Abstract: Animal experiments have shown that the coronary circulation is pressure distensible, i.e., myocardial blood volume (MBV) increases with perfusion pressure. In humans, however, corresponding measurements are lacking so far. We sought to quantify parameters reflecting coronary distensibility such as MBV and coronary resistance (CR) during and after coronary angioplasty. Thirty patients with stable coronary artery disease underwent simultaneous coronary perfusion pressure assessment and myocardial contrast echocardiography (MCE) of 37 coronary arteries and their territories during and after angioplasty. MCE yielded MBV and myocardial blood flow (MBF; in ml·min(-1)·g(-1)). Complete data sets were obtained in 32 coronary arteries and their territories from 26 patients. During angioplasty, perfusion pressure, i.e., coronary occlusive pressure, and MBV varied between 9 and 57 mmHg (26.9 ± 11.9 mmHg) and between 1.2 and 14.5 ml/100 g (6.7 ± 3.7 ml/100 g), respectively. After successful angioplasty, perfusion pressure and MBV increased significantly (P < 0.001 for both) and varied between 64 and 118 mmHg (93.5 ± 12.8 mmHg) and between 3.7 and 17.3 ml/100 g (9.8 ± 3.4 ml/100 g), respectively. Mean MBF increased from 31 ± 20 ml·min(-1)·g(-1) during coronary occlusion, reflecting collateral flow, to 121 ± 33 ml·min(-1)·g(-1) (P < 0.01), whereas mean CR, i.e., the ratio of perfusion pressure and MBF, decreased by 20% (P < 0.001). In conclusion, the human coronary circulation is pressure distensible. MCE allows for the quantification of CR and MBV in humans.
Abstract: OBJECTIVES: We aimed at comparing the long term clinical outcome of SES and PES in routine clinical practice.
BACKGROUND: Although sirolimus-eluting stents (SES) more effectively reduce neointimal hyperplasia than paclitaxel-eluting stents (PES), uncertainty prevails whether this difference translates into differences in clinical outcomes outside randomized controlled trials with selected patient populations and protocol-mandated angiographic follow-up.
METHODS: Nine hundred and four consecutive patients who underwent implantation of a drug-eluting stent between May 2004 and February 2005: 467 patients with 646 lesions received SES, 437 patients with 600 lesions received PES. Clinical follow-up was obtained at 2 years without intervening routine angiographic follow-up. The primary endpoint was a composite of death, myocardial infarction (MI), or target vessel revascularization (TVR).
RESULTS: At 2 years, the primary endpoint was less frequent with SES (12.9%) than PES (17.6%, HR = 0.70, 95% CI 0.50-0.98, P = 0.04). The difference in favor of SES was largely driven by a lower rate of target lesion revascularisation (TLR; 4.1% vs. 6.9%, P = 0.05), whereas rates of death (6.4% vs. 7.6%, P = 0.49), MI (1.9% vs. 3.2%, P = 0.21), or definite stent thrombosis (0.6% vs. 1.4%, P = 0.27) were similar for both stent types. The benefit regarding reduced rates of TLR was significant in nondiabetic (3.6% vs. 7.1%, P = 0.04) but not in diabetic patients (5.6% vs. 6.1%, P = 0.80).
CONCLUSIONS: SES more effectively reduced the need for repeat revascularization procedures than PES when used in routine clinical practice. The beneficial effect is maintained up to 2 years and may be less pronounced in diabetic patients.
Abstract: Background: The function of the coronary collateral circulation in heart transplant patients has not been investigated in a controlled fashion. Since it partly belongs to the microcirculation, which is affected by transplant vasculopathy, the hypothesis was tested that the coronary collateral circulation in heart transplant recipients is less developed than in coronary artery disease (CAD) patients.
Methods: 40 heart transplant patients underwent a total of 51 quantitative, coronary pressure-derived collateral measurements and intravascular ultrasound (IVUS). The collateral flow index (CFI) was calculated as mean coronary occlusive pressure divided by mean aortic pressure, both subtracted by central venous pressure. A propensity score matching for angiographic coronary stenosis severity, heart rate, the presence of arterial hypertension and dyslipidaemia was performed using CAD patients of the institutional CFI database (n=1076) as the control group.
Results: Eighty per cent (32/40) of the heart transplant patients showed transplant vasculopathy as assessed by IVUS (intima thickness ≥0.5 mm). Without propensity score matching, CFI was equal to 0.152±0.102 in the heart transplant group (age 55±14 years) and 0.189±0.134 in the entire CAD group (p=0.054). After matching, CFI was 0.152±0.102 in the heart transplant group and 0.176±0.096 (p=0.37) in the matched CAD group (age 63±10 years). IVUS data were unrelated to CFI in the heart transplant group.
Conclusions: Heart transplant patients present with the same degree of functional collateral flow compared with a matched group of CAD patients.
Abstract: Objectives: We compared the angiographic and long-term clinical outcomes of patients with and without overlap of drug-eluting stents (DES).
Background: DES overlap has been associated with delayed healing and increased inflammation in experimental studies, but its impact on clinical outcome is not well established.
Methods: We analyzed the angiographic and clinical outcomes of 1,012 patients treated with DES in the SIRTAX (Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization) trial according to the presence or absence of stent overlap and the number of stents per vessel: 134 (13.2%) patients with multiple DES in a vessel with overlap, 199 (19.7%) patients with multiple DES in a vessel without overlap, and 679 (67.1%) patients with 1 DES per vessel.
Results: Angiographic follow-up at 8 months showed an increased late loss in DES overlap patients (0.33 ± 0.61 mm) compared with the other groups (0.18 ± 0.43 mm and 0.15 ± 0.38 mm, p < 0.01). The smallest minimal lumen diameter was located at the zone of stent overlap in 17 (68%) of 25 patients with stent overlap who underwent target lesion revascularization. Major adverse cardiac events were more common in patients with DES overlap (34 events, 25.4%) than in the other groups (42 events, 21.1% and 95 events, 14.0%) at 3 years (p < 0.01). Both the risk of target lesion revascularization (20.2% vs. 16.1% vs. 9.7%, p < 0.01) and the composite of death or myocardial infarction (17.2% vs. 14.1% vs. 9.1%, p = 0.01) were increased in patients with DES overlap compared with the other groups.
