Cardiac microcalcification burden: Global assessment in high cardiovascular risk subjects with Na[18F]F PET-CT.

BACKGROUND: Fluorine-18 sodium fluoride (Na[18F]F) atherosclerotic plaque uptake in positron emission tomography with computed tomography (PET-CT) identifies active microcalcification. We aim to evaluate global cardiac microcalcification activity with Na[18F]F, as a measure of unstable microcalcification burden, in high cardiovascular (CV) risk patients. METHODS AND RESULTS: Thirty-four high CV risk individuals without previous CV events were scanned with Na[18F]F PET-CT. Cardiac Na[18F]F uptake was assessed through the global molecular calcium score (GMCS), which was calculated by summing the product of the mean standardized uptake value times the area of the cardiac regions of interest times the slice thickness for all cardiac transaxial slices, divided by the total number of slices. Mean age is 63.5 ± 7.8 years and 62% male. Median GMCS is 320.9 (240.8-402.8). Individuals with more than five CV risk factors (50%) have increased GMCS [356.7 (321.0-409.6) vs. 261.1 (225.6-342.1), P = 0.01], which is positively correlated with predicted fatal CV risk by SCORE (rs = 0.32, P = 0.04). There is a positive correlation between GMCS and weight (rs = 0.61), body mass index (rs = 0.66), abdominal perimeter (rs = 0.74), thoracic fat volume (rs = 0.47), and epicardial adipose tissue (rs = 0.41), all with P ≤ 0.01. There is no correlation between GMCS and coronary calcium score nor coronary artery wall Na[18F]F uptake. CONCLUSIONS: In a high CV risk group, the global cardiac microcalcification burden is related to CV risk factors, metabolic syndrome variables and cardiac fat. Cardiac GMCS is a promising risk stratification tool, combining a straightforward and objective methodology with a comprehensive analysis of both coronary and valvular microcalcification.

Multimodality imaging in cardiac amyloidosis: State-of-the-art review.

Amyloidosis is a systemic disease, characterized by deposition of amyloid fibrils in various organs, including the heart. For the diagnosis of cardiac amyloidosis (CA) it is required a high level of clinical suspicion and in the presence of clinical, laboratorial, and electrocardiographic red flags, a comprehensive multimodality imaging evaluation is warranted, including echocardiography, magnetic resonance, scintigraphy, and computed tomography, that will confirm diagnosis and define the CA subtype, which is of the utmost importance to plan a treatment strategy. We will review the use of multimodality imaging in the evaluation of CA, including the latest applications, and a practical flow-chart will sum-up this evidence.

Sodium fluoride in cardiovascular disorders: A systematic review.

BACKGROUND: 18-Fluorine sodium fluoride is a well-known radiotracer used for bone metastasis diagnosis. Its uptake correlation with cardiovascular (CV) risk was primarily suggested in oncological patients. Moreover, as a specific marker of microcalcification, it seems to correlate with CV disease progression and plaque instability. METHODS AND RESULTS: Our purpose was to systematically review clinical studies that characterized the use of this marker in CV conditions. In atherosclerosis, most studies report a positive correlation with the burden of CV risk factors and vascular calcification. A higher uptake was found in culprit plaques/rupture sites in coronary and carotid arteries and it was also linked to high-risk features in histology and intravascular imaging analysis of the plaques. In aortic stenosis, this tracer displayed an increasing uptake with disease severity. CONCLUSIONS: Sodium fluoride positron emission tomography is a promising non-invasive technique to identify high-risk plaques, which sets ground to a potential use of this tracer in evaluating atherosclerotic disease progression and degenerative changes in aortic valve stenosis. Nevertheless, there is a need for further prospective evidence that demonstrates this technique's value in predicting clinical events, adjusting treatment strategies, and improving patient outcomes.

Insights into secrets along the pollen tube pathway in need to be discovered.

