Michele Genoni

Low-Dose CT Coronary Angiography in the Step-and-Shoot Mode: Diagnostic Performance

Objective: To investigate the performance of low-dose, dual-source computed tomography (DSCT) coronary angiography in the step-and-shoot (SAS) mode for the diagnosis of significant coronary artery stenoses in comparison with conventional coronary angiography (CCA). Design, setting and patients: Prospective, single-centre study conducted in a referral centre enrolling 120 patients (71 men, mean (SD) age 68 (9) years, mean (SD) body mass index 26.2 (3.2) kg/m2). All study participants underwent DSCT in the SAS mode and CCA within 14 days. Twenty-seven patients were given intravenous β blockers for heart rate reduction before CT. Patients were excluded if a target heart rate ⩽70 bpm could not be achieved by β blockers or when the patients were in non-sinus rhythm. Two blinded readers independently evaluated coronary artery segments for assessability and for the presence of significant (>50%) stenoses. Sensitivity, specificity, negative (NPV) and positive predictive values (PPV) were determined, with CCA being the standard of reference. Radiation dose values were calculated. Results: DSCT coronary angiography in the SAS mode was successfully performed in all 120 patients. Mean (SD) heart rate during scanning was 59 (6) bpm (range 44–69). 1773/1803 coronary segments (98%) were depicted with a diagnostic image quality in 109/120 patients (91%). The overall patient-based sensitivity, specificity, PPV and NPV for the diagnosis of significant stenoses were 100%, 93%, 94% and 100%, respectively. The mean (SD) effective dose of the CT protocol was 2.5 (0.8) mSv (range 1.2–4.4). Conclusions: DSCT coronary angiography in the SAS mode allows, in selected patients with a regular heart rate, the accurate diagnosis of significant coronary stenoses at a low radiation dose.

Dual-source CT in step-and-shoot mode: noninvasive coronary angiography with low radiation dose.

PURPOSE To prospectively investigate computed tomographic (CT) image quality parameters by using different protocols and to calculate radiation dose estimates for noninvasive coronary angiography performed with dual-source CT in the step-and-shoot (SAS) mode. MATERIALS AND METHODS This study was local ethics board approved; written informed consent was obtained from all patients. In the preliminary portion of the study, 40 patients underwent CT coronary angiography in the SAS mode: at 100 kV (protocol A) in 22 patients with a body mass index (BMI) of less than 25 kg/m(2) and at 120 kV (protocol B) in 18 patients with a BMI of 25-30 kg/m(2). Both protocols involved use of an attenuation-based tube current and 1 mL of contrast material per kilogram of body weight. The final portion of the study involved 50 additional patients: 21 patients with a BMI of 25-30 kg/cm(2) assigned to protocol B and 29 patients with a BMI of less than 25 kg/cm(2) assigned to protocol C, which was performed with 100 kV, an attenuation-based tube current, and a reduced contrast material dose of 0.8 mL/kg. Image quality was independently assessed. Attenuation in the aorta and coronary arteries and image noise were measured. Radiation dose was estimated. RESULTS Mean image noise was similar with protocols A and B. Mean attenuation in the aorta and coronary arteries with protocol A (444 HU) was significantly (P < .001) higher than that with protocol B (358 HU). The reduced contrast material dose in protocol C yielded attenuation similar to that with protocol B. Diagnostic image quality was achieved with all protocols in 1237 (97.9%) of 1264 coronary segments. No significant differences in image quality between the 100- and 120-kV protocols were found. Mean heart rate had a significant effect on motion artifacts (area under receiver operating characteristic curve [AUC] = 0.818; 95% confidence interval [CI]: 0.723, 0.892; P < .001), whereas heart rate variability had a significant effect on stair-step artifacts (AUC = 0.79; 95% CI: 0.687, 0.865; P < .001). The mean estimated effective dose was 1.2 mSv +/- 0.2 for protocols A and C and 2.6 mSv +/- 0.5 for protocol B. CONCLUSION Dual-source SAS-mode CT coronary angiography yielded diagnostic image quality for 97.9% of coronary segments at a low radiation dose.