Conclusions: DES overlap occurs in >10% of patients undergoing percutaneous coronary intervention in routine clinical practice and is associated with impaired angiographic and long-term clinical outcome, including death or myocardial infarction.
Abstract: In patients with coronary artery disease, the size of myocardial infarction mainly determines the subsequent clinical outcome. Accordingly, it is the primary strategy to decrease cardiovascular mortality by minimizing infarct size. Promotion of collateral artery growth (arteriogenesis) is an appealing option of reducing infarct size. It has been demonstrated in experimental models that tangential fluid shear stress is the major trigger of arterial remodeling and, thus, of collateral growth. Lower-leg, high-pressure external counterpulsation triggered to occur during diastole induces a flow velocity signal and thus tangential endothelial shear stress in addition to the flow signal caused by cardiac stroke volume. We here present two cases of cardiac transplant recipients as human "models" of physical coronary arteriogenesis, providing an example of progressing and regressing clinical arteriogenesis, and review available evidence from clinical studies on other feasible forms of physical arteriogenesis.
Abstract: BACKGROUND: The efficacy of external counterpulsation (ECP) on coronary collateral growth has not been investigated in a randomised controlled study. Objective To test the hypothesis that ECP augments collateral function during a 1 min coronary balloon occlusion.
PATIENTS AND METHODS: Twenty patients with chronic stable coronary artery disease were studied. Before and after 30 h of randomly allocated ECP (20 90 min sessions over 4 weeks at 300 mm Hg inflation pressure) or sham ECP (same setting at 80 mm Hg inflation pressure), the invasive collateral flow index (CFI, no unit) was obtained in 34 vessels without coronary intervention. CFI was determined by the ratio of mean distal coronary occlusive pressure to mean aortic pressure with central venous pressure subtracted from both. Additionally, coronary collateral conductance (occlusive myocardial blood flow per aorto-coronary pressure drop) was determined by myocardial contrast echocardiography, and brachial artery flow-mediated dilatation was obtained.
RESULTS: CFI changed from 0.125 (0.073; interquartile range) at baseline to 0.174 (0.104) at follow-up in the ECP group (p=0.006), and from 0.129 (0.122) to 0.111 (0.125) in the sham ECP group (p=0.14). Baseline to follow-up change of coronary collateral conductance was from 0.365 (0.268) to 0.568 (0.585) ml/min/100 mm Hg in the ECP group (p=0.072), and from 0.229 (0.212) to 0.305 (0.422) ml/min/100 mm Hg in the sham ECP group (p=0.45). There was a correlation between the flow-mediated dilatation change from baseline to follow-up and the corresponding CFI change (r=0.584, p=0.027).
CONCLUSIONS: ECP appears to be effective in promoting coronary collateral growth. The extent of collateral function improvement is related to the amount of improvement in the systemic endothelial function.
Abstract: OBJECTIVE: A consequence in patients with d-transposition of the great arteries (d-TGA) and tetralogy of Fallot (TOF) is right ventricular hypertrophy (RVH) and right ventricular failure. Myocardial contrast echocardiography (MCE) permits the determination of the myocardial microvascular density reflected by the relative myocardial blood volume (rBV; ml/ml). This study was conducted to elucidate the relationship between RVH and myocardial microvascular changes by quantitative MCE in patients with d-TGA and TOF.
METHODS: Three groups of individuals were included in the study: 22 patients with d-TGA, 18 patients with TOF and 22 healthy individuals (controls). MCE was performed at rest and during adenosine-induced hyperaemia. rBV and myocardial blood flow (MBF; ml/min per gram) were derived from steady state and refill sequences of ultrasound contrast agent.
RESULTS: Hyperaemic septal rBV differed significantly between the groups and was highest in controls: d-TGA 0.141+/-0.060 ml/ml, TOF 0.134+/-0.080 ml/ml, controls 0.189+/-0.074 ml/ml, p=0.005. Myocardial blood flow reserve (MBFR), that is the ratio of hyperaemic to baseline MBF, differed significantly between the groups and was lowest in d-TGA (2.68+/-1.13) versus TOF (3.37+/-1.57) and controls (4.22+/-1.17, p=0.001). Hyperaemic septal rBV, MBF and MBFR showed a significant correlation with right ventricular systolic function as determined by tricuspid annular plane systolic excursion.
CONCLUSIONS: Right ventricular myocardial microvascular density of the septal wall in d-TGA and TOF patients with RVH due to pressure and/or volume overload is reduced. This appears to be related to a reduced myocardial perfusion reserve and impaired right ventricular systolic function.
Abstract: AIMS: We investigated the impact of arterial injury on neointimal hyperplasia following implantation of drug-eluting stents (DES).
METHODS AND RESULTS: A total of 196 patients with 223 segments (sirolimus-eluting stents [SES]: 104, paclitaxel-eluting stents [PES]: 119) underwent intravascular ultrasound eight months after DES implantation. Arterial injury was defined as the balloon-to-artery ratio (BAR). Segments were categorised into two groups: high BAR defined as BAR>1.1 (120 segments), and low BAR defined as BAR < or =1.1 (103 segments). Baseline clinical characteristics were similar for both groups. Although reference vessel diameter was smaller, stent diameter, maximal balloon pressure and balloon diameter were higher in the high BAR compared with the low BAR group. Lumen (7.10±1.91 vs. 6.25±1.69, p=0.001), stent (7.31±1.95 vs. 6.41±1.80, p=0.001), and external elastic membrane (17.1±4.9 vs. 14.8±4.0, p<0.0001) areas (mm2) were higher, but neointimal hyperplasia (0.21±0.36 vs. 0.16±0.48, p=0.42) area (mm2) was similar in the high BAR compared with the low BAR group. Arterial injury as assessed by BAR was not associated with the amount of neointimal hyperplasia (R2=0.003, p=0.40).
CONCLUSIONS: Arterial injury does not correlate with the amount of neointimal hyperplasia following DES implantation. Conventionally aggressive DES implantation techniques do not adversely affect long-term outcome with respect to restenosis.
