zucker rats both at fasting and during acute hyperglycemia. The most stable genes in the heart were Sdha, Tbp, and Hprt1; in kidney, Tbp, Actb, and Gapdh were chosen, while Actb, Ywhag, and Sdha were selected as the most stably expressed set for pulmonary tissue. The normalization strategy was used to analyze mRNA expression of tumor necrosis factor α, the main inflammatory mediator in obesity, whose variations were more significant when normalized with the appropriately selected reference genes. The findings obtained in this study underline the importance of having three stably expressed reference gene sets for use in the cardiac, renal, and pulmonary tissues of an experimental model of obese and hyperglycemic Zucker rats.
Natriuretic peptides (NPs) play an important role in obesity and aim of this study was to evaluate, in cardiac tissue of obese Zucker rats (O, n = 29) their transcriptomic profile compared to ...controls (CO, n = 24) by Real-Time PCR study; CNP protein expression was evaluated by immunostaining and immunometric tests. Myocardial histology was performed, confirming no alteration of organ structure. While ANP and BNP are cardiac peptides, CNP is mainly an endothelial hormone; thus its expression, as well as that of NPR-B and NPR-C, was also evaluated in kidney and lung of an animal subgroup (n = 20). In heart, lower BNP mRNA levels in O vs CO (p = 0.02) as well as ANP and CNP (p = ns), were detected. NPR-B/NPR-A mRNA was similar in O and CO, while NPR-C was numerically lower (p = ns) in O than in CO. In kidney, CNP/NPR-B/NPR-C mRNA was similar in O and CO, while in lung CNP/NPR-C expression decreased and NPR-B increased (p = ns) in O vs CO. Subdividing into fasting and hyperglycemic rats, the pattern of mRNA expression for each gene analyzed remained unchanged. The trend observed in heart, kidney and lung for CNP protein concentrations and immunohistochemistry reflected the mRNA expression. TNF-α and IL-6 mRNA were measured in each tissue and no significant genotype effect was detected in any tissue. The main NP variations were observed at the cardiac level, suggesting a reduced release by cardiac cells. The understanding of mechanisms involved in the modulation of the NP system in obesity could be a useful starting point for future clinical study devoted to identifying new obesity treatment strategies.
C-type natriuretic peptide (CNP) was recently found in the myocardium, but possible insights into differences between atrium and ventricle production are so far lacking. Our aim was to evaluate, in ...an experimental model of pacing-induced heart failure (HF), plasma and tissue levels of CNP and mRNA expression of the peptide and of its specific receptor, NPR-B. Cardiac tissue was collected from male adult minipigs without (control,
n
=
5) and with pacing-induced HF (
n
=
5). Blood samples were collected at baseline and after pacing (10
min, 1, 2, 3 weeks). CNP in plasma and in cardiac extracts was determined by a radioimmunoassay, while the expression of mRNA by real time PCR. Compared to control, plasma CNP was increased after 1 week of pacing stress (36.9
±
10.4
pg/ml vs.16.7
±
1.1,
p
=
0.013, mean
±
S.E.M.). As to myocardial extract, at baseline, CNP was found in all cardiac chambers and its content was 10-fold higher in atria than in ventricles (RA: 13.7
±
1.9
pg/mg protein; LA: 8.7
±
3.8; RV: 1.07
±
0.33; LV: 0.93
±
0.17). At 3 weeks of pacing, myocardial levels of CNP in left ventricle were higher than in controls (15.8
±
9.9
pg/mg protein vs. 0.9
±
0.17,
p
=
0.01). CNP gene expression was observed in controls and at 3 weeks of pacing. NPR-B gene expression was found in all cardiac regions analyzed, and a down-regulation was observed in ventricles after HF. The co-localization of the CNP system and NPR-B suggests a possible role of CNP in HF and may prompt novel therapeutical strategies.
Cardiac natriuretic hormones (CNHs) are a family of related peptides, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and other peptides derived from the N-terminal ...portion of the proANP and proBNP peptide chains. Assays for cardiac natriuretic peptides have been proposed to help assess clinical conditions associated with expanded fluid volume. In particular, the assays can be useful for distinguishing healthy subjects from patients in different stages of heart failure. Measurements of these hormones have also been considered for prognostic indicators of long-term survival in patients with heart failure and/or after acute myocardial infarction. The different CNHs differ in their production/secretion patterns and have different clearance rates. Furthermore, there are numerous proposed assay configurations for each of these hormones, and it is not clear which assay provides the best pathophysiological and/or clinical information.
