Ghrelin receptor-knockout mice display alterations in circadian rhythms of activity and feeding under constant lighting conditions.

Ghrelin is an orexigenic hormone produced by the stomach. Ghrelin, however, may also be a modulator of the circadian system given that ghrelin receptors are expressed in the master clock, the suprachiasmatic nucleus (SCN) and several outputs of this region. To investigate this, we performed analyses of running wheel activity and neuronal activation in wild type (WT) and growth hormone secretagogue receptor-knockout (GHSR-KO) mice under various lighting conditions. GHSR-KO and WT mice were maintained under constant dark (DD) or constant light (LL) with ad libitum access to food before being placed on a schedule of temporally restricted access to food (4 h/day) for 2 weeks. There were no differences between KO and WT mice in free-running period under DD, but GHSR-KO mice required more days to develop a high level of food anticipatory activity, and this was lower than that observed in WT mice. Under LL, GHSR-KO mice showed greater activity overall, lengthening of their circadian period, and more resistance to the disorganisational effects of LL. Furthermore, GHSR-KO mice showed greater activity overall, and greater activity in anticipation of a scheduled meal under LL. These behavioral effects were not correlated with changes in the circadian expression of the Fos, Per1 or Per2 proteins under any lighting conditions. These results suggest that the ghrelin receptor plays a role in modulating the activity of the circadian system under normal conditions and under restricted feeding schedules, but does so through mechanisms that remain to be determined.

Motivation to obtain preferred foods is enhanced by ghrelin in the ventral tegmental area.

Ghrelin is an orexigenic peptide that acts within the central nervous system to stimulate appetite and food intake via the growth hormone secretagogue receptor (GHS-R). It has been hypothesized that ghrelin modulates food intake in part by stimulating reward pathways in the brain and potentially stimulating the intake of palatable foods. Here we examined the effects of chronic ghrelin administration in the ventral tegmental area (VTA) via osmotic minipumps on 1) ad libitum food intake and bodyweight; 2) macronutrient preference; and 3) motivation to obtain chocolate pellets. In the first study rats receiving ghrelin into the VTA showed a dose-dependent increase in the intake of regular chow, also resulting in increased body weight gain. A second study revealed that intra-VTA delivery of the ghrelin receptor antagonist [Lys-3]-GHRP-6 selectively reduced caloric intake of high-fat chow and reduced body weight gain relative to control and ghrelin treated rats. The third study demonstrated that food restricted rats worked harder for food pellets when infused with ghrelin than when infused with vehicle or ghrelin receptor antagonist treated rats. Finally, rats trained on an FR1 schedule but returned to ad libitum during ghrelin infusion, responded at 86% of baseline levels when they were not hungry, whereas saline infused rats responded at 36% of baseline. Together, these results suggest that ghrelin acts directly on the VTA to increase preference for and motivation to obtain highly-palatable food.

Altered metabolic and neurochemical responses to chronic unpredictable stressors in ghrelin receptor-deficient mice.

Ghrelin, a hormone produced by the stomach, is generally associated with feeding responses and the regulation of food intake. Recent evidence, however, suggests that ghrelin is also a stress hormone, given that it is released following acute and chronic stressors. The present study examined the role of ghrelin in producing normal metabolic and neurochemical responses to chronic stress. This was achieved by examining these responses in mice with targeted deletions of the ghrelin receptor gene (GHSR KO mice), and comparing them with the same responses in their wild-type (WT) littermates. As expected, WT stressed mice decreased their caloric intake, body weight gain and caloric efficiency while maintaining adiposity. GHSR KO mice, however, did not show these alterations despite having normal glucocorticoid responses to stress. In parallel with these changes, chronic unpredictable stress caused changes in norepinephrine, dopamine and serotonin in a number of brain regions. Of these, norepinephrine neurotransmission in the arcuate nucleus and prefrontal cortex was differentially altered in GHSR KO mice. Within the nucleus acumbens, dopamine utilization was increased in WT mice but not in GHSR KO mice. Finally, there were strain differences in serotonin neurotransmission that may explain interstrain body weight and adiposity differences. These results suggest that the metabolic changes necessary to deal with the energetic challenge presented by repeated exposure to stressors do not occur in GHSR KO mice, and they are discussed within the context of the potential vulnerability to stress-induced pathology.