Abstract: BACKGROUND: Although rare, iatrogenic left main coronary artery (LM) dissection is a feared complication of coronary catheterization. Its incidence, optimal therapeutic management, and prognosis remain largely unknown. The aim of the present study was to estimate the incidence, characterize the population at risk, depict the initial management, and evaluate the long-term prognosis of iatrogenic LM dissection.
METHODS: Thirty-eight patients who fulfilled the National Heart, Lung, and Blood Institute diagnostic criteria for iatrogenic LM dissection were retrieved from our database and followed up by telephone or physician visit. The primary end point was freedom from major adverse cardiac events (MACE) at 5 years.
RESULTS: The overall incidence of iatrogenic LM dissection during the study period was 0.07% (38/51,452 patients) and almost twice as common with percutaneous coronary intervention than coronary angiography. From 38 patients, 1 (3%) patient died before any therapeutic attempt was performed, 6 (16%) patients were treated conservatively, and 31 (82%) patients underwent stent implantation and/or coronary artery bypass grafting (CABG). In-hospital outcome was favorable irrespective of the therapeutic strategy. During the 5-year follow-up, among 31 patients who underwent revascularization treatment by stenting or CABG, one patient died in each group from a cardiac cause, and MACE were observed in 12 patients (39%). Kaplan-Meier cumulative survival estimates showed no significant difference between different revascularization treatment strategies.
CONCLUSIONS: Iatrogenic LM dissection is a rare complication of cardiac catheterization procedures with favorable early and long-term outcome when recognized timely and managed properly..
Abstract: AIM: To test whether quantitative stress echocardiography using contrast-based myocardial blood flow (MBF, ml x min(-1) x g(-1)) measurements can detect coronary artery disease in humans.
METHODS: 48 patients eligible for pharmacological stress testing by myocardial contrast echocardiography (MCE) and willing to undergo subsequent coronary angiography were prospectively enrolled in the study. Baseline and adenosine-induced (140 microg x kg(-1) x min(-1)) hyperaemic MBF was analysed according to a three-coronary-artery-territory model. Vascular territories were categorised into three groups with increasing stenosis severity defined as percentage diameter reduction by quantitative coronary angiography.
RESULTS: Myocardial blood flow reserve (MBFR)-that is, the ratio of hyperaemic to baseline MBF, was obtained in 128 (89%) territories. Mean (SD) baseline MBF was 1.073 (0.395) ml x min(-1) x g(-1) and did not differ between territories supplied by coronary arteries with mild (<50% stenosis), moderate (50%-74% stenosis) or severe (>or=75% stenosis) disease. Mean (SD) hyperaemic MBF and MBFR were 2.509 (1.078) ml x min(-1) x g(-1) and 2.54 (1.03), respectively, and decreased linearly (r2 = 0.21 and r2 = 0.39) with stenosis severity. ROC analysis revealed that a territorial MBFR <1.94 detected >or=50% stenosis with 89% sensitivity and 92% specificity.
CONCLUSION: Quantitative stress testing based on MBF measurements derived from contrast echocardiography is a new method for the non-invasive and reliable assessment of coronary artery disease in humans.
Abstract: The definition of spinal instability is still controversial. For this reason, it is essential to better understand the difference in biomechanical behaviour between healthy and degenerated human spinal segments in vivo. A novel computer-assisted instrument was developed with the objective to characterize the biomechanical parameters of the spinal segment. Investigation of the viscoelastic properties as well as the dynamic spinal stiffness was performed during a minimally invasive procedure (microdiscectomy) on five patients. Measurements were performed intraoperatively and the protocol consisted of a dynamic part, where spinal stiffness was computed, and a static part, where force relaxation of the segment under constant elongation was studied. The repeatability of the measurement procedure was demonstrated with five replicated tests. The spinal segment tissues were found to have viscoelastic properties. Preliminary tests confirmed a decrease in stiffness after decompression surgery. Patients with non-relaxed muscles showed higher stiffness and relaxation rate compared to patients with relaxed muscles, which can be explained by the contraction and relaxation reflex of muscles under fast and then static elongation. The results show the usefulness of the biomechanical characterization of the human lumbar spinal segment to improve the understanding of the contribution of individual anatomical structures to spinal stability.
Abstract: AIMS: We conducted a meta-analysis to evaluate the accuracy of quantitative stress myocardial contrast echocardiography (MCE) in coronary artery disease (CAD).
METHODS AND RESULTS: Database search was performed through January 2008. We included studies evaluating accuracy of quantitative stress MCE for detection of CAD compared with coronary angiography or single-photon emission computed tomography (SPECT) and measuring reserve parameters of A, beta, and Abeta. Data from studies were verified and supplemented by the authors of each study. Using random effects meta-analysis, we estimated weighted mean difference (WMD), likelihood ratios (LRs), diagnostic odds ratios (DORs), and summary area under curve (AUC), all with 95% confidence interval (CI). Of 1443 studies, 13 including 627 patients (age range, 38-75 years) and comparing MCE with angiography (n = 10), SPECT (n = 1), or both (n = 2) were eligible. WMD (95% CI) were significantly less in CAD group than no-CAD group: 0.12 (0.06-0.18) (P < 0.001), 1.38 (1.28-1.52) (P < 0.001), and 1.47 (1.18-1.76) (P < 0.001) for A, beta, and Abeta reserves, respectively. Pooled LRs for positive test were 1.33 (1.13-1.57), 3.76 (2.43-5.80), and 3.64 (2.87-4.78) and LRs for negative test were 0.68 (0.55-0.83), 0.30 (0.24-0.38), and 0.27 (0.22-0.34) for A, beta, and Abeta reserves, respectively. Pooled DORs were 2.09 (1.42-3.07), 15.11 (7.90-28.91), and 14.73 (9.61-22.57) and AUCs were 0.637 (0.594-0.677), 0.851 (0.828-0.872), and 0.859 (0.842-0.750) for A, beta, and Abeta reserves, respectively.
CONCLUSION: Evidence supports the use of quantitative MCE as a non-invasive test for detection of CAD. Standardizing MCE quantification analysis and adherence to reporting standards for diagnostic tests could enhance the quality of evidence in this field.
Abstract: BACKGROUND: The efficacy of granulocyte colony-stimulating factor (G-CSF) for coronary collateral growth promotion and thus impending myocardial salvage has not been studied so far, to our best knowledge.