Regulatory Role of G Protein–Coupled Estrogen Receptor for Vascular Function and Obesity

We found that the selective stimulation of the intracellular, transmembrane G protein-coupled estrogen receptor (GPER), also known as GPR30, acutely lowers blood pressure after infusion in normotensive rats and dilates both rodent and human arterial blood vessels. Stimulation of GPER blocks vasoconstrictor-induced changes in intracellular calcium concentrations and vascular tone, as well as serum-stimulated cell proliferation of human vascular smooth muscle cells. Deletion of the GPER gene in mice abrogates vascular effects of GPER activation and is associated with visceral obesity. These findings suggest novel roles for GPER in protecting from cardiovascular disease and obesity.

Paravalvular leakage after mitral valve replacement: improved long-term survival with aggressive surgery?

BACKGROUND Following mitral valve replacement, surgical closure of paravalvular leaks is usually advised in severely symptomatic patients and in those requiring blood transfusions for persisting haemolysis. However, the long-term prognosis of less symptomatic patients or those not needing blood transfusions is unknown. METHODS Between 1987 and 1997, we observed 96 patients with mitral paravalvular leakage. A paraprosthetic leak was diagnosed after a median time of 119 days (range: 1 day-23 years) after primary mitral valve replacement. During an average follow-up of 5 years (range: 1-23 years), 50/96 patients were referred for surgical closure. RESULTS Compared with patients who received conservative treatment, those referred for surgery had a significantly lower mean preoperative haematocrit (P = 0.002) with a higher proportion of patients being in the NYHA class III/IV (P = 0.03). Age, gender, left ventricular function and number and size of leaks did not differ between the groups. The 30-day postoperative mortality for valve reoperation was 6% (3/50); during follow-up three further patients died, resulting in an overall mortality rate of 12%. In the group treated conservatively there was a mortality rate of 26% (12/46). Thus, the actuarial survival for patients referred for surgery was 98, 90 and 88% after 1, 5 and 10 years, compared with 90, 75 and 68% for patients treated conservatively (long-rank P = 0.03). In addition, there was a significant increase in mean haematocrit levels (P = 0.0001) and an improvement in NYHA class III/IV symptoms (P = 0.002), vertigo (P = 0.001) and fatigue (P = 0.001) after surgery. CONCLUSIONS Following mitral valve replacement, a more aggressive surgical treatment is recommended for patients with paraprosthetic leaks. Surgery should be offered to less symptomatic patients, as well as those not requiring blood transfusion.

Image quality and reconstruction intervals of dual-source CT coronary angiography: recommendations for ECG-pulsing windowing.

Purpose:To evaluate reconstruction intervals and image quality in dual-source computed tomography (DSCT) coronary angiography for optimal placement of the ECG-pulsing window. Materials and Methods:DSCT coronary angiography was performed in 60 patients. Thirteen datasets were reconstructed in 5% increments from 20–80%. Two readers independently assessed image quality of each segment in each percentage-interval, using scores ranging from 1 (no motion artifacts) to 4 (nonevaluable). Results:Mean heart rate (HR) was 69.0 ± 18.9 beats per minute (bpm) (range, 35–117 bpm). Diagnostic image quality (scores 1–3) was found in 97.8% of all segments (763 of 780). The 70% RR-interval provided best image quality in all patients and all HRs. The narrowest reconstruction window providing diagnostic image quality was 60–70% for HR <60 bpm, 60–80% for 60–70 bpm, 55–80% for 70–80 bpm, and 30–80% for HR >80 bpm. Conclusions:DSCT coronary angiography provides best image quality for various HRs at 70%. The ECG-pulsing window can be adapted according to the HR while maintaining diagnostic image quality.

