Translating proof-of-concept for platelet slip into improved antithrombotic therapeutic regimens.

Platelets are central to thrombosis. Research at the intersection of biological and physical sciences provides proof-of-concept for shear rate-dependent platelet slip at vascular stenosis and near device surfaces. Platelet slip extends the observed biological "slip-bonds" to the boundary of functional gliding without contact. As a result, there is diminished engagement of the coagulation cascade by platelets at these surfaces. Comprehending platelet slip would more precisely direct antithrombotic regimens for different shear environments, including for percutaneous coronary intervention (PCI). In this brief report we promote translation of the proof-of-concept for platelet slip into improved antithrombotic regimens by: (1) reviewing new supporting basic biological science and clinical research for platelet slip; (2) hypothesizing the principal variables that affect platelet slip; (3) applying the consequent construct model in support of-and in some cases to challenge-relevant contemporary guidelines and their foundations (including for urgent, higher-risk PCI); and (4) suggesting future research pathways (both basic and clinical). Should future research demonstrate, explain and control platelet slip, then a paradigm shift for choosing and recommending antithrombotic regimens based on predicted shear rate should follow. Improved clinical outcomes with decreased complications accompanying this paradigm shift for higher-risk PCI would also result in substantive cost savings.

Validated model of platelet slip at stenosis and device surfaces.

Platelets are central to thrombosis. However, it is unknown whether platelets slip at vascular or device surfaces. The presence of platelet slip at a surface would interrupt physical contact between the platelet and that surface, and therefore diminish adhesion and thrombosis. Unfortunately, no existing technology can directly measure platelet slip in a biological environment. The objective of this study was to explore whether microspheres-modeling platelets-slip at different vascular and device surfaces in an acrylic scaled-up model coronary artery. The microspheres (3.12 µm diameter) were suspended in a transparent glycerol/water experimental fluid, which flowed continuously at Reynolds numbers typical of coronary flow (200-400) through the model artery. We placed a series of axisymmetric acrylic stenoses (cross-sectional area reduction [CSAr], 20-90%) into the model artery, both without and with a central cylinder present (modeling a percutaneous interventional guide wire, and with a scaled-up Doppler catheter mounted upstream). We used laser Doppler velocimetry (LDV) to measure microsphere velocities within, proximal and distal to each stenosis, and compared to computer simulations of fluid flow with no-slip. For validation, we replaced the acrylic with paraffin stenoses (more biologically relevant from a surface roughness perspective) and then analyzed the signal recorded by the scaled-up Doppler catheter. Using the LDV, we identified progressive microsphere slip proportional to CSAr inside entrances for stenoses ≥60% and ≥40% without and with cylinder present, respectively. Additionally, microsphere slip occurred universally along the cylinder surface. Computer simulations indicated increased fluid shear rates (velocity gradients) at these particular locations, and logistic regression analysis comparing microsphere slip with fluid shear rate resulted in a c-index of 0.989 at a cut-point fluid shear rate of (10.61 [cm-1]×mean velocity [cm×sec-1]). Moreover, the presence of the cylinder caused disordering of microsphere shear rates distal to higher grade stenoses, indicating a disturbance in their flow. Finally, despite lower precision, the signal recorded by the scaled-up Doppler catheter nonetheless indicated slip at the entry into and at most locations distal to the 90% stenosis. Our validated model establishes proof of concept for platelet slip, and platelet slip explains several important basic and clinical observations. If technological advances allow confirmation in a true biologic environment, then our results will likely influence the development of shear-dependent antiplatelet drugs. Also, adding shear rate information, our results provide a direct experimental fluid dynamic foundation for antiplatelet-focused antithrombotic therapy during coronary interventions directed towards higher grade atherosclerotic stenoses.