METHODS AND RESULTS: In 52 patients with chronic stable coronary artery disease, age 62+/-11 years, the effect on a marker of myocardial infarct size (ECG ST segment elevation) and on quantitative collateral function during a 1-minute coronary balloon occlusion was tested in a randomized, placebo-controlled, double-blind fashion. The study protocol before coronary intervention consisted of occlusive surface and intracoronary lead ECG recording as well as collateral flow index (CFI, no unit) measurement in a stenotic and a > or =1 normal coronary artery before and after a 2-week period with subcutaneous G-CSF (10 microg/kg; n=26) or placebo (n=26). The CFI was determined by simultaneous measurement of mean aortic, distal coronary occlusive, and central venous pressure. The ECG ST segment elevation >0.1 mV disappeared significantly more often in response to G-CSF (11/53 vessels; 21%) than to placebo (0/55 vessels; P=0.0005), and simultaneously, CFI changed from 0.121+/-0.087 at baseline to 0.166+/-0.086 at follow-up in the G-CSF group, and from 0.152+/-0.082 to 0.131+/-0.071 in the placebo group (P<0.0001 for interaction of treatment and time). The absolute change in CFI from baseline to follow-up amounted to +0.049+/-0.062 in the G-CSF group and to -0.010+/-0.060 in the placebo group (P<0.0001).
CONCLUSIONS: Subcutaneous G-CSF is efficacious during a short-term protocol in improving signs of myocardial salvage by coronary collateral growth promotion.
Abstract: Background— Intravascular ultrasound of drug-eluting stent (DES) thrombosis (ST) reveals a high incidence of incomplete stent apposition (ISA) and vessel remodeling. Autopsy specimens of DES ST show delayed healing and hypersensitivity reactions. The present study sought to correlate histopathology of thrombus aspirates with intravascular ultrasound findings in patients with very late DES ST.
Methods and Results— The study population consisted of 54 patients (28 patients with very late DES ST and 26 controls). Of 28 patients with very late DES ST, 10 patients (1020±283 days after implantation) with 11 ST segments (5 sirolimus-eluting stents, 5 paclitaxel-eluting stents, 1 zotarolimus-eluting stent) underwent both thrombus aspiration and intravascular ultrasound investigation. ISA was present in 73% of cases with an ISA cross-sectional area of 6.2±2.4 mm2 and evidence of vessel remodeling (index, 1.6±0.3). Histopathological analysis showed pieces of fresh thrombus with inflammatory cell infiltrates (DES, 263±149 white blood cells per high-power field) and eosinophils (DES, 20±24 eosinophils per high-power field; sirolimus-eluting stents, 34±28; paclitaxel-eluting stents, 6±6; P for sirolimus-eluting stents versus paclitaxel-eluting stents=0.09). The mean number of eosinophils per high-power field was higher in specimens from very late DES ST (20±24) than in those from spontaneous acute myocardial infarction (7±10), early bare-metal stent ST (1±1), early DES ST (1±2), and late bare-metal stent ST (2±3; P from ANOVA=0.038). Eosinophil count correlated with ISA cross-sectional area, with an average increase of 5.4 eosinophils per high-power field per 1-mm2 increase in ISA cross-sectional area.
Conclusions— Very late DES thrombosis is associated with histopathological signs of inflammation and intravascular ultrasound evidence of vessel remodeling. Compared with other causes of myocardial infarction, eosinophilic infiltrates are more common in thrombi harvested from very late DES thrombosis, particularly in sirolimus-eluting stents, and correlate with the extent of stent malapposition
Abstract: BACKGROUND: Myocardial contrast echocardiography (MCE) is able to measure in vivo relative blood volume (rBV, i.e., capillary density), and its exchange frequency b, the constituents of myo-cardial blood flow (MBF, ml min-1 g-1). This study aimed to assess, by MCE, whether left ventricular hypertrophy (LVH) in hypertrophic cardiomyopathy (HCM) can be differentiated from LVH in triathletes (athlete's heart, AH) or from hypertensive heart disease patients (HHD).
METHODS: Sixty individuals, matched for age (33 +/- 10 years) and gender, and subdivided into four groups (n = 15) were examined: HCM, AH, HHD and a group of sedentary individuals without LVH (S). rBV (ml ml-1), b (min-1) and MBF, at rest and during adenosine-induced hyperaemia, were derived by MCE in mid septal, lateral and inferior regions. The ratio of MBF during hyperaemia and MBF at rest yielded myocardial blood flow reserve (MBFR).
RESULTS: Septal wall rBV at rest was lower in HCM (0.084 +/- 0.023 ml ml-1) than in AH (0.151 +/- 0.024 ml ml-1, p <0.01) and in S (0.129 +/- 0.026 ml ml-1, p <0.01), but was similar to HHD (0.097 +/- 0.016 ml ml-1). Conversely, MBFR was lowest in HCM (1.67 +/- 0.93), followed by HHD (2.8 +/- 0.93, p <0.01), by S (3.36 +/- 1.03, p <0.001) and by AH (4.74 +/- 1.46, p <0.0001). At rest, rBV <0.11 ml ml-1 accurately distinguished between HCM and AH (sensitivity 99%, specificity 99%), similarly MBFR < or =1.8 helped to distinguish between HCM and HHD (sensitivity 100%, specificity 77%).
CONCLUSIONS: rBV at rest, most accurately distinguishes between pathological LVH due to HCM and physiological, endurance-exercise induced LVH.
Abstract: The clinical value of early exercise stress testing (EST) after coronary stenting to predict long-term clinical outcomes is unknown. Of 1,000 unselected patients who underwent coronary stenting, 446 random patients underwent early EST the day after intervention. Clinical long-term outcomes (41 +/- 20 months) were correlated with normal (n = 314 [70%]) or positive (n = 102 [23%]) EST results. Patients with inconclusive test results (n = 30 [7%]) were excluded from the analysis. Overall mortality was significantly higher in patients with positive EST results (9.3% vs 3.9%, p = 0.04). Major adverse cardiac events and cardiac mortality also tended to be higher in patients with positive stress test results (45.4% vs 35.4%, p = 0.08, and 4.1% vs 1.1%, p = 0.05, respectively). Patients with the combination of positive stress test results and incomplete revascularization appeared to be the group at highest risk for major adverse cardiac events (47.1% vs 33.3% for patients with normal stress test results and complete revascularization, p = NS). Negative stress test results reduced (odds ratio 0.329, 95% confidence interval 0.120 to 0.905, p = 0.031) and a lower ejection fraction increased (odds ratio 0.942, 95% confidence interval 0.897 to 0.989, p = 0.017) the risk for death. In conclusion, an early stress test after coronary stenting provides important prognostic information. Positive stress test results, especially in combination with incomplete revascularization, are associated with higher mortality, a trend toward more repeat revascularization procedures, and higher risk for major adverse cardiac events.