The process of plant fertilization provides an outstanding example of refined control of gene expression. During this elegant process, subtle communication occurs between neighboring cells, based on chemical signals, that induces cellular mechanisms of patterning and growth. Having faced an immediate issue of self-incompatibility responses, the pathway to fertilization starts once the stigmatic cells recognize a compatible pollen grain, and it continues with numerous players interacting to affect pollen tube growth and the puzzling process of navigation along the transmitting tract. The pollen tube goes through a guidance process that begins with a preovular stage (i.e. prior to the influence of the target ovule), with interactions with factors from the transmitting tissue. In the subsequent ovular-guidance stage a specific relationship develops between the pollen tube and its target ovule. This stage is divided into the funicular and micropylar guidance steps, with numerous receptors working in signalling cascades. Finally, just after the pollen tube has passed beyond the synergids, fusion of the gametes occurs and the developing seed-the ultimate aim of the process-will start to mature. In this paper, we review the existing knowledge of the crucial biological processes involved in pollen-pistil interactions that give rise to the new seed.

Assessment of atherosclerotic plaque calcification using F18-NaF PET-CT.

BACKGROUND: The aim of the present study was to evaluate the uptake of F18-NaF by the arterial wall in patients with high cardiovascular (CV) risk profile. The tracer uptake was assessed in relation to gender and the number of CV risk factors. METHODS AND RESULTS: 25 patients without known CV disease were included and evaluated by PET-CT with F18-NaF: 14 (56%) men and 11 (44%) women. The mean target-to-background ratio (TBR: max SUV/mean blood-pool SUV) but not the corrected uptake per lesion (CUL: max SUV - mean blood-pool SUV) was higher in men than women (TBR: 1.8 ± 0.6 vs 1.7 ± 0.2; P = 0.04; CUL: 0.7 ± 0.3 vs W 0.6 ± 0.1; P = 0.4). Patients with >3 CV risk factors had higher CUL (0.8 ± 0.1 vs 0.6 ± 0.2; P = 0.01) but not TBR (1.8 ± 0.2 vs 1.7 ± 0.6; P = 0.7) than patients with <3 risk factors. CONCLUSIONS: The TBR but not CUL is higher in men than women while the CUL but not TBR is related to the number of CV risk factors. These results are hypothesis-generating and require validation in larger studies.

Identification of clear cell renal cell carcinoma and oncocytoma using a three-gene promoter methylation panel.

BACKGROUND: Promoter methylation has emerged as a promising class of epigenetic biomarkers for diagnosis and prognosis of renal cell tumors (RCTs). Although differential gene promoter methylation patterns have been reported for the major subtypes (clear cell, papillary and chromophobe renal cell carcinoma, and oncocytoma), validation of diagnostic performance in independent series have been seldom performed. Herein, we aimed at assessing the diagnostic performance of genes previously shown to be hypermethylated in RCTs in different clinical settings. METHODS: Promoter methylation levels of HOXA9 and OXR1 were assessed by quantitative methylation specific PCR. ROC curves were generated for OXR1, OXR1 combined with MST1R and HOXA9. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were computed, maximizing specificity. Methylation levels were also correlated with clinical and pathological relevant parameters. RESULTS: HOXA9 and OXR1 promoter methylation was disclosed in 73 and 87% of RCTs, respectively. A two-gene methylation panel comprising OXR1 and MST1R identified malignancy with 98% sensitivity and 100% specificity, and clear cell renal cell carcinoma with 90% sensitivity and 98% specificity. HOXA9 promoter methylation allowed for discrimination between oncocytoma and both papillary and chromophobe renal cell carcinoma but only with 77% sensitivity and 73% specificity. Significantly higher OXR1 promoter methylation levels (p = 0.005) were associated with high nuclear grade in ccRCC. CONCLUSIONS: A panel including OXR1 and MST1R promoter methylation allows specific and sensitive identification of renal cell tumors, and, especially, of clear cell renal cell carcinoma. Moreover, higher OXR1 promoter methylation levels associate with clear cell renal cell carcinoma nuclear grade, a surrogate for tumor aggressiveness. Thus, gene promoter methylation analysis might a useful ancillary tool in diagnostic management of renal masses.

Interrogating the Role of Receptor-Mediated Mechanisms: Biological Fate of Peptide-Functionalized Radiolabeled Gold Nanoparticles in Tumor Mice.