Stress and glucocorticoid modulation of feeding and metabolism.

This perspective highlights research presented as part of the symposium entitled, "Stress and Glucocorticoid Modulation of Feeding and Metabolism" at the 2018 Neurobiology of Stress Workshop held in Banff, AB, Canada. The symposium comprised five researchers at different career stages who each study different aspects of the interaction between the stress response and metabolic control. Their collective results reveal the complexity of this relationship in terms of behavioural and physiological outcomes. Their work emphasizes the need to consider the level of interaction (cellular, tissue, systems) as well as the timing and context in which the interaction is studied. Rather than a comprehensive review on the work presented at the Symposium, here we discuss recurring themes that emerged at the biennial workshop, which address new avenues of research that will drive the field forward.

Hypothalamic and pituitary expression of ghrelin receptor message is increased during lactation.

In the lactating rat there is a dramatic increase in food intake that peaks at around day 15 postpartum, a time when pups are near weaning age, yet still fully dependant on maternal nourishment. We examined whether the orexigenic hormone ghrelin plays a role in increasing food intake during lactation. To do this, we compared plasma levels ghrelin, as well as brain and pituitary expression of the growth hormone secretagogue receptor (GHS-R 1a) rats in one of three groups: (1) dams whose litters were removed the day after giving birth (non-lactating); (2) dams whose litters were removed on day 13 postpartum (litter removed), and dams allowed keeping their litters (lactating). On day 15 postpartum, all dams were decapitated and trunk blood collected for plasma analysis of active ghrelin levels. Also, brain and pituitaries were collected and snap frozen using liquid nitrogen and stored at -80 degrees C before mRNA extraction and RT-PCR analysis. Results show no differences in ghrelin concentrations between lactating and non-lactating rats. Hypothalamic and pituitary expression of GHS-R 1a, however, was significantly increased in lactating animals compared to non-lactating animals. Interestingly, litter removed dams had higher levels of plasma ghrelin concentrations than either lactating or non-lactating females. Furthermore, GHS-R mRNA expression in these animals remained elevated in the pituitary but not the hypothalamus. These data suggest that the hypothalamus and pituitary of lactating rats are more sensitive to the effects of ghrelin, and that hypothalamic sensitivity to ghrelin depends on the presence of a suckling litter.

Future stent drug delivery systems.

Drug-eluting stents (DES) with antiproliferative drugs attached via polymers on the stent surface have reduced in-stent restenosis and repeat revascularization compared with bare metal stent (BMS) across nearly all lesion and patient subsets. However, the small number of patients with in-stent restenosis after DES treatment still exists. Furthermore, concerns about long-term safety of DES are raised, particularly regarding the higher-than-expected late-event thrombosis. There is no doubt that the DES will continue to play a pivotal role in the treatment of coronary artery disease, yet future designs need to incorporate features that reduce thrombosis and promote endothelialization along with maintaining the efficacy. This review focuses on novel generation of DES, discussing new programs, including new antiproliferative agents, novel polymeric and non polymeric stents.

Food-Restriction Lowers the Acoustic Startle Response in both Male and Female Rats, and, in Combination with Acute Ghrelin Injection, Abolishes the Expression of Fear-Potentiated Startle in Male Rats.