Association of aortic stiffness and wave reflections with coronary flow reserve in women without obstructive coronary artery disease: An ancillary study from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Increased aortic stiffness and reduced coronary flow reserve (CFR) independently predict adverse outcomes. But information about relationships between arterial properties and CFR in subjects without obstructive coronary artery disease (CAD) is limited. METHODS: CFR was measured (Doppler flow wire and intracoronary adenosine) in 50 women (age 53 ± 11 years) with symptoms and signs of myocardial ischemia without obstructive CAD. Aortic pulse wave velocity (aPWV), a measure of aortic stiffness, was obtained via catheter pullback; radial artery pressure waves were measured by applanation tonometry and central aortic pressure synthesized. RESULTS: Overall, CFR (mean 2.61 ± 0.47) was significantly correlated with aPWV (r = -0.51), pulse wave amplification (r = 0.45), augmented pressure (r = -0.48), augmentation index (AIx, r = -0.44), aortic systolic pressure (r = -0.49), left ventricular wasted energy (LVEw, r = -0.47) (all P < .001), systolic pressure time index (r = -0.37, P < .008), and rate pressure product (r = -0.29, P < .04). In the multiple regression model including aPWV, CFR was still significantly correlated with aPWV (P < .008) and aortic systolic pressure (P < .01). No other measures contributed significant additional information. Women with CFR ≤2.5 versus those with CFR >2.5 had greater aPWV (894 ± 117 vs 747 ± 93 cm/s, P < .001), augmented pressure (14 ± 4.9 vs 11 ± 4.1 mmHg, P < .008), AIx (32 ± 6.6 vs 27 ± 6.6%, P < .003), LVEw (30 ± 12 vs 21 ± 10 dyne-s/cm(2) × 10(2), P < .02) and reduced pulse pressure amplification (1.20 ± .07 vs 1.26 ± .10, P < .008) and pressure wave travel time (133 ± 7.3 vs 138 ± 6.9 milliseconds, P < .04). CONCLUSIONS: Among symptomatic women without obstructive CAD, CFR was inversely related to aortic systolic pressure and indices of aortic stiffness. These changes in arterial properties increase left ventricular afterload requiring the ventricle to generate additional, but wasted, energy that increases indices of myocardial oxygen demand, reduces CFR and increases vulnerability to ischemia.

An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: a substudy from the National Heart, Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).

AIMS: Using intravascular ultrasound (IVUS), we sought to characterize coronary morphology in women with chest pain without major epicardial obstructive coronary artery disease (CAD). We have previously observed an unexpectedly high rate of adverse outcomes among women with chest pain and normal or insignificant obstructive CAD. Information about the presence and characteristics of coronary atherosclerosis in these women could provide insight into the mechanisms related to increased risk, as well as improved diagnosis, prevention, and treatment. METHODS: Women (n = 100) with suspected ischemia without obstructive CAD (>50% stenosis) underwent IVUS of a left coronary segment with measurements by a core lab masked to clinical and angiographic findings. RESULTS: Angiograhic core lab analysis found 69.6% of patients had no (≤20%) and 30.4% had minimal (20-<50%) CAD. IVUS segmental images were interpretable by the core lab in 92 women, with 19 (21%) having no atherosclerosis (intimal-medial thickness <0.5 mm). In the remaining 73 women (79%), percent atheroma volume was 27 ± 8% and mean maximum plaque thickness was 0.53 ± 0.22 mm. Thirty-eight women with atherosclerosis (53%) had ≥30% of interrogated vessel involved. The average vessel involvement was 40%, and the maximum plaque thickness was 1.27 mm. The number of risk factors strongly correlated with percent atheroma volume (r = 0.53, P < 0.0001) and percent vessel involvement (r = 0.51, P < 0.0001), with the strongest independent predictor of both being age. Remodeling was assessed in 59/73 women (81%), and 73% had evidence of positive remodeling. CONCLUSIONS: In symptomatic women without significant luminal obstructive CAD, we observed a high prevalence of atherosclerosis with positive remodeling and preserved lumen size. These findings may help explain increased risk and emphasize need for improved diagnostic and treatment options for women with concealed CAD.

Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease.

