Michael Billinger

Incomplete Stent Apposition and Very Late Stent Thrombosis After Drug-Eluting Stent Implantation

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. Conclusions— Incomplete stent apposition is highly prevalent in patients with very late stent thrombosis after DES implantation, suggesting a role in the pathogenesis of this adverse event.

Correlation of Intravascular Ultrasound Findings With Histopathological Analysis of Thrombus Aspirates in Patients With Very Late Drug-Eluting Stent Thrombosis

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.

Beneficial Effect of Recruitable Collaterals A 10-Year Follow-Up Study in Patients With Stable Coronary Artery Disease Undergoing Quantitative Collateral Measurements

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: where Poccl is mean coronary occlusive pressure, Pao 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 ≥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.

Frequency distribution of collateral flow and factors influencing collateral channel development: Functional collateral channel measurement in 450 patients with coronary artery disease☆

OBJECTIVES We sought to determine the pathogenetic predictors of collateral channels in a large cohort of patients with coronary artery disease (CAD). BACKGROUND The frequency distribution of collateral flow in patients with CAD is unknown. Only small qualitative studies have investigated which factors influence the development of collateral channels. METHODS In 450 patients with one- to three-vessel CAD undergoing percutaneous transluminal coronary angioplasty (PTCA), collateral flow was measured. A collateral flow index (CFI; no unit) expressing collateral flow relative to normal anterograde flow was determined using coronary wedge pressure or Doppler measurements through sensor-tipped PTCA guide wires. Frequency distribution analysis of CFI and univariate and multivariate analyses of 32 factors, including gender, age, patient history, cardiovascular risk factors, medication and coronary angiographic data, were performed. RESULTS Two-thirds of the patients had a CFI < 0.25 and approximately 40% of patients had a CFI < 0.15, but only approximately 10% of the patients had a recruitable CFI > or =0.4. By univariate analysis, the following were predictors of CFI > or =0.25: high levels of high-density lipoprotein cholesterol, the absence of previous non-Q-wave myocardial infarction, angina pectoris during an exercise test, angiographic indicators of severe CAD and the left circumflex or right coronary artery as the collateral-receiving vessel. Percent diameter stenosis of the lesion undergoing PTCA was the only independent predictor of a high CFI. CONCLUSIONS This large clinical study of patients with CAD in whom collateral flow was quantitatively assessed reveals that two-thirds of the patients do not have enough collateral flow to prevent myocardial ischemia during coronary occlusion, and that coronary lesion severity is the only independent pathogenetic variable related to collateral flow.

Physiologically assessed coronary collateral flow and adverse cardiac ischemic events: a follow-up study in 403 patients with coronary artery disease.

OBJECTIVES We sought to evaluate whether coronary collateral flow is clinically relevant for future cardiac ischemic events. BACKGROUND The link between good collateral supply related to less myocardial damage and fewer cardiac events has not been established prospectively beyond doubt. METHODS In 403 patients with stable angina pectoris undergoing percutaneous transluminal coronary angioplasty (PTCA) and quantitative collateral assessment, the occurrence of major adverse cardiac events ([MACE] cardiac death, myocardial infarction, unstable angina pectoris) and stable angina pectoris was monitored during follow-up. Collateral flow index (CFI) was determined using intracoronary pressure or Doppler guidewires. Mean aortic ([P(ao)] mm Hg) and distal coronary artery occlusive pressure ([P(occl)] mm Hg) during balloon angioplasty (PTCA), or distal coronary flow velocity time integral during ([V(occl)] cm) and after ([V(ø-occl)] cm) PTCA were measured continuously. Pressure-derived CFI was calculated as follows: (P(occl) - 5)/(P(ao) - 5). Doppler-derived CFI: V(occl)/V(ø-occl). Patients were subdivided into a group with well (CFI > or = 0.25) and poorly developed collaterals (CFI < 0.25). RESULTS Average follow-up was 94 +/- 56 (15 to 202) weeks. There were 134 patients with CFI >or =0.25 (61 +/- 11 years) and 269 with CFI <0.25 (61 +/- 10 years). The overall cardiac ischemic event rate (MACE and stable angina pectoris) during follow-up was 23% in patients with CFI > or =0.25 and 20% in patients with CFI <0.25 (p = NS). However, only 2.2% of patients with good collateral flow suffered a major cardiac ischemic event, compared with 9.0% among patients with poorly developed collaterals (p = 0.01). The incidence of stable angina pectoris was significantly higher in patients with well developed collaterals than in those with poorly developed collaterals (21% vs. 12%; p = 0.01). CONCLUSIONS In this relatively large population with chronic stable coronary artery disease undergoing quantitative collateral measurement, the beneficial impact of well developed collateral vessels on the occurrence of future major cardiac ischemic events is clearly demonstrated.