Food restriction has been reported to reduce anxiety-like behaviour in male rats, whereas the effects of food restriction on anxiety in female rats are less clear. Ghrelin is a peptide hormone produced and secreted in the stomach that stimulates food intake and is considered to play a role in reward and emotional responses such as fear expression. Under food restriction, endogenous ghrelin levels increase. In the present study, we examined the effect of moderate food restriction (80% of ad libitum fed weight), with or without an acute application of a small dose of exogenous ghrelin intended to cause an immediate hunger response, on the expression of the acoustic startle reflex (ASR). This was carried out under basal conditions (baseline ASR to 90- and 95-dB noise bursts), and in the presence of a light cue associated with a mild foot-shock, as measured by fear-potentiated startle, which compares the proportional change in ASR in the presence of the conditioned stimulus. The results obtained show that food-restriction reduces basal ASR in both male and female rats, apart from any concomitant change in motor activity, suggesting that food-restriction reduces anxiety levels in both sexes. In addition, the data show that food-restriction reduces fear-potentiated startle in male but not female rats. Acute ghrelin injection, prior to fear-potentiated startle testing, eliminates the expression of fear-potentiated startle in food-restricted male rats alone, suggesting a role for ghrelin in the reduction of fear expression in food-restricted male rats. These data imply that, although food-restriction decreases anxiety in both sexes, learned fear responses remain intact after food-restriction in female but not male rats.

Investigation of a role for ghrelin signaling in binge-like feeding in mice under limited access to high-fat diet.

Binge eating is defined by the consumption of an excessive amount of food in a short time, reflecting a form of hedonic eating that is not necessarily motivated by caloric need. Foods consumed during a binge are also often high in fat and/or sugar. Ghrelin, signaling centrally via the growth-hormone secretagogue receptor (GHSR), stimulates growth hormone release and appetite. GHSR signaling also enhances the rewarding value of palatable foods and increases the motivation for such foods. As ghrelin interacts directly with dopaminergic reward circuitry, shown to be involved in binge eating, the current studies explored the role of GHSR signaling in a limited access model of binge eating in mice. In this model, mice received either intermittent (INT) or daily (DAILY) access to a nutritionally complete high-fat diet (HFD) for 2h late in the light cycle, alongside 24-h ad libitum chow. In CD-1 mice, 2-h exposure to HFD generated substantial binge-like intake of HFD, as well as a binge-compensate pattern of 24-h daily intake. INT and daily groups did not differ in 2-h HFD consumption, while INT mice maintained stable intake of chow despite access to HFD. GHSR knock-out (KO) and wild-type (WT) mice both binged during HFD access, and exhibited the same binge-compensate pattern. INT GHSR KO mice did not binge as much as WT, while DAILY KO and WT were comparable. Overall, GHSR KO mice consumed fewer calories from HFD, regardless of access condition. GHSR KO mice also had reduced activation of the nucleus accumbens shell, but not core, following HFD consumption. These data support the ability of INT HFD in mice to induce a binge-compensate pattern of intake that emulates select components of binge eating in humans. There also appears to be a role for GHSR signaling in driving HFD consumption under these conditions, potentially via mediation of reward-related circuitry.

Long-term follow-up after percutaneous transluminal coronary angioplasty was not performed based on intravascular ultrasound findings: importance of lumen dimensions.

BACKGROUND: Angiography is limited in determining the anatomic severity of coronary artery stenoses. Clinical decision-making in patients with symptoms and intermediate lesions remains challenging. METHODS AND RESULTS: The current analysis included 300 patients (357 intermediate native artery lesions) in whom intervention was deferred based on intravascular ultrasound (IVUS) findings. Standard clinical, angiographic, and IVUS parameters were collected. Patients were followed for >1 year. Events occurred in 24 patients (8%). They included 2 cardiac deaths, 4 myocardial infarctions, and 18 target-lesion revascularizations (TLR; 12 percutaneous transluminal coronary angiographies and 6 coronary artery bypass grafts; only 3 TLRs occurred within 6 months after the IVUS study). All significant univariate clinical, angiographic, and IVUS parameters (P<0.05) were tested in multivariate models. These included diabetes mellitus, IVUS lesion lumen area, maximum lumen diameter, minimum lumen diameter, plaque area, plaque burden, and area stenosis (AS). No angiographic measurement was significant at P<0.05. The only independent predictors of an event (death, myocardial infarction, or TLR) were IVUS minimum lumen area and AS. The only independent predictors of TLR were diabetes mellitus, IVUS minimum lumen area, and AS. In 248 lesions with a minimum lumen area >/=4.0 mm(2), the event rate was only 4.4% and the TLR rate 2.8%. CONCLUSIONS: Long-term follow-up after IVUS-guided deferred interventions in patients with de novo intermediate native artery lesions showed a low event rate. In patients with a minimum lumen area >/=4.0 mm(2), the event rate was especially low. IVUS imaging is an acceptable alternative to physiological assessment in these patients.

Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up.

BACKGROUND: We have previously reported a virtual absence of neointimal hyperplasia 4 months after implantation of sirolimus-eluting stents. The aim of the present investigation was to determine whether these results are sustained over a period of 1 year. METHODS AND RESULTS: Forty-five patients with de novo coronary disease were successfully treated with the implantation of a single sirolimus-eluting Bx VELOCITY stent in São Paulo, Brazil (n=30, 15 fast release [group I, GI] and 15 slow release [GII]) and Rotterdam, The Netherlands (15 slow release, GIII). Angiographic and volumetric intravascular ultrasound (IVUS) follow-up was obtained at 4 and 12 months (GI and GII) and 6 months (GIII). In-stent minimal lumen diameter and percent diameter stenosis remained essentially unchanged in all groups (at 12 months, GI and GII; at 6 months, GIII). Follow-up in-lesion minimal lumen diameter was 2.28 mm (GIII), 2.32 mm (GI), and 2.48 mm (GII). No patient approached the >/=50% diameter stenosis at 1 year by angiography or IVUS assessment, and no edge restenosis was observed. Neointimal hyperplasia, as detected by IVUS, was virtually absent at 6 months (2+/-5% obstruction volume, GIII) and at 12 months (GI=2+/-5% and GII=2+/-3%). CONCLUSIONS: This study demonstrates a sustained suppression of neointimal proliferation by sirolimus-eluting Bx VELOCITY stents 1 year after implantation.

Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary disease patients: insights from the Arterial Revascularization Therapy Study (ARTS) trial.

BACKGROUND: Our aims were to compare coronary artery bypass grafting (CABG) and stenting for the treatment of diabetic patients with multivessel coronary disease enrolled in the Arterial Revascularization Therapy Study (ARTS) trial and to determine the costs of these 2 treatment strategies. METHODS AND RESULTS: Patients (n=1205) were randomly assigned to stent implantation (n=600; diabetic, 112) or CABG (n=605; diabetic, 96). Costs per patient were calculated as the product of each patient's use of resources and the corresponding unit costs. Baseline characteristics were similar between the groups. At 1 year, diabetic patients treated with stenting had the lowest event-free survival rate (63.4%) because of a higher incidence of repeat revascularization compared with both diabetic patients treated with CABG (84.4%, P<0.001) and nondiabetic patients treated with stents (76.2%, P=0.04). Conversely, diabetic and nondiabetic patients experienced similar 1-year event-free survival rates when treated with CABG (84.4% and 88.4%). The total 1-year costs for stenting and CABG in diabetic patients were $12 855 and $16 585 (P<0.001) and in the nondiabetic groups, $10 164 for stenting and $13 082 for surgery. CONCLUSIONS: Multivessel diabetic patients treated with stenting had a worse 1-year outcome than patients assigned to CABG or nondiabetics treated with stenting. The strategy of stenting was less costly than CABG, however, regardless of diabetic status.

Treatment of in-stent restenosis with excimer laser coronary angioplasty versus rotational atherectomy: comparative mechanisms and results.

