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Aims: To date, no studies have investigated the association between lipid species and coronary plaque changes over time, quantitatively assessed by serial imaging. We aimed to prospectively determine the association between lipid species quantified by a plasma lipidomic analysis and coronary plaque changes according to composition assessed by a quantitative serial analysis of coronary computed tomography angiography (CTA)., Methods and Results: Patients with suspected coronary artery disease (CAD) undergoing baseline coronary CTA were prospectively enrolled by seven EU centres in the SMARTool study and submitted to clinical, molecular, and coronary CTA re-evaluation at follow-up (an inter-scan period of 6.39 ± 1.17 years). Out of 202 patients who were analysed in the SMARTool main clinical study, a lipidomic analysis was performed in 154 patients before the baseline coronary CTA, and this group was included in the present study. A quantitative CTA analysis was performed by using a separate core laboratory blinded from clinical data. In the univariable analysis, it was found that no lipid species were significantly associated with annual total and calcified plaque changes. After adjusting for clinical variables at baseline and statin use, it was found that three lipid species were significantly associated with non-calcified plaque progression. In detail, cholesteryl ester(20:3), sphingomyelin (SM)(40:3), and SM(41:1) were found to be positively related to non-calcified plaque progression (Bonferroni-adjusted P-values = 0.005, 0.016, and 0.004, respectively)., Conclusion: The current study showed an independent relationship between specific lipid species determined by a plasma lipidomic analysis and non-calcified coronary plaque progression assessed by a serial, quantitative coronary CTA analysis., Competing Interests: Conflict of interest: A.S. received fees for consultancy or lectures from Abbot, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD)., Aim: To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD., Methods: A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient., Results: In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD., Conclusion: In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD., (© 2024. The Author(s).)

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure >20 mmHg at rest during right heart catheterization. PH prevalence is about 1% of the global population. The PH clinical classification includes five groups: pulmonary arterial hypertension, PH associated with left heart disease, PH associated with lung disease, PH associated with pulmonary artery obstructions, PH with unclear and/or multifactorial mechanisms. In case of clinical suspicion, echocardiography is the first-line tool to start the diagnostic process. Right heart catheterization is the gold standard for diagnosis of PH, requires great experience and should be performed in expert centers. The classification of the PH patient in a specific subgroup requires multidisciplinary clinical and instrumental skills that only a reference center can provide. This document proposes a clinical pathway for the management of PH patients in the Tuscany region in order to standardize access to specialized care.