CONTEXT: Hypertension guidelines advocate treating systolic blood pressure (BP) to less than 130 mm Hg for patients with diabetes mellitus; however, data are lacking for the growing population who also have coronary artery disease (CAD). OBJECTIVE: To determine the association of systolic BP control achieved and adverse cardiovascular outcomes in a cohort of patients with diabetes and CAD. DESIGN, SETTING, AND PATIENTS: Observational subgroup analysis of 6400 of the 22,576 participants in the International Verapamil SR-Trandolapril Study (INVEST). For this analysis, participants were at least 50 years old and had diabetes and CAD. Participants were recruited between September 1997 and December 2000 from 862 sites in 14 countries and were followed up through March 2003 with an extended follow-up through August 2008 through the National Death Index for US participants. INTERVENTION: Patients received first-line treatment of either a calcium antagonist or beta-blocker followed by angiotensin-converting enzyme inhibitor, a diuretic, or both to achieve systolic BP of less than 130 and diastolic BP of less than 85 mm Hg. Patients were categorized as having tight control if they could maintain their systolic BP at less than 130 mm Hg; usual control if it ranged from 130 mm Hg to less than 140 mm Hg; and uncontrolled if it was 140 mm Hg or higher. MAIN OUTCOME MEASURES: Adverse cardiovascular outcomes, including the primary outcomes which was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: During 16,893 patient-years of follow-up, 286 patients (12.7%) who maintained tight control, 249 (12.6%) who had usual control, and 431 (19.8%) who had uncontrolled systolic BP experienced a primary outcome event. Patients in the usual-control group had a cardiovascular event rate of 12.6% vs a 19.8% event rate for those in the uncontrolled group (adjusted hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.25-1.71; P < .001). However, little difference existed between those with usual control and those with tight control. Their respective event rates were 12.6% vs 12.7% (adjusted HR, 1.11; 95% CI, 0.93-1.32; P = .24). The all-cause mortality rate was 11.0% in the tight-control group vs 10.2% in the usual-control group (adjusted HR, 1.20; 95% CI, 0.99-1.45; P = .06); however, when extended follow-up was included, risk of all-cause mortality was 22.8% in the tight control vs 21.8% in the usual control group (adjusted HR, 1.15; 95% CI, 1.01-1.32; P = .04). CONCLUSION: Tight control of systolic BP among patients with diabetes and CAD was not associated with improved cardiovascular outcomes compared with usual control. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00133692.

Effects of arterial stiffness, pulse wave velocity, and wave reflections on the central aortic pressure waveform.

Brachial systolic and pulse blood pressures (BPs) are better predictors of adverse cardiovascular (CV) events than diastolic BP in individuals older than 50 years. The principal cause of increased systolic and pulse BP is increased stiffness of the elastic arteries as a result of degeneration and hyperplasia of the arterial wall. Recent studies have shown that central BP, the pressure exerted on the heart, brain, and kidneys, is a better predictor of CV risk than brachial BP. As stiffness increases, reflected wave amplitude increases and augments pressure in late systole, producing an increase in left ventricular afterload and myocardial oxygen demand. Vasoactive drugs have little direct effect on large human elastic arteries but can markedly modify wave reflection by altering stiffness of the muscular arteries and changing pulse wave velocity of the reflected wave from the periphery to the heart. Vasodilators decrease the amplitude and increase the travel time (or delay) of the reflected wave, causing a generalized decrease in systolic BP. The decrease in systolic BP brought about by this mechanism is grossly underestimated when systolic BP is measured in the brachial artery.

Effectiveness and safety of reduced-dose enoxaparin in non-ST-segment elevation acute coronary syndrome followed by antiplatelet therapy alone for percutaneous coronary intervention.

Adjunctive pharmacotherapy for stabilizing patients with acute coronary syndrome/non-ST-segment elevation myocardial infarction (ACS/NSTEMI) and for subsequent percutaneous coronary intervention (PCI) includes a combination of anticoagulant and antiplatelet agents. However, all anticoagulants have been shown to paradoxically activate platelets and induce other prothrombotic activities, increase bleeding, and/or cause thrombocytopenia. A single-center experience of 1,400 consecutive patients presenting with ACS/NSTEMI managed using decreased-dose anticoagulation (enoxaparin) and dual-antiplatelet therapy (aspirin and clopidogrel) followed by triple-antiplatelet therapy (aspirin, clopidogrel, and eptifibatide) alone, without additional anticoagulation, during subsequent PCI was retrospectively analyzed. Patients received a median of 3 doses of enoxaparin at a mean dose of 0.51 mg/kg. The final dose was administered 10.8 hours (mean) before PCI. Medical management "failed" in 8 patients (0.6%), and each required emergency PCI. The overall technical success rate was 99.8%. One major adverse clinical event (0.1%) occurred within 24 hours after PCI. Non-Q-wave myocardial infarction occurred in 1.8% of patients, major and minor bleeding complications, in 0.1% and 2.1%, respectively, and thrombocytopenia in 1.3%. Five additional major adverse clinical events (0.4%) occurred within 30 days after PCI, none involving target vessel thrombosis. In conclusion, for patients with ACS/NSTEMI, reduced-dose enoxaparin combined with dual-antiplatelet therapy followed by triple-antiplatelet therapy alone (without additional anticoagulation) during subsequent PCI appears safe and may prove efficacious.