BACKGROUND: Atheroablation yields improved clinical results for balloon angioplasty (percutaneous transluminal coronary angioplasty, PTCA) in the treatment of diffuse in-stent restenosis (ISR). METHODS AND RESULTS: We compared the mechanisms and clinical results of excimer laser coronary angioplasty (ELCA) versus rotational atherectomy (RA), both followed by adjunct PTCA; 119 patients (158 ISR lesions) were treated with ELCA+PTCA and 130 patients (161 ISR lesions) were treated with RA+PTCA. Quantitative coronary angiographic and planar intravascular ultrasound (IVUS) measurements were performed routinely. In addition, volumetric IVUS analysis to compare the mechanisms of lumen enlargement was performed in 28 patients with 30 lesions (16 ELCA+PTCA, 14 RA+PTCA). There were no significant between-group differences in preintervention or final postintervention quantitative coronary angiographic or planar IVUS measurements of luminal dimensions. Angiographic success and major in-hospital complications with the 2 techniques were also similar. Volumetric IVUS analysis showed significantly greater reduction in intimal hyperplasia volume after RA than after ELCA (43+/-14 versus 19+/-10 mm(3), P<0.001) because of a significantly higher ablation efficiency (90+/-10% versus 76+/-12%, P = 0.004). However, both interventional strategies had similar long-term clinical outcome; 1-year target lesion revascularization rate was 26% with ELCA+PTCA versus 28% with RA+PTCA (P = NS). CONCLUSIONS: Despite certain differences in the mechanisms of lumen enlargement, both ELCA+PTCA and RA+PTCA can be used to treat diffuse ISR with similar clinical results.

Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome.

BACKGROUND: The angiographic presentation of in-stent restenosis (ISR) may convey prognostic information on subsequent target vessel revascularizations (TLR). METHODS AND RESULTS: We developed an angiographic classification of ISR according to the geographic distribution of intimal hyperplasia in reference to the implanted stent. Pattern I includes focal (< or =10 mm in length) lesions, pattern II is ISR>10 mm within the stent, pattern III includes ISR>10 mm extending outside the stent, and pattern IV is totally occluded ISR. We classified a total of 288 ISR lesions in 245 patients and verified the angiographic accuracy of the classification by intravascular ultrasound. Pattern I was found in 42% of patients, pattern II in 21%, pattern III in 30%, and pattern IV in 7%. Previously recurrent ISR was more frequent with increasing grades of classification (9%, 20%, 34%, and 50% for classes I to IV, respectively; P=0.0001), as was diabetes (28%, 32%, 39%, and 48% in classes I to IV, respectively; P<0.01). Angioplasty and stenting were used predominantly in classes I and II, whereas classes III and IV were treated with atheroablation. Final diameter stenosis ranged between 21% and 28% (P=NS among ISR patterns). TLR increased with increasing ISR class; it was 19%, 35%, 50%, and 83% in classes I to IV, respectively (P<0.001). Multivariate analysis showed that diabetes (odds ratio, 2.8), previously recurrent ISR (odds ratio, 2. 7), and ISR class (odds ratio, 1.7) were independent predictors of TLR. CONCLUSIONS: The introduced angiographic classification is prognostically important, and it may be used for appropriate and early patient triage for clinical and investigational purposes.

One-year follow-up after intravascular ultrasound assessment of moderate left main coronary artery disease in patients with ambiguous angiograms.