Is the development of myocardial tolerance to repeated ischemia in humans due to preconditioning or to collateral recruitment

OBJECTIVES The purpose of this study in patients with quantitatively determined, poorly developed coronary collaterals was to assess the contribution of ischemic as well as adenosine-induced preconditioning and of collateral recruitment to the development of tolerance against repetitive myocardial ischemia. BACKGROUND The development of myocardial tolerance to repeated ischemia is nowadays interpreted to be due to biochemical adaptation (i.e., ischemic preconditioning). METHODS In 30 patients undergoing percutaneous transluminal coronary angioplasty, myocardial adaptation to ischemia was measured using intracoronary (i.c.) electrocardiographic (ECG) ST segment elevation changes obtained from a 0.014-in. (0.036 cm) pressure guidewire positioned distal to the stenosis during three subsequent 2-min balloon occlusions. Simultaneously, an i.c. pressure-derived collateral flow index (CFI, no unit) was determined as the ratio between distal occlusive minus central venous pressure divided by the mean aortic minus central venous pressure. The study patients were divided into two groups according to the pretreatment with i.c. adenosine (2.4 mg/min for 10 min starting 20 min before the first occlusion, n = 15) or with normal saline (control group, n = 15). RESULTS Collateral flow index at the first occlusion was not different between the groups (0.15 +/- 0.10 in the adenosine group and 0.13 +/- 0.11 in the control group, p = NS), and it increased significantly and similarly to 0.20 +/- 0.14 and to 0.19 +/- 0.10, respectively (p < 0.01) during the third occlusion. The i.c. ECG ST elevation (normalized for the QRS amplitude) was not different between the two groups at the first occlusion (0.25 +/- 0.13 in the adenosine group, 0.25 +/- 0.19 in the control group). It decreased significantly during subsequent coronary occlusions to 0.20 +/- 0.15 and to 0.17 +/- 0.13, respectively. There was a correlation between the change in CFI (first to third occlusion; deltaCFI) and the respective ST elevation shift (deltaST): deltaST = -0.02 to 0.78 x deltaCFI; r = 0.54, p = 0.02. CONCLUSIONS Even in patients with few coronary collaterals, the myocardial adaptation to repetitive ischemia is closely related to collateral recruitment. Pharmacologic preconditioning using a treatment with i.c. adenosine before angioplasty does not occur. The variable responses of ECG signs of ischemic adaptation to collateral channel opening suggest that ischemic preconditioning is a relevant factor in the development of ischemic tolerance.

Two-year clinical outcome after implantation of sirolimus-eluting and paclitaxel-eluting stents in diabetic patients

AIMS Percutaneous coronary intervention (PCI) in diabetic patients is associated with an increased risk of restenosis and major adverse cardiac events (MACE). We assessed the impact of diabetes on long-term outcome after PCI with sirolimus-eluting (SES) and paclitaxel-eluting (PES) stents. METHODS AND RESULTS In the SIRTAX trial, 1012 patients were randomized to treatment with SES (n = 503) or PES (n = 509). A stratified analysis of outcomes was performed according to the presence or absence of diabetes. Baseline characteristics were well balanced between SES and PES in patients with (N = 201) and without diabetes (N = 811). Clinical outcome was worse in diabetic compared with non-diabetic patients regarding death (9.0% vs. 4.1%, P = 0.004) and MACE (defined as cardiac death, myocardial infarction, or TLR; 19.9% vs. 12.7%, P = 0.007) at 2 years. Among diabetic patients, SES reduced MACE by 47% (14.8% vs. 25.8%, HR = 0.52, P = 0.05) and TLR by 61% (7.4% vs. 17.2%, HR = 0.39, P = 0.03) compared with PES at 2 years. CONCLUSION Diabetic patients have worse prognosis than non-diabetic patients undergoing PCI with DES. Among the diabetic patient population of this trial, SES reduce repeat revascularization procedures and MACE more effectively than PES and to a similar degree as in non-diabetic patients.

Coronary collateral flow in response to endurance exercise training.