Abstract: OBJECTIVE: To test a new tiny-tipped intraoperative diagnostic tool that was designed to provide the surgeon with reliable stiffness data on the motion segment during microdiscectomy. A decrease in stiffness after nuclectomy and a measurable influence of muscle tension were assumed. If the influence of muscle tension on the motion segment could at least be ruled out, there should be no difference with regard to stiffness between women and men. If these criteria are met, this new intraoperative diagnostic tool could be used in further studies for objective decision-making regarding additional stabilization systems after microdiscectomy.
METHODS: After evaluation of the influence of muscle relaxation during in vivo measurements with a spinal spreader between the spinous processes, 21 motion segments were investigated in 21 patients. Using a standardized protocol, including quantified muscle relaxation, spinal stiffness was measured before laminotomy and after nuclectomy.
RESULTS: The decrease in stiffness after microdiscectomy was highly significant. There were no statistically significant differences between men and women. The average stiffness value before discectomy was 33.7 N/mm, and it decreased to 25.6 N/mm after discectomy. The average decrease in stiffness was 8.1 N/mm (24%).
CONCLUSION: In the moderately degenerated spine, stiffness decreases significantly after microdiscectomy. Control for muscle relaxation is essential when measuring in vivo spinal stiffness. The new spinal spreader was found to provide reliable data. This spreader could be used in further studies for objective decision-making about additional stabilization systems after microdiscectomy.
Abstract: Background— Stent thrombosis may occur late after drug-eluting stent (DES) implantation, and its cause remains unknown. The present study investigated differences of the stented segment between patients with and without very late stent thrombosis with the use of intravascular ultrasound.
Methods and Results— Since January 2004, patients presenting with very late stent thrombosis (>1 year) after DES implantation underwent intravascular ultrasound. Findings in patients with very late stent thrombosis were compared with intravascular ultrasound routinely obtained 8 months after DES implantation in 144 control patients, who did not experience stent thrombosis for 2 years. Very late stent thrombosis was encountered in 13 patients at a mean of 630±166 days after DES implantation. Compared with DES controls, patients with very late stent thrombosis had longer lesions (23.9±16.0 versus 13.3±7.9 mm; P<0.001) and stents (34.6±22.4 versus 18.6±9.5 mm; P<0.001), more stents per lesion (1.6±0.9 versus 1.1±0.4; P<0.001), and stent overlap (39% versus 8%; P<0.001). Vessel cross-sectional area was similar for the reference segment (cross-sectional area of the external elastic membrane: 18.9±6.9 versus 20.4±7.2 mm2; P=0.46) but significantly larger for the in-stent segment (28.6±11.9 versus 20.1±6.7 mm2; P=0.03) in very late stent thrombosis patients compared with DES controls. Incomplete stent apposition was more frequent (77% versus 12%; P<0.001) and maximal incomplete stent apposition area was larger (8.3±7.5 versus 4.0±3.8 mm2; P=0.03) in patients with very late stent thrombosis compared with controls.
Abstract: OBJECTIVES: We assessed the impact of vessel size on angiographic and long-term clinical outcome after percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) within a randomized trial (SIRTAX [Sirolimus-Eluting Stent Compared With Paclitaxel-Eluting Stent for Coronary Revascularization]).
BACKGROUND: Percutaneous coronary intervention in small-vessel disease is associated with an increased risk of major adverse cardiac events (MACE).
METHODS: A total of 1,012 patients were randomly assigned to treatment with SES (n = 503) or PES (n = 509). A stratified analysis of angiographic and clinical outcome was performed up to 2 years after PCI according to size of the treated vessel (reference vessel diameter < or =2.75 vs. >2.75 mm).
RESULTS: Of 1,012 patients, 370 patients (37%) with 495 lesions underwent stent implantation in small vessels only, 504 patients (50%) with 613 lesions in large vessels only, and 138 patients (14%) with 301 lesions in both small and large vessels (mixed). In patients with small-vessel stents, SES reduced MACE by 55% (10.4% vs. 21.4%; p = 0.004), mainly driven by a 69% reduction of target lesion revascularization (TLR) (6.0% vs. 17.7%; p = 0.001) compared with PES at 2 years. In patients with large- and mixed-vessel stents, rates of MACE (large: 10.4% vs. 13.1%; p = 0.33; mixed: 16.7% vs. 18.0%; p = 0.83) and TLR (large: 6.9% vs. 8.6%; p = 0.47; mixed: 16.7% vs. 15.4%; p = 0.86) were similar for SES and PES. There were no significant differences with respect to death and myocardial infarction between the 3 groups.
CONCLUSIONS: Compared with PES, SES more effectively reduced MACE and TLR in small-vessel disease. Differences between SES and PES appear less pronounced in patients with large- and mixed-vessel disease.
Abstract: BACKGROUND: The prognostic relevance of the collateral circulation is still controversial. The goal of this study was to assess the impact on survival of quantitatively obtained, recruitable coronary collateral flow in patients with stable coronary artery disease during 10 years of follow-up.