Baseline Hemodynamics and Response to Contrast Media During Diagnostic Cardiac Catheterization Predict Adverse Events in Heart Failure Patients.

BACKGROUND: Contrast media administered during cardiac catheterization can affect hemodynamic variables. However, little is documented about the effects of contrast on hemodynamics in heart failure patients or the prognostic value of baseline and changes in hemodynamics for predicting subsequent adverse events. METHODS AND RESULTS: In this prospective study of 150 heart failure patients, we measured hemodynamics at baseline and after administration of iodixanol or iopamidol contrast. One-year Kaplan-Meier estimates of adverse event-free survival (death, heart failure hospitalization, and rehospitalization) were generated, grouping patients by baseline measures of pulmonary capillary wedge pressure (PCWP) and cardiac index (CI), and by changes in those measures after contrast administration. We used Cox proportional hazards modeling to assess sequentially adding baseline PCWP and change in CI to 5 validated risk models (Seattle Heart Failure Score, ESCAPE [Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness], CHARM [Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity], CORONA [Controlled Rosuvastatin Multinational Trial in Heart Failure], and MAGGIC [Meta-Analysis Global Group in Chronic Heart Failure]). Median contrast volume was 109 mL. Both contrast media caused similarly small but statistically significant changes in most hemodynamic variables. There were 39 adverse events (26.0%). Adverse event rates increased using the composite metric of baseline PCWP and change in CI (P<0.01); elevated baseline PCWP and decreased CI after contrast correlated with the poorest prognosis. Adding both baseline PCWP and change in CI to the 5 risk models universally improved their predictive value (P≤0.02). CONCLUSIONS: In heart failure patients, the administration of contrast causes small but significant changes in hemodynamics. Calculating baseline PCWP with change in CI after contrast predicts adverse events and increases the predictive value of existing models. Patients with elevated baseline PCWP and decreased CI after contrast merit greatest concern.

Correction: Effects of Verapamil SR and Atenolol on 24-Hour Blood Pressure and Heart Rate in Hypertension Patients with Coronary Artery Disease: An International Verapamil SR-Trandolapril Ambulatory Monitoring Substudy.

[This corrects the article DOI: 10.1371/journal.pone.0122726.].

Elective percutaneous coronary intervention using broad-spectrum antiplatelet therapy (eptifibatide, clopidogrel, and aspirin) alone, without scheduled unfractionated heparin or other antithrombin therapy.

BACKGROUND: Adjunctive pharmacotherapy during percutaneous coronary intervention (PCI) has historically consisted of a regimen of antiplatelet agents accompanied by an antithrombin agent, typically unfractionated heparin. Paradoxically, unfractionated heparin may activate platelets, induce other pro-thrombotic activities, increase bleeding complications, and cause thrombocytopenia. To optimize patient care and avoid the potential risks of unfractionated heparin in patients undergoing elective PCI, one of the authors began to use adjunctive pharmacotherapy consisting of broad-spectrum antiplatelet therapy alone, without scheduled unfractionated heparin or other antithrombin therapy. METHODS: Five hundred consecutive patients undergoing scheduled, elective PCI (stent deployment, cutting balloon atherotomy, conventional balloon angioplasty, or high-speed rotational atherectomy) received adjunctive pharmacotherapy consisting of eptifibatide, clopidogrel, and aspirin. RESULTS: The technical success rate was 100%. During the first 24 hours, there were no major adverse clinical events. Non-Q-wave myocardial infarction occurred in 1.6% of patients, major and minor bleeding complications in 0.2% and 0.6%, respectively, and thrombocytopenia in 0.6%. During the first 30 days, there was 1 (0.2%) major adverse clinical event. CONCLUSIONS: For elective PCI, adjunctive pharmacotherapy consisting of broad-spectrum antiplatelet therapy alone, without scheduled unfractionated heparin or other antithrombin therapy, appears to be safe and may prove to be efficacious.