Background In humans, it is not known whether physical endurance exercise training promotes coronary collateral growth. The following hypotheses were tested: the expected collateral flow reduction after percutaneous coronary intervention of a stenotic lesion is prevented by endurance exercise training; collateral flow supplied to an angiographically normal coronary artery improves in response to exercise training; there is a direct relationship between the change of fitness after training and the coronary collateral flow change. Methods and results Forty patients (age 61 ± 8 years) underwent a 3-month endurance exercise training program with baseline and follow-up assessments of coronary collateral flow. Patients were divided into an exercise training group (n = 24) and a sedentary group (n = 16) according to the fact whether they adhered or not to the prescribed exercise program, and whether or not they showed increased endurance (V o 2max in ml/min per kg) and performance (W/kg) during follow-up versus baseline bicycle spiroergometry. Collateral flow index (no unit) was obtained using pressure sensor guidewires positioned in the coronary artery undergoing percutaneous coronary intervention and in a normal vessel. In the vessel initially undergoing percutaneous coronary intervention, there was an increase in collateral flow index among exercising but not sedentary patients from 0.155 ± 0.081 to 0.204 ± 0.056 (P=0.03) and from 0.189 ± 0.084 to 0.212 ± 0.077 (NS), respectively. In the normal vessel, collateral flow index changes were from 0.176 ± 0.075 to 0.227 ± 0.070 in the exercise group (P=0.0002), and from 0.219 ± 0.103 to 0.238 ± 0.086 in the sedentary group (NS). A direct correlation existed between the change in collateral flow index from baseline to follow-up and the respective alteration of V o 2max (P=0.007) and Watt (P=0.03). Conclusion A 3-month endurance exercise training program augments coronary collateral supply to normal vessels, and even to previously stenotic arteries having undergone percutaneous coronary intervention before initiating the program. There appears to be a dose–response relation between coronary collateral flow augmentation and exercise capacity gained.

Physiologically Assessed Coronary Collateral Flow and Intracoronary Growth Factor Concentrations in Patients With 1- to 3-Vessel Coronary Artery Disease

BACKGROUND The purpose of this study was to test the hypothesis that there is a relation between collateral flow and intracoronary concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and that the combined concentrations of both growth factors and the extent of coronary artery disease (CAD) play a role as covariables in such an association. METHODS AND RESULTS In 76 patients undergoing balloon angioplasty, a collateral flow index (CFI, no units) was determined with sensor-tipped guidewires. Simultaneously, serum concentrations of bFGF and VEGF, obtained at the aortic root from the ostium of the collateralized coronary artery (n = 76) and from the distal position of the occluded coronary artery (n = 34), were determined. There was a direct correlation between CFI and distal VEGF (r = 0.33, P = 0.05) but not bFGF concentrations. Focusing on the proximal sampling site, there was a direct correlation between CFI and both bFGF (r = 0.29, P = 0.01) and VEGF concentrations (r = 0.44, P < 0.0001). The sum of the concentrations of both growth factors was directly associated with CFI irrespective of the proximal (r = 0.51, P < 0.0001) or distal sampling site (r = 0.34, P = 0.048). There was a trend toward higher proximal VEGF concentrations in patients with higher numbers of coronary stenotic lesions (r = 0.25, P = 0.03). CONCLUSIONS In patients with CAD, there is an association between a directly measured index of collateral flow and intracoronary concentrations of bFGF and VEGF. This direct relation is dependent on the site of blood sampling within the coronary artery tree. The association is closest when the combined bFGF and VEGF concentrations are taken into account. In the case of VEGF, it is influenced by the degree of coronary atherosclerosis.

Simultaneous intracoronary velocity- and pressure-derived assessment of adenosine-induced collateral hemodynamics in patients with one- to two-vessel coronary artery disease

OBJECTIVES The purpose of this investigation in patients with poorly and well developed coronary collaterals was to assess the influence of collateral and collateral adjacent vascular resistances and, in part, a stenotic lesion of the collateral supplying vessel on the hemodynamic collateral responses to adenosine. BACKGROUND In humans, little is known about the functional behavior of the coronary collateral circulation. METHODS In 50 patients with one- and two-vessel coronary artery disease (CAD) undergoing percutaneous transluminal coronary angioplasty (PTCA), collateral flow index (CFI, no unit) changes and vascular resistance index (R, cm/mm Hg) changes of the collateral (R(coll)) and the distal collateral receiving (R4) vessel in response to adenosine (140 microg/min/kg IV) were measured by intracoronary (i.c.) Doppler and pressure guidewires. The variables were determined at baseline and during adenosine in patients with poor (angiographic collateral degree before PTCA <2 of 0 to 3) and good coronary collaterals. RESULTS Pressure-derived CFI (CFI(p)) decreased under adenosine in patients with poor collaterals, and it increased in the group with good collaterals. There were inverse correlations between the adenosine-induced change in CFI(p) and the change in R(coll) (r = 0.61, p = 0.0001). In the group with good, but not with poor collaterals, there was also a significant correlation between CFI(p) increase and the decrease in R4, between the severity of the contralateral stenosis and CFI(p) augmentation and among the left versus right coronary artery as ipsilateral vessel and CFI(p) change. CONCLUSIONS Overall, patients with well, versus poorly developed coronary collaterals do better regarding the capacity to increase collateral flow in response to adenosine. In patients with good, but not poor, collaterals, an adenosine-induced collateral flow increase depends on the ipsilateral distal vascular resistance decrease, but is also directly influenced by the severity of a contralateral stenosis and probably by the size of the collateralized vascular bed.