OBJECTIVES: The purpose of this study was to correlate angiographic and intravascular ultrasound (IVUS) findings in left main coronary artery (LMCA) disease and identify the predictors of coronary events at one year in patients with LMCA stenoses. BACKGROUND: Significant (> or =50% diameter stenosis [DS]) LMCA disease has a poor long-term prognosis. METHODS: One hundred twenty-two patients who underwent angiographic and IVUS assessment of the severity of LMCA disease and who did not have subsequent catheter or surgical intervention were followed for one year. Standard clinical, angiographic and IVUS parameters were collected. RESULTS: The quantitative coronary angiography (QCA) reference diameter (3.91 +/- 0.76 mm, mean +/- 1 SD) correlated moderately with IVUS (4.25 +/- 0.78 mm, r = 0.492, p = 0.0001). The lesion site minimum lumen diameter (MLD) (2.26 +/- 0.82 mm) by QCA correlated less well with IVUS (2.8 +/- 0.82 mm, r = 0.364, p = 0.0005). The QCA DS measured 42 +/- 16%. During the follow-up period, 4 patients died, none had a myocardial infarction, 3 underwent catheter-based LMCA intervention and 11 underwent bypass surgery. Univariate predictors of events (p < 0.05) were diabetes, presence of another lesion whether treated with catheter-based intervention or untreated with DS > 50% and IVUS reference plaque burden and lesion lumen area, maximum lumen diameter, MLD, plaque area and area stenosis. Using logistic regression analysis diabetes mellitus, an untreated vessel (with a DS > 50%) and IVUS MLD were independent predictors of cardiac events. CONCLUSIONS: In selected patients assessed by IVUS, moderate LMCA disease had a one-year event rate of only 14%. Intravascular ultrasound MLD was the most important quantitative predictor of cardiac events. For any given MLD, the event rate was exaggerated in the presence of diabetes or another untreated lesion (>50% DS).

The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation.

OBJECTIVES: We compared the clinical outcomes following coronary stent implantation in insulin-treated diabetes mellitus (IDDM), non-IDDM patients, and nondiabetic patients. BACKGROUND: Diabetic patients have increased restenosis and late morbidity following balloon angioplasty. The impact of diabetes mellitus (DM), especially IDDM, on in-stent restenosis is not known. METHODS: We studied 954 consecutive patients with native coronary artery lesions treated with elective Palmaz-Schatz stents implantation using conventional coronary angiographic and intravascular ultrasound methodology. Procedural success, major in-hospital complications, and 1-year clinical outcome were compared according to the diabetic status. RESULTS. In-hospital mortality was 2% in IDDM, significantly higher (p <0.02) compared with non-IDDM (0%) and nondiabetics (0.3%). Stent thrombosis did not differ among groups (0.9% in IDDM vs. 0% in non-IDDM and 0% in nondiabetics, p >0.1). During follow-up, target lesion revascularization (TLR) was 28% in IDDM, significantly higher (p <0.05) compared with non-IDDM (17.6%) and nondiabetics (16.3%). Late cardiac event-free survival (including death, myocardial infarction [MI], and any coronary revascularization procedure) was significantly lower (p=0.0004) in IDDM (60%) compared with non-IDDM (70%) and nondiabetic patients (76%). By multivariate analysis, IDDM was an independent predictor for any late cardiac event (OR=2.05, p=0.0002) in general and TLR (odds ratio=2.51, p=0.0001) in particular. CONCLUSIONS. In a large consecutive series of patients treated by elective stent implantation, IDDM patients were at higher risk for in-hospital mortality and subsequent TLR and, as a result, had a significantly lower cardiac event-free survival rate. On the other hand, acute and long-term procedural outcome was found to be similar for non-IDDM compared with nondiabetic patients.

Thrombus aspiration in ST-segment elevation myocardial infarction.

Primary percutaneous coronary intervention (PCI) has become the treatment of choice in patients with ST-segment elevation myocardial infarction (STEMI) throughout the last years. A significant number of studies have demonstrated a morbidity and mortality benefit over thrombolysis, which has been attributed to better coronary perfusion in patients undergoing primary PCI. Even though it usually achieves normal flow in the affected epicardial vessel, myocardial reperfusion is not fully restored in a significant percentage of patients. This is commonly the result of distal thrombus embolization with subsequent impairment of myocardial microcirculation. Recognition of this has led to the development of a number of devices with different mechanisms, including thrombus aspiration catheters, in order to reduce distal embolization and therefore improve myocardial perfusion. Recent studies indeed demonstrate that the use of such devices offer additional clinical advantage in patients undergoing primary PCI in comparison to the standard PCI, whether in other trials it could not be proved. This paper focuses on general mechanisms of thrombus formation and discusses favorable and unfavorable studies towards thrombus aspiration in STEMI and its main aspects and it comes up with specific subjects that could benefit or not from the procedure of thrombus aspiration.

Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements.

BACKGROUND: Fractional flow reserve (FFR) is a measure of coronary stenosis severity that is based on pressure measurements obtained at maximal hyperemia. The most widely used pharmacologic stimulus for maximal coronary hyperemia is adenosine, administered either as a continuous intravenous (IV) infusion or intracoronary (IC) bolus. IV adenosine has more side effects and is more costly than IC adenosine but has a more stable and prolonged hyperemic effect. METHODS: We compared the efficacy of IC and IV adenosine administration for the measurement of FFR in a multicenter trial. Fifty-two patients with 60 lesions underwent determination of FFR with both IV and IC adenosine. IV adenosine was administered as a continuous infusion at a rate of 140 microgram/kg per minute until a steady state hyperemia was achieved. IC adenosine boluses were administered at a dose of 15 to 20 microgram in the right and 18 to 24 microgram in the left coronary artery. FFR was calculated as the ratio of the distal coronary pressure (from pressure guide wire) to the aortic pressure (guide catheter) at maximal hyperemia. RESULTS: A total of 26 left anterior descending, 23 right, 9 left circumflex, and 3 left main coronary arteries were evaluated. Mean percent stenosis for both groups was 55.8% +/- 23.6% (range 0% to 95%), and mean FFR was 0.78 +/- 0.15 (range 0.41 to 0.98). There was a strong and linear correlation between FFR measurements with IV and IC adenosine (R = 0.978, y = 0. 032 + 0.964x, P <.001). The agreement between the 2 sets of measurements was also high, with a mean difference in FFR of -0.004 +/- 0.03. However, a small random scatter in both directions of FFR measurements was noted with 5 lesions (8.3%) where FFR with IC adenosine was higher by 0.05 or more compared with IV infusions, suggesting a suboptimal hyperemic response in these patients. Changes in heart rate and blood pressure were significantly higher with IV adenosine. Two patients with IV, but none with IC adenosine, had severe side effects (bronchospasm and severe nausea). CONCLUSION: These results suggest that IC adenosine is equivalent to IV infusion for the determination of FFR in the majority of patients. However, in a small percentage of cases, coronary hyperemia was suboptimal with IC adenosine.

Influence of patient age on acute and late clinical outcomes following Palmaz-Schatz coronary stent implantation.

Procedural success may be lower and complication rates higher after balloon angioplasty in older patients. Elective stent implantation improves procedural outcome in younger patients; however, few series have specifically analyzed the octogenarian population. Therefore, we studied 2,534 consecutive patients (3,965 native coronary artery stenoses) who were treated electively with Palmaz-Schatz stents and divided them into 3 groups: (1) < or = 70 years old (n = 1,805), (2) 71 to 80 years old (elderly, n = 607), and (3) > 80 years old (octogenarian, n = 122). Major in-hospital complications (death, myocardial infarction, and urgent bypass surgery) were significantly higher in the octogenarians than in the elderly and patients < or = 70 years of age (4.5% vs 2.0% and 1.5%; p = 0.001). At 1-year follow-up, cardiac events (death, nonfatal myocardial infarction, and need for any revascularization) did not differ among groups; however, there was a stepwise increase in late death in octogenarians (5%) compared with elderly patients (2%) and patients aged < or = 70 years (1%) (p = 0.001). Target lesion revascularization was similar among the groups (11% in octogenarian vs 14% in elderly and 15% in patients < or = 70 years, p = 0.791). By multivariate logistic regression analysis, age was an independent predictor of late mortality (odds ratio 1.05, p = 0.0001), but not a predictor of target lesion revascularization. Stent implantation in octogenarians is associated with (1) more acute complications, (2) a higher in-hospital mortality, (3) a higher late mortality, and (4) a target lesion revascularization similar to younger patients.