To get a better insight on the transport mechanism of peptide-conjugated nanoparticles to tumors, we performed in vivo biological studies of bombesin (BBN) peptide functionalized gold nanoparticles (AuNPs) in human prostate tumor bearing mice. Initially, we sought to compare AuNPs with thiol derivatives of acyclic and macrocyclic chelators of DTPA and DOTA types. The DTPA derivatives were unable to provide a stable coordination of (67)Ga, and therefore, the functionalization with the BBN analogues was pursued for the DOTA-containing AuNPs. The DOTA-coated AuNPs were functionalized with BBN[7-14] using a unidentate cysteine group or a bidentate thioctic group to attach the peptide. AuNPs functionalized with thioctic-BBN displayed the highest in vitro cellular internalization (≈ 25%, 15 min) in gastrin releasing peptide (GRP) receptor expressing cancer cells. However, these results fail to translate to in vivo tumor uptake. Biodistribution studies following intravenous (IV) and intraperitoneal (IP) administration of nanoconjugates in tumor bearing mice indicated that the presence of BBN influences to some degree the biological profile of the nanoconstructs. For IV administration, the receptor-mediated pathway appears to be outweighed by the EPR effect. By contrast, in IP administration, it is reasoned that the GRPr-mediated mechanism plays a role in pancreas uptake.

Cardiovascular magnetic resonance imaging assessment of diastolic dysfunction in a population without heart disease: a gender-based study.

OBJECTIVES: Asymptomatic left ventricular (LV) diastolic dysfunction is increasingly recognised as an important diagnosis. Our goal was to study the prevalence and gender differences in subclinical LV diastolic dysfunction, using cardiovascular magnetic resonance imaging (CMR) at 3 T. METHODS: We prospectively studied 48 volunteers (19 male and 29 female, mean age 49 ± 7 years) with no evidence of cardiovascular disease. We used CMR to measure left atrium (LA) and LV volumes, LV peak filling rate and transmitral flow. RESULTS: The overall prevalence of LV diastolic dysfunction in our cohort varied between 20 % (based on evaluation of LV filing profiles) and 24 % (based on the evaluation of the transmitral flow). The prevalence of diastolic dysfunction was higher in men than in women, independently of the criteria used (P between 0.004 and 0.022). Indexed LV end-diastolic volume, indexed LV stroke volume, indexed LV mass, indexed LA minimum volume and indexed LA maximum volume were significantly greater in men than in women (P < 0.05). All the subjects had LV ejection fractions within the normal range. CONCLUSIONS: It is clinically feasible to study diastolic flow and LV filling with CMR. CMR detected diastolic dysfunction in asymptomatic men and women. KEY POINTS: • CMR imaging offers new possibilities in assessing left ventricular diastolic function. • The prevalence of diastolic dysfunction is higher in men than in women. • The prevalence of some diastolic dysfunction in a normal population is 24 %.

Left atrial dysfunction in type 2 diabetes mellitus: insights from cardiac MRI.

OBJECTIVES: The left atrium (LA) modulates left ventricular filling through reservoir, conduit and booster pump functions. Only limited data exist on LA involvement in type 2 diabetes mellitus (DM2). This study sought to assess LA function in asymptomatic DM2 with cardiac MRI. We hypothesized that cardiac MRI can detect LA dysfunction in asymptomatic DM2. METHODS: Forty-five patients with asymptomatic DM2 and 24 normoglycaemic controls were studied. MRI cine imaging was performed to measure LA maximal and minimal volumes. A flow-sensitive phase-contrast gradient-echo sequence was used for flow measurements perpendicular to the orifice of the mitral valve, to quantify active LA stroke volume. LA total, passive and active emptying volumes and fractions were calculated. RESULTS: LA reservoir function, namely LA total ejection fraction, was significantly greater in controls compared to patients with DM2 (62.2 ± 5.2 vs 57.0 ± 7.6 %, P = 0.004). LA passive ejection fraction was also greater in the controls (26.2 ± 9.5 vs 16.1 ± 11.0 %, P < 0.001). Regarding parameters of LA booster pump function, LA active ejection fraction was not significantly different between groups. DM2 was demonstrated to be an independent determinant of LA function. CONCLUSIONS: Cardiac MRI enables the detection of LA dysfunction in asymptomatic DM2, characterized by a reduction in LA reservoir and conduit functions. KEY POINTS: • Evaluation of left atrial function is feasible with cardiac MRI • Type 2 diabetes mellitus is associated with left atrial dysfunction • Left atrial function modulates left ventricular filling.