Background and Aims: MMP-9 is a predictor of atherosclerotic plaque instability and adverse cardiovascular events, but longitudinal data on the association between MMP9 and coronary disease progression are lacking. This study is aimed at investigating whether MMP9 is associated with atherosclerotic plaque progression and the related molecular basis in stable patients with chronic coronary syndrome (CCS)., Methods: MMP9 serum levels were measured in 157 CCS patients (58 ± 8 years of age; 66% male) undergoing coronary computed tomography angiography at baseline and after a follow up period of 6.5 ± 1.1 years to assess progression of Total, Fibrous, Fibro-fatty, Necrotic Core, and Dense Calcium plaque volumes (PV). Gene expression analysis was evaluated in whole blood using a transcriptomic approach by RNA-seq., Results: At multivariate analysis, serum MMP9 was associated with annual change of Total and Necrotic Core PV (Coefficient 3.205, SE 1.321, P = 0.017; 1.449, SE 0.690, P = 0.038, respectively), while MMP9 gene expression with Necrotic Core PV (Coefficient 70.559, SE 32.629, P = 0.034), independently from traditional cardiovascular risk factors, medications, and presence of obstructive CAD. After transcriptomic analysis, MMP9 expression was linked to expression of genes involved in the innate immunity., Conclusions: Among CCS patients, MMP9 is an independent predictive marker of progression of adverse coronary plaques, possibly reflecting the activity of inflammatory pathways conditioning adverse plaque phenotypes. Thus, blood MMP9 might be used for the identification of patients with residual risk even with optimal management of classical cardiovascular risk factors who may derive the greatest benefit from targeted anti-inflammatory drugs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MS is an employee of Alacris Theranostics GmbH., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) define a specific lipid profile associated with residual coronary artery disease (CAD) risk independently of total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. Aim of the present study was to assess whether TG/HDL-C ratio, coronary atherosclerosis and their change over time are characterized by a specific lipidomic profiling in stable patients with chronic coronary syndrome (CCS)., Methods: TG/HDL-C ratio was calculated in 193 patients (57.8 ± 7.6 years, 115 males) with CCS characterized by clinical, bio-humoral profiles and cardiac imaging. Patient-specific plasma targeted lipidomics was defined through a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) strategy. Patients underwent coronary computed tomography angiography (CTA) and an individual CTA risk score, combining extent, severity, composition, and location of plaques, was calculated. All patients entered a follow-up (6.39 ± 1.17 years), including clinical, lipidomics and coronary CTA assessments., Results: Patients were divided in groups according to baseline TG/HDL-C quartiles: IQ (<1.391), IIQ (1.392-2.000), IIIQ (2.001-3.286), and IVQ (≥3.287). A specific pattern of altered lipids, characterized by reduced plasma levels of cholesterol esters, phosphatidylcholines and sphingomyelins, was associated with higher TG/HDL-C both at baseline and follow-up (IVQ vs IQ). The CTA risk score increased over time and this lipid signature was also associated with higher CTA score at follow-up., Conclusions: In stable CCS, a specific lipidomic signature identifies those patients with higher TG/HDL- C ratio and higher CTA score over time, suggesting possible molecular pathways of residual CAD risk not tackled by current optimal medical treatments., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background Progression of coronary artery disease using serial coronary computed tomography angiography (CTA) is of clinical interest. Our primary aim was to prospectively assess the impact of clinical characteristics and statin use on quantitatively assessed coronary plaque progression in a low-risk study population during long-term follow-up. Methods Patients who previously underwent coronary CTA for suspected coronary artery disease were prospectively included to undergo follow-up coronary CTA. The primary end point was coronary artery disease progression, defined as the absolute annual increase in total, calcified, and noncalcified plaque volume by quantitative CTA analysis. Results In total, 202 patients underwent serial coronary CTA with a mean interscan period of 6.2±1.4 years. On a per-plaque basis, increasing age (β=0.070; P =0.058) and hypertension (β=1.380; P =0.075) were nonsignificantly associated with annual total plaque progression. Male sex (β=1.676; P =0.009), diabetes mellitus (β=1.725; P =0.012), and statin use (β=1.498; P =0.046) showed an independent association with annual progression of calcified plaque. While hypertension (β=2.259; P =0.015) was an independent determinant of noncalcified plaque progression, statin use (β=-2.178; P =0.050) was borderline significantly associated with a reduced progression of noncalcified plaque. Conclusions Statin use was associated with an increased progression of calcified coronary plaque and a reduced progression of noncalcified coronary plaque, potentially reflecting calcification of the noncalcified plaque component. Whereas hypertension was the only modifiable risk factor predictive of noncalcified plaque progression, diabetes mellitus mainly led to an increase in calcified plaque. These findings could yield the need for intensified preventive treatment of patients with diabetes mellitus and hypertension to slow and stabilize coronary artery disease progression and improve clinical outcome.

The use of cardiac magnetic resonance (cMR) to assess remodeling and tissue characterization in primitive and secondary cardiomyopathies has progressively increased, and it carries important prognostic informations. The aim of this study was to assess the overall clinical value of cMR before implantable cardioverter defibrillator (ICD). All patients referred to our center for an ICD implantation and submitted to cMR (n = 134) were analyzed. All the cMR diagnostic findings and following clinical events were reviewed to assess clinical relevance in patients care. The use of cMR before ICD implantation has progressively increased during the decade studied (13% to 53%, p <0.001). Subjects who underwent cMR were younger, more often female, with lower NYHA class and higher ejection fraction (p <0.05 for all). Unexpected diagnostic findings were observed in 34 patients (25%), resulting in an immediate therapeutic strategy modification in 13%. A pattern of fibrosis leading to a change in the disease's etiology and thrombus detection were the most frequent cMR findings, followed by anatomical incidental findings. Any grade of fibrosis carried a higher annual incidence of combined death or ventricular arrhythmias (9.92% vs 1.83%, p = 0.02). Annual event rate was related to the extent of scarring. In conclusion, we observed a progressively increase of cMR utilization before ICD implantation during the last decade. This practice has yielded a significant increase of new diagnostic findings, carrying unique prognostic information linked to tissue characterization., (Copyright © 2018. Published by Elsevier Inc.)