METHODS AND RESULTS: Eight-hundred forty-five individuals (age, 62+/-11 years), 106 patients without coronary artery disease and 739 patients with chronic stable coronary artery disease, underwent a total of 1053 quantitative, coronary pressure-derived collateral measurements between March 1996 and April 2006. All patients were prospectively included in a collateral flow index (CFI) database containing information on recruitable collateral flow parameters obtained during a 1-minute coronary balloon occlusion. CFI was calculated as follows: CFI = (P(occl) - CVP)/(P(ao) - CVP) where P(occl) is mean coronary occlusive pressure, P(ao) is mean aortic pressure, and CVP is central venous pressure. Patients were divided into groups with poorly developed (CFI < 0.25) or well-grown collateral vessels (CFI > or = 0.25). Follow-up information on the occurrence of all-cause mortality and major adverse cardiac events after study inclusion was collected. Cumulative 10-year survival rates in relation to all-cause deaths and cardiac deaths were 71% and 88%, respectively, in patients with low CFI and 89% and 97% in the group with high CFI (P=0.0395, P=0.0109). Through the use of Cox proportional hazards analysis, the following variables independently predicted elevated cardiac mortality: age, low CFI (as a continuous variable), and current smoking.
CONCLUSIONS: A well-functioning coronary collateral circulation saves lives in patients with chronic stable coronary artery disease. Depending on the exact amount of collateral flow recruitable during a brief coronary occlusion, long-term cardiac mortality is reduced to one fourth compared with the situation without collateral supply.
Abstract: Human HeLa cells expressing mouse connexin30 were used to study the electrical properties of gap junction channel substates. Experiments were performed on cell pairs using a dual voltage-clamp method. Single-channel currents revealed discrete levels attributable to a main state, a residual state, and five substates interposed, suggesting the operation of six subgates provided by the six connexins of a gap junction hemichannel. Substate conductances, gamma(j,substate), were unevenly distributed between the main-state and the residual-state conductance (gamma(j,main state) = 141 pS, gamma(j,residual state) = 21 pS). Activation of the first subgate reduced the channel conductance by approximately 30%, and activation of subsequent subgates resulted in conductance decrements of 10-15% each. Current transitions between the states were fast (<2 ms). Substate events were usually demarcated by transitions from and back to the main state; transitions among substates were rare. Hence, subgates are recruited simultaneously rather than sequentially. The incidence of substate events was larger at larger gradients of V(j). Frequency and duration of substate events increased with increasing number of synchronously activated subgates. Our mathematical model, which describes the operation of gap junction channels, was expanded to include channel substates. Based on the established V(j)-sensitivity of gamma(j,main state) and gamma(j,residual state), the simulation yielded unique functions gamma(j,substate) = f(V(j)) for each substate. Hence, the spacing of subconductance levels between the channel main state and residual state were uneven and characteristic for each V(j).
Abstract: AIMS: The adaptation of the myocardial microcirculation in humans to pathologic and physiologic stress has not been examined in vivo so far. We sought to test whether the relative blood volume (rBV) measured by myocardial contrast echocardiography (MCE) can differentiate between left ventricular (LV) hypertrophy (LVH) in hypertensive heart disease and athlete's heart.
METHODS AND RESULTS: Four groups were investigated: hypertensive patients with LVH (n = 15), semi-professional triathletes with LVH (n = 15), professional football players (n = 15), and sedentary control individuals without cardiovascular disease (n = 15). MCE was performed at rest and during adenosine-induced hyperaemia. The rBV (mL mL(-1)), its exchange frequency (beta, min(-1)), and myocardial blood flow (mL min(-1) g(-1)) were derived from steady state and refill sequences of ultrasound contrast agent. Hypertensive patients had lower rBV (0.093 +/- 0.013 mL mL(-1)) than triathletes (0.141 +/- 0.012 mL mL(-1), P < 0.001), football players (0.129 +/- 0.014 mL mL(-1), P < 0.001), and sedentary individuals (0.126 +/- 0.018 mL mL(-1), P < 0.001). Conversely, the exchange frequency (beta) was significantly higher in hypertensive patients (11.3 +/- 3.8 min(-1)) than in triathletes (7.4 +/- 1.8 min(-1)), football players (7.7 +/- 2.3 min(-1)), and sedentary individuals (9.0+/-2.5 min(-1)). An rBV below 0.114 mL mL(-1) distinguished hypertensive patients and triathletes with a sensitivity of 93% and a specificity of 100%.
CONCLUSION: Pathologic and physiologic LVH were differentiated non-invasively and accurately by rBV, a measure of vascularisation assessed by MCE.
Abstract: Aims Myocardial blood flow (MBF) is the gold standard to assess myocardial blood supply and, as recently shown, can be obtained by myocardial contrast echocardiography (MCE). The aims of this human study are (i) to test whether measurements of collateral-derived MBF by MCE are feasible during elective angioplasty and (ii) to validate the concept of pressure-derived collateral-flow assessment.
Methods and results Thirty patients with stable coronary artery disease underwent MCE of the collateral-receiving territory during and after angioplasty of 37 stenoses. MCE perfusion analysis was successful in 32 cases. MBF during and after angioplasty varied between 0.060–0.876 mL min−1 g−1 (0.304±0.196 mL min−1 g−1) and 0.676–1.773 mL min−1 g−1 (1.207±0.327 mL min−1 g−1), respectively. Collateral-perfusion index (CPI) is defined as the rate of MBF during and after angioplasty varied between 0.05 and 0.67 (0.26±0.15). During angioplasty, simultaneous measurements of mean aortic pressure, coronary wedge pressure, and central venous pressure determined the pressure-derived collateral-flow index (CFIp), which varied between 0.04 and 0.61 (0.23±0.14). Linear-regression analysis demonstrated an excellent agreement between CFIp and CPI (y=0.88x+0.01; r2=0.92; P<0.0001).
Conclusion Collateral-derived MBF measurements by MCE during angioplasty are feasible and proved that the pressure-derived CFI exactly reflects collateral relative to normal myocardial perfusion in humans.
Abstract: Left ventricular free-wall perforation can complicate catheter-based diagnostic or interventional procedures and may require immediate needle pericardiocentesis followed by surgical repair in about 20% of the cases. We describe the transcatheter closure of a left ventricular free-wall perforation as an option in the event of maintained access to the perforation site after defect creation.
Abstract: OBJECTIVES: We sought to test whether myocardial blood flow (MBF) can be quantified by myocardial contrast echocardiography (MCE) using a volumetric model of ultrasound contrast agent (UCA) kinetics for the description of refill curves after ultrasound-induced microsphere destruction.
BACKGROUND: Absolute myocardial perfusion or MBF (ml.min(-1).g(-1)) is the gold standard to assess myocardial blood supply, and so far it could not be obtained by ultrasound.