Dual-source computed tomography coronary angiography: influence of obesity, calcium load, and heart rate on diagnostic accuracy

AIMS To prospectively investigate the diagnostic accuracy of dual-source computed tomography coronary angiography (CTCA) to diagnose coronary stenoses in relation to body mass index (BMI), Agatston score (AS), and heart rate (HR) as compared with catheter coronary angiography (CCA). METHODS AND RESULTS Hundred and fifty consecutive patients (47 female, mean age 62.9 +/- 12.1 years) underwent dual-source CTCA without HR control. Patients were divided into subgroups depending on the median of their BMI (26.0 kg/m2), AS (194), and HR (66 b.p.m.). CCA was considered the standard of reference. Mean BMI was 26.5 +/- 4.2 kg/m2 (range 18.3-39.1 kg/m2), mean AS was 309 +/- 408 (range 0-4387), and HR was 68.5 +/- 12.6 b.p.m. (range 35-102 b.p.m.). Diagnostic image quality was found in 98.1% of all segments (2020/2059). Considering not-evaluative segments at CTCA as false-positive, overall per-patient sensitivity, specificity, positive, and negative predictive value were 96.6%, 86.8%, 82.6%, and 97.5%, respectively. High HR did not deteriorate diagnostic accuracy of CTCA. High BMI and AS were associated with a decrease in per-patient specificity to 84.1% and 77.8%, respectively, while sensitivity and negative predictive value remained high. CONCLUSION Dual-source CTCA provides high diagnostic accuracy irrespective of the HR and serves as a modality to rule-out coronary artery stenoses even in patients with high BMI and AS.

Functional Growth in Tissue-Engineered Living, Vascular Grafts Follow-Up at 100 Weeks in a Large Animal Model

Background— Living autologous vascular grafts with the capacity for regeneration and growth may overcome the limitations of contemporary artificial prostheses. Particularly in congenital cardiovascular surgery, there is an unmet medical need for growing replacement materials. Here we investigate growth capacity of tissue-engineered living pulmonary arteries in a growing lamb model. Methods and Results— Vascular grafts fabricated from biodegradable scaffolds (ID 18±l mm) were sequentially seeded with vascular cells. The seeded constructs were grown in vitro for 21days using biomimetic conditions. Thereafter, these tissue-engineered vascular grafts (TEVGs) were surgically implanted as main pulmonary artery replacements in 14 lambs using cardiopulmonary bypass and followed up for ≤100 weeks. The animals more than doubled their body weight during the 2-year period. The TEVG showed good functional performance demonstrated by regular echocardiography at 20, 50, 80, and 100 weeks and computed tomography–angiography. In particular, there was no evidence of thrombus, calcification, stenosis, suture dehiscence, or aneurysm. There was a significant increase in diameter by 30% and length by 45%. Histology showed tissue formation reminiscent of native artery. Biochemical analysis revealed cellularity and proteoglycans and increased collagen contents in all of the groups, analogous to those of native vessels. The mechanical profiles of the TEVG showed stronger but less elastic tissue properties than native pulmonary arteries. Conclusions— This study provides evidence of growth in living, functional pulmonary arteries engineered from vascular cells in a full growth animal model.

Differential Effects of 17β-Estradiol on Function and Expression of Estrogen Receptor α, Estrogen Receptor β, and GPR30 in Arteries and Veins of Patients With Atherosclerosis

Venous complications have been implicated in the adverse effects of hormone replacement therapy. This study investigated acute effects of the natural estrogen, 17&bgr;-estradiol, on function, estrogen receptors/GPR30 expression, and kinase activation in vascular rings and cultured smooth muscle cells from arteries and veins of patients with coronary artery disease. Changes in vascular tone of internal mammary arteries and saphenous veins exposed to the steroid were recorded. 17&bgr;-Estradiol caused concentration-dependent, endothelium-independent relaxation in arteries (P<0.05 versus solvent control) but not in veins (P not significant). 17&bgr;-Estradiol enhanced contractions to endothelin-1 in veins but not in arteries. The novel membrane estrogen receptor GPR30 was detected in both vessels. Moreover, gene expression of estrogen receptor &bgr; was 10-fold higher than that of estrogen receptor &agr; or GPR30 (P<0.05). Expression of all 3 of the receptors was reduced after exposure to 17&bgr;-estradiol in arteries but not in veins (P<0.05). Basal phosphorylation levels of extracellular signal-regulated kinase were higher in venous than in arterial smooth muscle cells and were increased by 17&bgr;-estradiol in arterial cells only. In summary, this is the first study to report that, in human arteries but not in veins, 17&bgr;-estradiol acutely affects vascular tone, estrogen receptor expression, including GPR30, and extracellular signal-regulated kinase phosphorylation. These data indicate that effects of natural estrogens in humans differ between arterial and venous vascular beds, which may contribute to the vascular risks associated with menopause or hormone therapy.