Background: Multidetector coronary computed tomography angiography (CCTA) is increasingly used for noninvasive imaging of the coronary arteries. Radiation exposure, however, is a potential limitation to a more extensive use of this imaging modality. We aimed to demonstrate that a professional teamwork approach, including a cardiologist and a radiologist in performing CCTA, may allow to obtain best quality exams with very low radiation doses., Methods: A total of 998 consecutive patients underwent CCTA in accordance with the most recent guidelines. The following procedures were undertaken to reduce the radiation dose: (a) preliminary cardiological evaluation to check for CCTA eligibility; (b) optimized heart rate control with beta-blockers and/or ivabradine; and (c) the use of nonstandardized computed tomography protocols and algorithms for dose reduction., Results: All the patients underwent a preliminary cardiological evaluation; 89% of them were pretreated with oral or intravenous beta-blockers and/or ivabradine; 806 patients (81%) were scanned by means of prospective gating, which allowed a radiation dose exposure of 161 ± 68.64 mGy; 192 patients (19%) underwent a retrospective gating protocol, with a radiation dose exposure of 1135.15 ± 485.87 mGy. In 13 patients (1%) CCTA was uninterpretable because of artifacts. Exam quality was not affected by the use of low-dose computed tomography scanning. Coronary calcium score and/or left ventricular functional analysis were never performed., Conclusions: The preliminary selection and preparation of patients and optimized scanner utilization allow a substantial reduction in radiation dose for most of the patients submitted to CCTA without affecting image quality. In our experience, a team approach was necessary to allow a "low-dose learning curve" and a progressive reduction in radiation doses administered to patients by means of the prospective gating protocol.

Aims: 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., Methods and Results: 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., Conclusion: 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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: With the widespread use of multidetector computed tomography (MDCT) coronary angiography, cardiac and extracardiac incidental findings in cardiac imaging might be detected. The aim of this study was to determine the prevalence of cardiac and extracardiac incidental findings in a population of consecutive patients undergoing coronary MDCT., Methods: A total of 840 consecutive patients with known or suspected heart disease underwent cardiac MDCT. All patients were assessed with 64-slice MDCT; the examination was performed by limiting the anatomical region examined between the bifurcation of the trachea and the cardiac apex with the aim of obtaining excellent image quality and low cardiac radiological exposure., Results: Overall, 81 incidental findings in 72 patients (9%) were identified, of which 18 were cardiac (2%) and 63 extracardiac (7%). Extracardiac incidental findings were mainly represented by pulmonary nodules (19%)., Conclusions: A significant number of cardiac and extracardiac incidental findings were observed at cardiac MDCT, with the prevalence depending on technical aspects of image acquisition and patient characteristics. Incidental findings should be carefully searched for and reported because they may have an impact on clinical follow-up indications that is not without cost and risk.