METHODS: The volumetric model yielded MBF = rBV.beta/rho(T), where rho(T) equals tissue density. The relative myocardial blood volume rBV and its exchange frequency beta were derived from UCA refill sequences. Healthy volunteers underwent MCE and positron emission tomography (PET) at rest (group I: n = 15; group II: n = 5) and during adenosine-induced hyperemia (group II). Fifteen patients with coronary artery disease underwent simultaneous MCE and intracoronary Doppler measurements before and during intracoronary adenosine injection.
RESULTS: In vitro experiments confirmed the volumetric model and the reliable determination of rBV and beta for physiologic flow velocities. In group I, 187 of 240 segments were analyzable by MCE, and a linear relation was found between MCE and PET perfusion data (y = 0.899x + 0.079; r(2) = 0.88). In group II, resting and hyperemic perfusion data showed good agreement between MCE and PET (y = 1.011x + 0.124; r(2) = 0.92). In patients, coronary stenosis varied between 0% to 89%, and myocardial perfusion reserve was in good agreement with coronary flow velocity reserve (y = 0.92x + 0.14; r(2) = 0.73).
CONCLUSIONS: The volumetric model of UCA kinetics allows the quantification of MBF in humans using MCE and provides the basis for the noninvasive and quantitative assessment of coronary artery disease.
Abstract: Pairs of human HeLa cells expressing rat connexin46 were used to study the electrical properties of gap junction channels with the dual voltage-clamp method. The steady-state conductance ( g(j,ss)) had a bell-shaped dependence on transjunctional voltage ( V(j)). The parameters of the Boltzmann fit were: V(j,0)=42 mV, g(j,min)=0.12, z=2.5 (pipette solution: K(+) aspartate(-); 27 degrees C). The Boltzmann parameters were sensitive to the ionic composition of the pipette solution (KCl, K(+) aspartate(-), TEA(+) Cl(-), TEA(+) aspartate(-)). The V(j)-dependent inactivation of the junctional current I(j) was approximated by single exponentials (exceptions: two exponentials with KCl at V(j)>or=75 mV and K(+) aspartate(-) at V(j)=125 mV). The time constant of inactivation (tau(i)) decreased with increasing V(j) and was sensitive to the pipette solution. The larger the ions, the slower the inactivation. Recovery from inactivation followed a single exponential. The time constant of recovery (tau(r)) increased with increasing V(j). Single-channel currents showed a main state, several substates and a residual state. The corresponding conductances gamma(j,main) and gamma(j,residual) decreased slightly with increasing V(j); extrapolation to V(j)=0 mV yielded values of 152 and 28 pS, respectively (K(+) aspartate(-); 37 degrees C). The values of gamma(j,main) and gamma(j,residual) were dependent on pipette solution. The ratio gamma(j,main)/gamma(j,residual) increased with increasing ionic size, suggesting that the residual state impairs ion permeation more severely than the main state. The gamma(j,main) data suggest that the ionic selectivity of Cx46 channels may be controlled primarily by ionic size. Compared with hemichannel results, docking of connexons may modify the channel structure and thereby affect the ionic selectivity of gap junction channels. The open channel probability at steady state ( P(o)) decreased with increasing V(j). The parameters of the Boltzmann fit were: V(j,0)=41 mV, z=2.2 (K(+) aspartate(-); 27 degrees C).
Abstract: In most tissues of vertebrates, gap junctions control the exchange of ions and small molecules between adjacent cells, thus co-ordinating the cellular activities. The application of the dual voltage-clamp method to cell pair preparations enables one to elucidate the electrical properties of gap junctions and gap junction channels. The conductive and kinetic data obtained at the multichannel and single channel level led to a generalised concept for the operation of gap junction channels. Based on the biological data gained in this way, a mathematical model has been developed. This model is versatile and allows to simulate the electrophysiological behaviour of different types of vertebrate gap junctions.
Abstract: The gap junction connecting cardiac myocytes is voltage and time dependent. This simulation study investigated the effects of dynamic gap junctions on both the shape and conduction velocity of a propagating action potential. The dynamic gap junction model is based on that described by Vogel and Weingart (J. Physiol. (Lond.). 1998, 510:177-189) for the voltage- and time-dependent conductance changes measured in cell pairs. The model assumes that the conductive gap junction channels have four conformational states. The gap junction model was used to couple 300 cells in a linear strand with membrane dynamics of the cells defined by the Luo-Rudy I model. The results show that, when the cells are tightly coupled (6700 channels), little change occurs in the gap junction resistance during propagation. Thus, for tight coupling, there are negligible differences in the waveshape and propagation velocity when comparing the dynamic and static gap junction representations. For poor coupling (85 channels), the gap junction resistance increases 33 MOmega during propagation. This transient change in resistance resulted in increased transjunctional conduction delays, changes in action potential upstroke, and block of conduction at a lower junction resting resistance relative to a static gap junction model. The results suggest that the dynamics of the gap junction enhance cellular decoupling as a possible protective mechanism of isolating injured cells from their neighbors.
Abstract: Myocytes were isolated from neonatal rat hearts using an enzymatic procedure. Cell pairs were used to control the junctional voltage, V(j), and to measure the transjunctional current, I(j), using the dual voltage-clamp method. V(j) gradients provoked I(j) signals with voltage-dependent inactivation. During voltage pulses, I(j) remained virtually constant at ¿V(j)¿ <40 mV. At ¿V(j)¿>40 mV, it inactivated with time to a residual level. The inactivation followed a single exponential. The time constant of I(j) inactivation, taui, and the size of I(j) at steady state, I(j,ss), were both sensitive to the ions in the pipette solution. I(j,ss) was smaller in the presence of tetraethylammonium aspartate (TEA+ aspartate-) than KC1, while taui was smaller in the presence of KC1 than TEA+ aspartate-. The modification of I(j,ss) is readily explained by a change in the residual conductance of the gap junction channels, gammaj,residual x The alterations in taui are correlated with a change in beta, the rate constant that describes the transition of the channel from the main state to the residual state. Pipette solutions may affect the kinetics of gap junction currents by altering the conductive and/or kinetic parameters. Computer simulations revealed a substantial influence of the latter, but only a marginal effect of the former. Conceivably, ions of the pipette solution may affect the kinetics of gap junction channels by screening surface charges of the channel wall.