Living autologous heart valves engineered from human prenatally harvested progenitors

Background— Heart valve tissue engineering is a promising strategy to overcome the lack of autologous growing replacements, particularly for the repair of congenital malformations. Here, we present a novel concept using human prenatal progenitor cells as new and exclusive cell source to generate autologous implants ready for use at birth. Methods and Results— Human fetal mesenchymal progenitors were isolated from routinely sampled prenatal chorionic villus specimens and expanded in vitro. A portion was cryopreserved. After phenotyping and genotyping, cells were seeded onto synthetic biodegradable leaflet scaffolds (n=12) and conditioned in a bioreactor. After 21 days, leaflets were endothelialized with umbilical cord blood-derived endothelial progenitor cells and conditioned for additional 7 days. Resulting tissues were analyzed by histology, immunohistochemistry, biochemistry (amounts of extracellular matrix, DNA), mechanical testing, and scanning electron microscopy (SEM) and were compared with native neonatal heart valve leaflets. Fresh and cryopreserved cells showed comparable myofibroblast-like phenotypes. Genotyping confirmed their fetal origin. Neo-tissues exhibited organization, cell phenotypes, extracellular matrix production, and DNA content comparable to their native counterparts. Leaflet surfaces were covered with functional endothelia. SEM showed cellular distribution throughout the polymer and smooth surfaces. Mechanical profiles approximated those of native heart valves. Conclusions— Prenatal fetal progenitors obtained from routine chorionic villus sampling were successfully used as an exclusive, new cell source for the engineering of living heart valve leaflets. This concept may enable autologous replacements with growth potential ready for use at birth. Combined with the use of cell banking technology, this approach may be applied also for postnatal applications.

Prenatally Fabricated Autologous Human Living Heart Valves Based on Amniotic Fluid–Derived Progenitor Cells as Single Cell Source

Background— A novel concept providing prenatally tissue engineered human autologous heart valves based on routinely obtained fetal amniotic fluid progenitors as single cell source is introduced. Methods and Results— Fetal human amniotic progenitors were isolated from routinely sampled amniotic fluid and sorted using CD133 magnetic beads. After expansion and differentiation, cell phenotypes of CD133− and CD133+ cells were analyzed by immunohistochemistry and flowcytometry. After characterization, CD133− derived cells were seeded onto heart valve leaflet scaffolds (n=18) fabricated from rapidly biodegradable polymers, conditioned in a pulse duplicator system, and subsequently coated with CD133+ derived cells. After in vitro maturation, opening and closing behavior of leaflets was investigated. Neo-tissues were analyzed by histology, immunohistochemistry, and scanning electron microscopy (SEM). Extracellular matrix (ECM) elements and cell numbers were quantified biochemically. Mechanical properties were assessed by tensile testing. CD133− derived cells demonstrated characteristics of mesenchymal progenitors expressing CD44 and CD105. Differentiated CD133+ cells showed features of functional endothelial cells by eNOS and CD141 expression. Engineered heart valve leaflets demonstrated endothelialized tissue formation with production of ECM elements (GAG 80%, HYP 5%, cell number 100% of native values). SEM showed intact endothelial surfaces. Opening and closing behavior was sufficient under half of systemic conditions. Conclusions— The use of amniotic fluid as single cell source is a promising low-risk approach enabling the prenatal fabrication of heart valves ready to use at birth. These living replacements with the potential of growth, remodeling, and regeneration may realize the early repair of congenital malformations.