Here we review recent studies concerning the competitive (such as RIA, enzyme immunoassay, or luminescence immunoassay) and noncompetitive immunoassays (such as two-site IRMA, ELISA, or immunoluminometric assay) for the different cardiac natriuretic peptides to compare the analytical characteristics and clinical relevance of assays for the different CNHs and the different assay formats.
Developing sensitive, precise, and accurate immunoassays for cardiac natriuretic peptides has been difficult because of their low concentrations (on average, approximately 3-6 pmol/L) in healthy subjects and because of their structural, metabolic, and physiological characteristics. Competitive assays have historically suffered from lack of sensitivity and specificity for the biologically active peptides. These usually require tedious extraction procedures prior to analysis. Recently, immunometric assays have been developed that have improved sensitivity and specificity; it appears these will be the methods of choice.
To date, there is no consensus on the best assay procedure of cardiac natriuretic peptides. To facilitate widespread propagation of determination of these hormones in routine clinical practice, it will be necessary to study the new generation of noncompetitive immunometric methods that are less time-consuming and more sensitive and specific. Although several studies suggest that BNP exhibits better clinical utility than the other CNHs, more studies examining multiple CNHs in the same cohorts of patients will be necessary.
Inflammatory mechanisms are associated with worse prognosis in end-stage heart failure (ESHF) patients who require left ventricular assist device (LVAD) support. Interagency Registry for Mechanically ...Assisted Circulatory Support (INTERMACS) profiles describe patient condition at pre-implant and outcome. This study assessed the relationship among inflammation patterns and INTERMACS profiles in LVAD recipients.
Thirty ESHF patients undergoing LVAD implantation as bridge to transplant were enrolled. Blood and urine samples were collected pre-operatively and serially up to 2 weeks post-operatively for assessment of inflammatory markers (plasma levels of interleukin IL-6, IL-8, IL-10, and osteopontin, a cardiac inflammatory-remodeling marker; and the urine neopterin/creatinine ratio, a monocyte activation marker). Multiorgan function was evaluated by the total sequential organ failure assessment (tSOFA) score. Outcomes of interest were early survival, post-LVAD tSOFA score, and intensive care unit (ICU) length of stay.
Fifteen patients had INTERMACS profiles 1 or 2 (Group A), and 15 had profiles 3 or 4 (Group B). At pre-implant, only IL-6 levels and the IL-6/IL-10 ratio were higher in Group A vs B. After LVAD implantation, neopterin/creatinine ratio and IL-8 levels increased more in Group A vs B. Osteopontin levels increased significantly only in Group B. The tSOFA score at 2 weeks post-LVAD and ICU duration were related with pre-implant IL-6 levels.
The INTERMACS profiles reflect the severity of the pre-operative inflammatory activation and the post-implant inflammatory response, affecting post-operative tSOFA score and ICU stay. Therefore, inflammation may contribute to poor outcome in patients with severe INTERMACS profile.
C-type natriuretic peptide (CNP) plasma levels are extremely low and a pre-analytical phase is necessary to assay plasma CNP concentrations. Amino-terminal CNP (NT-proCNP) circulates at higher ...concentrations than CNP, allowing a direct assay and the use of smaller amounts of plasma.
Aim of this study was to evaluate the analytical performance of a direct NT-proCNP assay and to measure its plasma levels in heart failure (CHF), diabetes and chirrosis patients.
NT-proCNP and CNP were measured in 130 CHF, 19 patients with diabetes, 24 with hepatic cirrhosis and 73 controls.
Plasma NT-proCNP was higher in all the clinical conditions studied (controls:45.5
±
1.84
pg/ml, CHF:67.09
±
7.36, diabetes:51.5
±
5.75 cirrhosis:78.4
±
19.9;
p
=
0.034,
p
=
0.04 controls vs. CHF and cirrhosis, respectively) and in CHF NT-proCNP concentration showed a significant increase as a function of clinical severity.