Background: In patients with chronic angina-like chest pain, the probability of coronary artery disease (CAD) is estimated by symptoms, age, and sex according to the Genders clinical model. We investigated the incremental value of circulating biomarkers over the Genders model to predict functionally significant CAD in patients with chronic chest pain., Methods: In 527 patients (60.4 years, standard deviation, 8.9 years; 61.3% male participants) enrolled in the European Evaluation of Integrated Cardiac Imaging (EVINCI) study, clinical and biohumoral data were collected., Results: Functionally significant CAD-ie, obstructive coronary disease seen at invasive angiography causing myocardial ischemia at stress imaging or associated with reduced fractional flow reserve (FFR < 0.8), or both-was present in 15.2% of patients. High-density lipoprotein (HDL) cholesterol, aspartate aminotransferase (AST) levels, and high-sensitivity C-reactive protein (hs-CRP) were the only independent predictors of disease among 31 biomarkers analyzed. The model integrating these biohumoral markers with clinical variables outperformed the Genders model by receiver operating characteristic curve (ROC) (area under the curve [AUC], 0.70 [standard error (SE), 0.03] vs 0.58 [SE, 0.03], respectively, P < 0.001) and reclassification analysis (net reclassification improvement, 0.15 [SE, 0.07]; P = 0.04). Cross-validation of the ROC analysis confirmed the discrimination ability of the new model (AUC, 0.66). As many as 56% of patients who were assigned to a higher pretest probability by the Genders model were correctly reassigned to a low probability class (< 15%) by the new integrated model., Conclusions: The Genders model has a low accuracy for predicting functionally significant CAD. A new model integrating HDL cholesterol, AST, and hs-CRP levels with common clinical variables has a higher predictive accuracy for functionally significant CAD and allows the reclassification of patients from an intermediate/high to a low pretest likelihood of CAD., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods and Results: 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)., Conclusions: 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., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00979199., (© 2015 American Heart Association, Inc.)

Background: Left ventricular (LV) twist represents a main aspect of ejection. It is defined as the difference between the apical and basal rotation and can be assessed by speckle tracking echocardiography (STE). Twist may be underestimated when assessed by two-dimensional-echocardiography due to the difficulty of identifying the real apex. Aim of this study was to evaluate the LV twist by means of three-dimensional (3D)-STE and verify if the inclusion of the apex can modify the assessment of the global twist., Methods: LV volume acquisition with a fully sampled matrix array transducer was performed in 30 healthy subjects and 79 patients with cardiomyopathy secondary to different etiologies. Thirty-nine patients had a LV ejection fraction (EF) ≥50% (Group A), 16 showed an EF between 40 and 50% (Group B), and 24 patients had an EF ≤40%(Group C). LV rotation was assessed by 3D-STE at basal, medium, apical, and apical-cap levels. Twist was computed considering the apex either at the apical level (Twist(Api) ) or at the apical-cap level (Twist(AC) )., Results: LV rotation resulted to be progressively higher from base to apical-cap (P < 0.0001) with a significant difference between the apex and the apical-cap level (6.20 ± 3.90° vs. 10.23 ± 7.52°; P < 0.001). Such a difference was constantly found in all Groups (P < 0.01 for Group A, P < 0.05 for Group B and C). Twist(Api) was also significantly lower than Twist(AC) both in the overall population (6.2 ± 3.89° vs. 10.23 ± 7.51°; P < 0.001) and in the different subgroups (, Controls: 9.61 ± 3.39° vs. 13.75 ± 6.51°; Group A: 10.49 ± 4.77° vs. 16.37 ± 8.49°; Group B: 6.67 ± 3.44° vs. 9.14 ± 5.55°; Group C: 33 ± 2.62° vs. 5.26 ± 3.74°; P < 0.05 for all the comparisons)., Conclusions: Identification and inclusion of apical-cap is relevant for twist assessment and can be carried out efficiently by 3D-STE. The inclusion of the true apex in the calculation significantly affects the analysis of twist both in normal individuals and patients with different myocardial diseases., (© 2012, Wiley Periodicals, Inc.)