Left ventricular diastolic function in type 2 diabetes mellitus and the association with coronary artery calcium score: a cardiac MRI study.

OBJECTIVE: The purpose of this study was to compare cardiac MRI-derived parameters of left ventricular (LV) diastolic function between uncomplicated type 2 diabetes mellitus (DM2) and normoglycemic control subjects and to evaluate whether these parameters of LV diastolic function are related to coronary atherosclerosis. SUBJECTS AND METHODS: We prospectively studied 41 subjects with DM2 and 21 normoglycemic control subjects (30 women and 32 men; mean age, 57.2 ± 7.1 [SD] years) with no evidence of overt cardiovascular disease. We used cardiac MRI to measure LV volumes, LV peak filling rate (PFR), and transmitral flow and CT to determine coronary artery calcium scores. RESULTS: Absolute values of the peak filling rate (PFR) were significantly lower in DM2 patients than in control subjects (mean ± SD, 293.2 ± 51.7 vs 375.7 ± 102.8 mL/s, respectively; p < 0.001). Mitral peak E velocities (mean ± SD, 42.8 ± 10.7 vs 48.8 ± 10.4 cm/s; p = 0.040) and peak E velocity-to-peak A velocity ratios (0.88 ± 0.3 vs 1.1 ± 0.3; p = 0.002) were also lower in DM2 patients compared with control subjects. DM2 patients with coronary artery calcification showed a lower PFR normalized to stroke volume (SV) (mean ± SD, 4.4 ± 1.0 vs 5.3 ± 1.4, respectively; p = 0.038) and lower mitral peak E velocities (40.1 ± 11.3 vs 48.0 ± 7.3 cm/s; p = 0.024) than DM2 patients without coronary calcification. PFR normalized to SV was independently associated with the presence of coronary artery calcification (ß = -1.5, p = 0.005). CONCLUSION: DM2 decreases cardiovascular MRI-derived parameters of LV diastolic function. Patients with DM2 and coronary atherosclerosis show a more impaired LV diastolic function than patients without coronary atherosclerosis.

Unstable Angina: Risk Stratification for Significant Coronary Artery Disease in The Era of High-Sensitivity Cardiac Troponin.

Introduction: High-sensitivity troponin (hsTn) has a very high diagnostic accuracy for myocardial infarction (MI), and patients who were formerly diagnosed with unstable angina (UA) are being reclassified as having NSTEMI in the era of hsTn. This paradigm shift has changed the clinical features of UA, which remain poorly characterized, specifically the occurrence of obstructive coronary artery disease (CAD) and the need for myocardial revascularization. The main purpose of this study was to clinically characterize contemporary UA patients, assess predictors of obstructive CAD, and develop a risk model to predict significant CAD in this population. Methods: We conducted a retrospective cohort study of 742 patients admitted to the hospital with UA. All patients underwent coronary angiography. The endpoint of the study was the presence of obstructive CAD on angiography. The cohort was divided into two groups: patients with significant coronary artery disease (CAD+) and those without CAD (CAD-). We developed a score (UA CAD Risk) based on the multivariate model and compared it with the GRACE, ESC, and TIMI risk scores using ROC analysis. Results: Obstructive CAD was observed on angiography in 53% of the patients. Age, dyslipidemia, troponin level, male sex, ST-segment depression, and wall motion abnormalities on echocardiography were independent predictors of obstructive CAD. hsTn levels (undetectable vs. nonsignificant detection) had a negative predictive value of 81% to exclude obstructive CAD. We developed a prediction model with obstructive CAD as the outcome (AUC: 0.60). Conclusions: In a contemporary UA cohort, approximately 50% of the patients did not have obstructive CAD on angiography. Commonly available cardiac tests at hospital admission show limited discrimination power in identifying patients at risk of obstructive CAD. A revised diagnostic and etiology algorithm for patients with UA is warranted.