Abstract: 1. Human HeLa cells expressing mouse connexin30 (Cx30) were used to study the electrical properties of Cx30 gap junction channels. Experiments were performed on cell pairs with the dual voltage-clamp method. 2. The gap junction conductance (gj) at steady state showed a bell-shaped dependence on junctional voltage (Vj; Boltzmann fit: Vj,0 = 27 mV, gj,min = 0.15, z = 4). The instantaneous gj decreased slightly with increasing Vj. 3. The gap junction currents (Ij) declined with time following a single exponential. The time constants of Ij inactivation (taui) decreased with increasing Vj. 4. Single channels exhibited a main state, a residual state and a closed state. The conductances gammaj,main and gammaj,residual were 179 and 48 pS, respectively (pipette solution, potassium aspartate; temperature, 36-37 degrees C; extrapolated to Vj = 0 mV). 5. The conductances gammaj,residual and gammaj,main showed a slight Vj dependence and were sensitive to temperature (Q10 values of 1.28 and 1.16, respectively). 6. Current transitions between open states (i.e. main state, substates, residual state) were fast (< 2 ms), while those between an open state and the closed state were slow (12 ms). 7. The open channel probability (Po) at steady state decreased from 1 to 0 with increasing Vj (Boltzmann fit: Vj,0 = 37 mV; z = 3). 8. Histograms of channel open times implied the presence of a single main state; histograms of channel closed times suggested the existence of two closed states (i.e. residual states). 9. We conclude that Cx30 channels are controlled by two types of gates, a fast one responsible for Vj gating involving transitions between open states (i.e. residual state, main state), and a slow one correlated with chemical gating involving transitions between the closed state and an open state.
Abstract: 1. A mathematical model has been developed which describes the conductive and kinetic properties of homotypic and heterotypic gap junction channels of vertebrates. 2. The model consists of two submodels connected in series. Each submodel simulates a hemichannel and consists of two conductances corresponding to a high (H) and low (L) conductance state and a switch, which simulates the voltage-dependent channel gating. 3. It has been assumed that the conductances of the high state and low state vary exponentially with the voltage across the hemichannel. 4. The parameters of the exponentials can be derived from data of heterotypic or homotypic channels. As a result, the behaviour of heterotypic channels can be predicted from homotypic channel data and vice versa. 5. The two switches of a channel are governed by the voltage drop across the respective hemichannel. The switches of a channel work independently, thus giving rise to four conformational states, i.e. HH, LH, HL and LL. 6. The computations show that the dogma of a constant conductance for homotypic channels results from the limited physiological range of transjunctional voltages (Vj) and the kinetic properties of the channel, so a new fitting procedure is presented. 7. Simulation of the kinetic properties at the multichannel level revealed current time courses which are consistent with a contingent gating. 8. The calculations have also shown that the channel state LL is rare and of short duration, and hence easy to miss experimentally. 9. The design of the model has been kept flexible. It can be easily expanded to include additional features, such as channel substates or a closed state.
Abstract: 1. Cell pairs of the insect cell line Sf9 (Spodoptera frugiperda) were chosen to examine the electrical properties of gap junction channels. The dual voltage-clamp method was used to control the membrane potential of each cell (Vm,1 and Vm,2) and hence the junctional voltage gradient (Vj), and to measure intercellular current. 2. Studies with preformed pairs revealed that the gap junction conductance (gj) is controlled by a Vj- and a Vm-sensitive gate. At steady state, gj = f(Vj) was bell shaped and symmetrical (Boltzmann: Vj.0 = -54 and 55 mV, the normalized minimum conductance at large Vj values (gj,min) = 0.24 and 0.23, z = 5.5 and 6.1 for negative and positive Vj, respectively) and gj = f(Vm) was S shaped (Vm.0 = 13 mV, gj,min = 0, z = 1.5). 3. Single channels exhibited two conductances, a main state (gamma j,main) of 224 pS and a residual state (gamma j,residual) of 42 pS. 4. We conclude that gap junctions in Sf9 cells behave similarly to those in the insect cell line C6/36 (Aedes albopictus). 5. An induced cell pair approach was used to examine heterotypic gap junction channels between Sf9 cells and C3/36 cells. 6. Heterotypic channels showed a gamma j,main of 303 pS and a gamma j,residual of 45 and 64 pS, depending on whether the Sf9 cell or C6/36 cell was positive inside. 7. In heterotypic gap junctions, gj = f(Vj) was bell shaped and asymmetrical (gj was more sensitive to Vj when the C6/36 cell was positive inside) and gj = f(Vm) was S shaped (Vm,0 = 2 mV, gj,min = 0, z = 2.9). 8. We conclude that heterotypic channels possess a Vj- and Vm-sensitive gating mechanism. Vj gating involves two gates, one located in each hemi-channel. Vj gates are operated independently and close when the cytoplasmic aspect is made positive. 9. A comparison of homo- and heterotypic channel data suggests that docking of hemi-channels may affect channel gating, but not channel conductance.
Abstract: Human energy harvesting has gained much interest in the last decade, since it opens new perspectives interms of long-term power supply for medical implants that remain in the body for many years. Severalenergy sources can be considered in the human body, one of them being the cardiovascular system, with theobvious advantage that the energy is provided continuously.The present project aims at modelling a generator that harvests energy from the variation in blood pressureby exploiting the motion of the arterial wall between the diastolic and systolic phase of the cardiac cycle. Theconcept is to use a highly electrically conductive fluid, which is driven by the motion of the arterial wallwithin a separate compartment outside the artery (Figures 1,2). A constant magnetic field is applied to thisloop, which allows converting the fluid’s motion into electrical energy based on the principle ofelectro-magneto-hydrodynamics [1,2,3]. The COMSOL simulation encompasses fluid-structure interactionsas well as magneto- and electrostatics. The multiphysics coupling are manifold, from the force on the arterialwall due to the pressure increase in blood, through the induced electrical field from the motion of the fluid inthe magnetic field (Figures 3,4), to the decelerating force on the fluid from the current flow through thegenerator. The simulation is built such that it allows for a parametric study of the geometry