By comparison of ROC curves, CNP assay resulted better associated with disease than NT-proCNP assay in all the different clinical conditions probably due to different release and clearance.
The determination of NT-proCNP adds a piece of information to better understanding the molecular mechanisms at the basis of CNP action in different diseases.
Due to its higher analytical feasibility, this determination could become widespread in clinical biochemistry laboratories and serve as a complementary marker of disease conditions.
► NT-proCNP circulates at higher concentrations than CNP, allowing a direct assay. ► Plasma NT-proCNP was higher in CHF, diabetes and cirrhosis with respect to controls. ► In CHF the NT-proCNP concentration showed a significant increase as a function of clinical severity. ► CNP assay resulted better associated with disease than NT-proCNP assay in all the different clinical conditions. ► NT-proCNP determination could become widespread in clinical biochemistry laboratories.
Heart failure (HF) is a major public health problem and the approach for an accurate individualization of HF risk and care should include a profile of laboratory data, in addition to clinical and ...imaging data. The possibility of identifying the most vulnerable patients is clinically important, especially considering that many therapeutic interventions are available today. This goal has not been yet reached although many novel biomarkers have been proposed and tested. The complexity of the biochemical network at the basis of HF pathophysiology clearly suggests that a single marker cannot reflect all the features of this syndrome, whereas the combined use of more indices would better characterize HF patients and create new options for their management, helping identify which patients to follow more closely. The multimarker approach, considering various biochemical pathways simultaneously, bases its robustness on a suitable choice of indices known to be individually associated with HF. The choice of biomarker combination is essential to the performance of the multimarker strategy. A major problem in selecting the biomarker profile is the proportional increase in economic burden; thus a “parsimonious” biomarker combination has to be used in a cost-effective evaluation. Statistical analysis and analytical performance of the different elements of the combination, in turn, may heavily influence results.
This review summarizes the results obtained using a multimarker approach for HF risk stratification, for predicting HF incidence in a population, and evaluating the response to therapy. An insight into transcriptomic biomarkers, recently proposed for HF individual risk assessment, is also reported. A reliable selection of biomarkers for the careful management of HF patients is of pivotal importance in reducing healthcare costs without reducing patient care.
•ADM in cardiac disease represents a protective mechanism.•IMD is a potential endogenous protector of the heart.•Evaluation of ADM/IDM transcriptomic profiling in human leukocytes of CHF ...patients.•Higher levels of ADM and IMD mRNA in CHF as a function of clinical severity.•The first demonstration that AMD and IDM mRNA levels are detectable in human whole blood samples.
Adrenomedullin (ADM) is a vasodilatory peptide expressed in many tissues. Its levels are elevated in various diseases including chronic heart failure (CHF) and it has been suggested that the up-regulation of ADM in cardiac disease represents a protective mechanism. Similarly, intermedin (IMD), a novel member of the calcitonin/calcitonin gene-related peptide family, is considered a potential endogenous protector of the heart. Previous studies demonstrated that in CHF patients, elevated plasma concentrations of ADM and IMD reflect the patient's disease severity and prognosis, while the behavior of mRNA expression is not known. The aim of this study was to evaluate ADM/IDM transcriptomic profiling in human leukocytes of CHF patients as a function of clinical severity, assessing possible changes with respect to healthy subjects (C). mRNA expression was evaluated by Real-Time PCR and total RNA was extracted from leukocytes of C (n=8) and from CHF patients (NYHA I–II n=10; NYHA III–IV n=14) with PAXgene Blood RNA Kit. Significantly higher levels of ADM and IMD mRNA were found in CHF as a function of clinical severity (ADM: C=0.03±0.013, NYHA I–II=0.11±0.084, NYHA III–IV=11.46±4.72, p=0.037 C vs NYHA III–IV, p=0.028 NYHA I–II vs NYHA III–IV; IMD: C=0.158±0.041, NYHA I–II=0.93±0.40, NYHA III–IV=2.6±0.67, p=0.014 C vs NYHA III–IV, p=0.014 NYHA I–II vs NYHA III–IV). This study highlights, for the first time, the possibility of evaluating ADM and IMD mRNA expression in human whole blood samples by Real-Time PCR study providing further relevant information and providing a more complete interpretation of the pathophysiology of the disease.
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