Acute and long-term results of an intravascular ultrasound-guided percutaneous transluminal coronary angioplasty/provisional stent implantation strategy.

Two hundred eighty-four consecutive patients with 438 native coronary artery stenoses were enrolled prospectively in a study of intravascular ultrasound (IVUS)-guided provisional percutaneous transluminal coronary angioplasty (PTCA): (1) IVUS-guided, aggressive lesion-site media-to-media balloon sizing, (2) IVUS assessment of residual lumen dimensions to identify optimal PTCA results (minimum lumen area > or =65% of the average of the proximal and distal reference lumen areas or > or =6.0 mm2 and no major dissection), and (3) liberal stent crossover. Overall, 206 stenoses in 134 patients were treated with PTCA alone. Reasons for crossover were flow-limiting or lumen compromising dissections in 28% of patients or a suboptimal IVUS minimum lumen area in 72% of patients. Sixty-three stenoses (27%) were treated with Gianturco-Roubin stents and 169 (73%) with Palmaz-Schatz stents. The clinical success rate and major in-hospital complication rates were similar in the optimal PTCA and stent crossover groups. At 1 year, 42 patients (15%) with 53 stenoses (12%) underwent revascularization: 8% of stenoses in the PTCA group and 16% in the stent crossover group. In approximately half of the patients treated using an IVUS guided aggressive PTCA strategy, stent implantation could be avoided without sacrificing an increase in acute complications or late clinical outcome. This provides an alternative strategy for interventionalists less inclined to use routine elective stenting.

Clinical, intravascular ultrasound, and quantitative angiographic determinants of the coronary flow reserve before and after percutaneous transluminal coronary angioplasty.

This study evaluated the clinical, intravascular ultrasound (IVUS), and angiographic determinants of the coronary flow reserve (CFR) as measured by guidewire Doppler velocimetry. Using standard methodology, 86 consecutive patients were studied before intervention (n = 73 patients, including the assessment of intermediate stenoses) and/or after intervention (n = 39 patients, including after percutaneous transluminal coronary angioplasty (PTCA) in 27 and post-Palmaz-Schatz stent placement + high-pressure adjunct PTCA in 12). Only 5 patients were studied before intervention, post-PTCA, and poststent. Univariate and multivariate clinical, quantitative coronary angiography (QCA), and IVUS correlates of the CFR were evaluated. There was a linear relation between CFR and IVUS minimum lumen cross-sectional area (CSA): r = 0.771, p <0.0001 for the overall cohort; r = 0.831, p <0.0001 before intervention; r = 0.514, p = 0.0061 post-PTCA; and r = 0.623, p = 0.0306 poststent placement. Overall, an IVUS minimum lumen CSA of > or = 4.0 mm2 had a diagnostic accuracy of 89% in identifying a CFR of > or = 2.0. This diagnostic accuracy increased slightly to 92% when only the preintervention observations were considered. Using multivariate linear regression analysis, the independent determinants of the CFR in the overall cohort of 112 observations were IVUS minimum lumen CSA (p <0.0001), angiographic lesion length (p = 0.0101), and diabetes mellitus (p = 0.0371): r2 = 0.6224. When the subset of preintervention observations were analyzed separately, the independent determinants of the CFR were minimum lumen CSA (p <0.0001) and angiographic lesion length (p = 0.0095); r2 = 0.7176. Thus, the major determinants of the CFR in patients with coronary artery disease are lumen compromise (which is best assessed by the IVUS measurement of the minimum lumen CSA) and lesion length. A minimum lumen CSA > or = 4.0 mm2 has a high diagnostic accuracy in predicting a CFR > or = 2.0, especially before intervention.