Aims: Three-dimensional (3D)-echocardiography speckle imaging allows the evaluation of frame-by-frame strain and volume changes simultaneously. The aim of the present investigation was to describe the strain-volume combined assessment in different patterns of cardiac remodelling., Methods and Results: Fifty patients received a 3D acquisition. Patients were classified as follows: healthy subjects (CNT), previous AMI, and normal ejection fraction (EF; group A); ischaemic cardiomyopathy with reduced EF (group B); hypertrophic/infiltrative cardiomyopathy (group C). Values of 3D strain were plotted vs. volume for each frame to build a strain-volume curve for each case. Peak of radial, longitudinal, and circumferential systolic strain (Rεp, Lεp, and Cεp, respectively), slopes of the curves (RεSl, LεSl, CεSl), and strain to end-diastolic volume (EDV) ratio (Rε/V, Lε/V, Cε/V) were computed for the analysis. Strain-volume curves of the CNT group were steep and clustered, whereas, due to progressive dilatation and reduction of strains, progressive flattening could be demonstrated in groups A and B. Quantitative data supported visual assessment with progressive lower slopes (P< 0.05 for RεSl, CεSl, P= 0.06 for LεSl) and significantly lower ratios (P< 0.01 for Rε/V, Lε/V, and Cε/V). Group C showed an opposite behaviour with slopes and ratios close to those of normal subjects. Correlation coefficients between EDV and slopes of the curves were significant for all the directions of strain (CεSl: r = 0.891; RєSl: r = 0.704; LєSl: r = 0.833; P< 0.0001 for all)., Conclusion: We measured left ventricular volumes and strain by 3D-echo and obtained strain-volume curve to evaluate their behaviour in remodelling. A distinctive and progressive pattern consistent with pathophysiology was observed. The analysis here shown could represent a new non-invasive method to assess myocardial mechanics and its relationship with volumes.

A clinical case of non-obstructive hypertrophic cardiomyopathy with involvement of the right ventricle is reported. The patient was a 42-year-old male with symptoms suggesting an effort angina of recent onset. The diagnosis was established by echocardiography, which showed asymmetric hypertrophy of the interventricular septum (20 mm), hypertrophy of the right ventricular free wall, and severe hypertrophy of the septal papillary muscle of the tricuspid valve. The patient underwent a complete diagnostic evaluation, including exercise stress test, Holter monitoring, magnetic resonance, myocardial tomoscintigraphy and complete hemodynamic assessment. Medical treatment with atenolol 50 mg day was started; at 1-year follow-up the patient's clinical conditions are good, with decrease of anginal episodes. The literature review elicits the paucity of information about this condition, despite a frequent involvement of both ventricles in hypertrophic obstructive cardiomyopathy. The case reported shows two atypical aspects: a) the involvement of the right ventricle in non-obstructive hypertrophic cardiomyopathy is anecdotal; b) this pattern of hypertrophy (right ventricular free wall/septal papillary muscle) has never been previously reported. Right ventricular involvement in patients with hypertrophic cardiomyopathy must be carefully investigated, because it may be more frequent than conventionally deemed.

Background: Depressed myocardial blood flow (MBF) has been reported in dilated cardiomyopathy. The aim of this study was to investigate whether MBF impairment is an independent predictor of prognosis in patients with idiopathic left ventricular (LV) dysfunction., Methods and Results: Sixty-seven patients (52 male, mean age 52+/-12 years) with different degrees of idiopathic LV systolic dysfunction (average LV ejection fraction, 0.34+/-0.10; range, 0.07 to 0.49) were prospectively enrolled. Thirty-four subjects (51%) had no history of heart failure symptoms at enrollment (NYHA class I). All patients underwent clinical and functional evaluation and a PET study to measure absolute MBF at rest and after intravenous dipyridamole. During a mean follow-up of 45+/-37 months, 24 patients had major cardiac events, including cardiac death in 8 and development or progression of heart failure in 16 patients. Multivariate regression analysis (Cox proportional hazards model) revealed heart rate (chi(2) 11.06, P<0.001), LV end-diastolic dimension (chi(2) 11.73, P<0.001), and dipyridamole MBF (chi(2) 11.04, P<0.001) as independent predictors of subsequent cardiac events. Dipyridamole MBF < or = 1.36 mL. min(-1). g(-1) was associated with an increase in the relative risk of death, development, or progression of heart failure of 3.5 times over other more common clinical and functional variables., Conclusions: The present study demonstrates that severely depressed MBF is a predictor of poor prognosis in patients with idiopathic LV dysfunction independently of the degree of LV functional impairment and of the presence of overt heart failure.