Advancements in non-invasive imaging of atherosclerosis: Future perspectives.

Atherosclerosis is a chronic inflammatory disease characterized by the buildup of plaques in arterial walls, leading to cardiovascular diseases and high morbidity and mortality rates worldwide. Non-invasive imaging techniques play a crucial role in evaluating patients with suspected or established atherosclerosis. However, there is a growing body of evidence suggesting the need to visualize the underlying processes of plaque progression and rupture to enhance risk stratification. This review explores recent advancements in non-invasive assessment of atherosclerosis, focusing on computed tomography, magnetic resonance imaging, and nuclear imaging. These advancements provide valuable insights into the assessment and management of atherosclerosis, potentially leading to better risk stratification and improved patient outcomes.

Unstable Angina Risk Stratification Using High-Sensitivity Cardiac Troponin and Coronary Angiography.

Patients formerly diagnosed with unstable angina (UA) are being reclassified as non-ST-elevation myocardial infarction with the widespread adoption of high-sensitivity troponin (hsTn) assays, leading to significant changes in the incidence and prognosis of UA. This study aimed to evaluate the value of hsTn and the presence of significant obstructive coronary artery disease (CAD) in the risk stratification of patients with UA. We conducted a retrospective, single-center study of 742 patients hospitalized for UA between 2016 and 2021. The primary end point of this study was all-cause mortality. The secondary outcome (major adverse cardiac events [MACEs]) was defined as a composite of nonfatal myocardial infarction (MI), hospitalization for heart failure (hHF), and repeated coronary angiography because of recurring UA (rUA) after the index event. The outcomes were assessed within 1 month, 1 year, and up to 5 years of follow-up. The average follow-up duration was 45 ± 24 months, and 37.2% (n = 276) of patients completed a 5-year follow-up. No in-hospital death was observed, and 6.9% of patients died during follow-up, which was more commonly a late event (>12 months). The composite secondary end point (MI+hHF+rUA) was observed in 16.7% of the patients. There were 3.2% nonfatal MI, 2.3% hHF, and 11.6% rUA during follow-up. We developed a risk model (UA mortality risk) using variables with the highest discriminatory power: age, hsTn, and ST-segment deviation. Our model performed well against the Global Registry of Acute Coronary Events and Thrombolysis in Myocardial Infarction risk scores in predicting death during follow-up. Obstructive CAD on coronary angiography was the only independent predictor of MACEs during follow-up. In conclusion, a contemporary cohort of patients with UA presented with favorable prognosis, particularly, within the first year after the index event. Nonsignificant increases in hsTn levels add to the risk stratification of patients with UA, and the presence of obstructive CAD was the only independent predictor of MACEs, highlighting the potential importance of assessing coronary anatomy.

Rosuvastatin effect on atherosclerotic plaque metabolism: A subclinical atherosclerosis imaging study with 18F-NaF PET-CT.

BACKGROUND AND AIMS: Atherosclerotic plaque fluorine-18 sodium fluoride (18F-NaF) uptake on positron emission tomography with computed tomography (PET-CT) identifies active microcalcification and has been shown to correlate with clinical instability in patients with cardiovascular (CV) disease. Statin therapy promotes coronary macrocalcification over time. Our aim was to investigate rosuvastatin effect on atheroma 18F-NaF uptake. METHODS: Subjects with high CV risk but without CV events underwent 18F-NaF-PET-CT in a single-centre. Those with subclinical atherosclerosis and significant 18F-NaF plaque uptake were included in a single-arm clinical trial, treated with rosuvastatin 20 mg/daily for six months, and re-evaluated by 18F-NaF-PET-CT. Primary endpoint was reduction in maximum atheroma 18F-NaF uptake in the coronary, aortic or carotid arteries, assessed by the tissue-to-background ratio (TBR). The secondary endpoint was corrected uptake per lesion (CUL) variation. RESULTS: Forty individuals were enrolled and 38 included in the pharmacological trial; mean age was 64 years, two-thirds were male and most were diabetic. The 10-year expected CV risk was 9.5% (6.0-15.3) for SCORE2 and 31.7 ± 18.7% for ASCVD systems. After six months of rosuvastatin treatment (n = 34), low-density lipoprotein cholesterol lowered from 133.6 ± 33.8 to 58.8 ± 20.7 mg dL-1 (60% relative reduction, p < 0.01). There was a significant 19% reduction in maximum plaque 18F-NaF uptake after treatment, from 1.96 (1.78-2.22) to 1.53 (1.40-2.10), p < 0.001 (primary endpoint analysis). The secondary endpoint CUL was reduced by 23% (p = 0.003). CONCLUSION: In a single-centre non-randomized clinical trial of high CV risk individuals with subclinical atherosclerosis, the maximum atherosclerotic plaque 18F-NaF uptake was significantly reduced after six months of high-intensity statin.