The rate of release of purines (adenosine, inosine, hypoxanthine, xanthine and uric acid) from isolated working rat hearts was measured and compared to tissue concentrations of high energy phosphate compounds. Hearts were subjected to different workloads, and perfusions were performed: with normal oxygen supply (group 1); with the addition of insulin to the standard perfusion buffer, which contained glucose as energy source (group 2); in hypoxic conditions (group 3). In each group purine release increased (P less than 0.01) at higher workload and was closely related to indices of mechanical performance such as cardiac output or minute work (r = 0.902 and 0.858 in group 1, r = 0.902 and 0.851 in group 2, r = 0.851 and 0.881 in group 3, P less than 0.001 in each case). Work had no effect on adenine nucleotides but produced a significant (P less than 0.01) reduction in phosphocreatine/creatine ratio. The comparison of different groups showed that at any level of heart performance purine release was higher (P less than 0.001) in group 3 vs. group 1, and lower (P less than 0.001) in group 2 vs. group 1. High energy phosphates were reduced in group 3 vs. group 1 but were unchanged in group 2 vs. group 1. We conclude that in the isolated heart purine release is directly related to the rate of energy consumption, and inversely related to the rate of energy production. Purine release provides a sensitive method to evaluate myocardial energy metabolism, which is more sensitive than measurement of high energy phosphates.

The action of amrinone on the isolated working rat heart was studied. In basal conditions up to 400 mg/l amrinone behaved as a pure chronotropic agent, raising the heart rate by 23%. In ischaemia-damaged hearts 100 mg/l amrinone had a true inotropic action, provoking significant increases in cardiac output (11%), aortic flow (10%) and double product (9%). The addition of 10 microM adenosine, which inhibits the inotropic action of catecholamines, did not modify the response to amrinone. However, when calcium was reduced from 2.5 to 1.25 mM, the inotropy of ischaemia-damaged hearts was not significantly affected by amrinone, and its chronotropic action was reduced. It is concluded that after acute ischaemic damage amrinone increases heart performance even in a poorly responsive species in which no inotropic effect can be produced under basal conditions. In this model its action is resistant to adenosine but depends on the availability of a sufficient amount of extracellular calcium.

Two classes of adenosine binding sites were identified in pig ventricular sarcolemma using 5'-N-[3H]ethylcarboxamideadenosine ([3H]NECA) as radioligand (Bmax = 88 fmol/mg protein, Kd = 28 nM; Bmax = 7100 fmol/mg protein, Kd = 730 nM). Competition experiments indicated that the higher affinity group had the pharmacological characteristics of the A2 adenosine receptors. The lower affinity binding sites may correspond to the A3 adenosine receptors demonstrated in rat brain. Results with the calcium antagonist [3H]nitrendipine suggest that adenosine exerts some of its effects on the heart also through a direct binding to specific calcium-channel subtypes.

We evaluated the adenosine hypothesis through a new approach, based on the study of the relationship between coronary flow or resistance and purine release, which is an accurate index of myocardial adenosine release. Isolated rat hearts were perfused at different work loads, in hypoxic conditions and after a short period of global ischaemia. When the results of all experiments were considered together, purine release was significantly but weakly related to coronary flow and coronary resistance (r = 0.416 v coronary flow, r = 0.378 v the reciprocal of coronary resistance, p less than 0.01). Closer relationships were obtained within the three subgroups: the correlation coefficients increased to 0.819 and 0.835 (p less than 0.001) in the hearts perfused at different work loads with normal oxygen supply, to 0.701 and 0.757 (p less than 0.02 and p less than 0.01) in the hypoxic hearts, and to 0.897 and 0.978 (p less than 0.02 and p less than 0.01) in the hearts recovering from ischaemia. The relationships between purine release and coronary flow or resistance were significantly different in the three subgroups (p less than 0.001): at any value of purine release coronary resistance was highest during hypoxia and lowest after ischaemia, while the opposite was true for coronary flow. We suggest that the adenosine hypothesis is converted into a "weaker" statement: adenosine is involved in the adjustment between heart performance and coronary resistance but other factors contribute to the regulation of coronary flow, and/or affect the response to adenosine.