Evaluation of left atrial deformation to predict left atrial stasis in patients with non-valvular atrial fibrillation - a pilot-study.

BACKGROUND: Speckle tracking-derived strain and strain rate are recently available parameters to assess left atrial (LA) deformation. We hypothesized that such new parameters could be of interest to evaluate the risk of LA stasis among patients with atrial fibrillation (AF). METHODS: Single-centre study enrolling all patients with non-valvular AF lasting longer than 48 hours for whom no therapeutic anticoagulation was given in the preceding 3 weeks and who were assessed through transesophageal and transthoracic echocardiogram during a 6 month time interval. LA deformation was assessed by transthoracic echocardiogram through speckle tracking analysis, whereas LA stasis parameters were sought on transesophageal echocardiogram. RESULTS: Among the 82 assessed patients, LA appendage thrombi or sludge were found in 16 (19.5%). A moderate positive correlation was found between peak positive strain rate and maximum emptying velocity (r = 0.589; P <0.001) and peak positive strain rate and maximum filling velocity of the LA appendage (r = 0.651; P <0.001). Peak negative strain rate was also found to be associated with both maximum emptying velocity (r = -0.513; P <0.001) and maximum filling velocity of the LAA (r = -0.552; P <0.001). AF duration, peak negative strain rate and time-to-peak positive strain were independent predictors of LAA thrombi or sludge on multivariate analysis logistic regression. The area under the curve for the estimated probabilities using the obtained logistic regression model was 0.89 (95%CI 0.81-0.96; P <0.001). CONCLUSION: Our findings suggest that LA mechanical dysfunction assessed through speckle tracking may be of interest to predict LA stasis in the setting of AF.

Rest myocardial perfusion imaging: a valuable tool in ED.

BACKGROUND: Acute chest pain is a frequent cause of emergency department (ED) visits. Rest myocardial perfusion imaging (RMPI) during or immediately after an episode of chest pain can provide diagnostic and prognostic information concerning acute coronary syndromes. AIM: Our purpose was to evaluate the RMPI score in risk stratification of chest pain suspected to be of cardiac ischemic origin and negative troponin assessment. METHODS: Ninety-six patients without an ongoing myocardial infarction or a history of coronary artery disease and in whom RMPI was performed in the ED because of chest pain suspected to be related with acute myocardial ischemia were included. Follow-up was performed considering the occurrence of death, myocardial infarction, or revascularization in a 12-month period admission. RESULTS: Fourteen (14.6%) patients had events. According to survival analysis, the variables related with events were a history of angina (hazard ratio [HR], 4.5; P ≤ .01), an ischemic electrocardiogram (HR, 4.0; P ≤ .01), the abnormal RMPI (HR, 11.4; P ≤ .05), and the RMPI score (HR, 1.1; P ≤ .0001). When the variables of interest were forced into a multivariate model, the χ(2) associated with the model that includes clinical and electrocardiogram information was 16.3 (P ≤ .005) and in the model that also includes RMPI score, it was 23.0 (P ≤ .0005). CONCLUSION: In a low- to intermediate-risk group of patients with suspected acute myocardial ischemia, RMPI gives not only diagnostic information but adds prognostic value to the traditional ED risk stratification tools.