Effects of verapamil SR and atenolol on 24-hour blood pressure and heart rate in hypertension patients with coronary artery disease: an international verapamil SR-trandolapril ambulatory monitoring substudy.

Elevated nighttime blood pressure (BP) and heart rate (HR), increased BP and HR variability, and altered diurnal variations of BP and HR (nighttime dipping and morning surge) in patients with systemic hypertension are each associated with increased adverse cardiovascular events. However, there are no reports on the effect of hypertension treatment on these important hemodynamic parameters in the growing population of hypertensive patients with atherosclerotic coronary artery disease (CAD). This was a pre-specified subgroup analysis of the INternational VErapamil SR-Trandolapril STudy (INVEST), which involved 22,576 clinically stable patients aged ≥ 50 years with hypertension and CAD randomized to either verapamil SR- or atenolol-based hypertension treatment strategies. The subgroup consisted of 117 patients undergoing 24-hour ambulatory monitoring at baseline and after 1 year of treatment. Hourly systolic and diastolic BP (SBP and DBP) decreased after 1 year for both verapamil SR- and atenolol-based treatment strategies compared with baseline (P<0.0001). Atenolol also decreased hourly HR (P<0.0001). Both treatment strategies decreased SBP variability (weighted standard deviation: P = 0.012 and 0.021, respectively). Compared with verapamil SR, atenolol also increased the prevalence of BP and HR nighttime dipping among prior non-dippers (BP: OR = 3.37; 95% CI: 1.26-8.97 P = 0.015; HR: OR = 4.06; 95% CI: 1.35-12.17; P = 0.012) and blunted HR morning surge (+2.8 vs. +4.5 beats/min/hr; P = 0.019). Both verapamil SR- and especially atenolol-based strategies resulted in favorable changes in ambulatory monitoring parameters that have been previously associated with increased adverse cardiovascular events.

Efficacy and safety of minimal dose (< or =1,000 units) unfractionated heparin with abciximab in percutaneous coronary intervention.

Abciximab decreases adverse cardiac ischemic events, and in some subgroups, decreases the need for revascularization after percutaneous coronary intervention (PCI). However, abciximab may cause bleeding complications and thrombocytopenia after PCI. We hypothesized that the efficacy and safety of PCI would be maintained, if not improved, when performed using abciximab accompanied by only minimal doses (< or =1,000 U) of unfractionated heparin. In this prospectively designed observational study, we assessed 500 consecutive patients who underwent PCI, consisting of either stent deployment or high-speed rotational atherectomy, and who received abciximab accompanied by only a minimal dose of unfractionated heparin, as directed by a novel dosing strategy: (1) if the patient was previously receiving an infusion of heparin, then it was terminated upon arrival to the cardiac catheterization laboratory, and no further heparin was administered; or (2) if the patient was not receiving an infusion of heparin, then a single bolus infusion of 1,000 U was administered after establishment of vascular access. The median activated clotting time for the patients during PCI was 168 seconds (25% quartiles, 153 to 185). The technical success rate was 99.8%. There were no major adverse clinical events during the 24 hours after PCI. The incidence of non-Q-wave myocardial infarction was 1.6%. The incidences of major and minor bleeding complications were 0.2% and 3.6%, respectively, and the incidence of thrombocytopenia was 2.2%. During the 30 days after PCI, there was 1 major adverse clinical event (0.2%). During the 1 year after PCI, among the remaining patients, there were 92 adverse events (18.4%). We conclude that, in the context of historical data, the efficacy and safety of PCI using either stent deployment or high-speed rotational atherectomy is maintained, if not improved, when performed using abciximab accompanied by only minimal doses of unfractionated heparin.

Increased wave reflection and ejection duration in women with chest pain and nonobstructive coronary artery disease: ancillary study from the Women's Ischemia Syndrome Evaluation.

OBJECTIVE: Wave reflections augment central aortic SBP and increase systolic pressure time integral (SPTI) thereby increasing left ventricular (LV) afterload and myocardial oxygen (MVO2) demand. When increased, such changes may contribute to myocardial ischemia and angina pectoris, especially when aortic diastolic time is decreased and myocardial perfusion pressure jeopardized. Accordingly, we examined pulse wave reflection characteristics and diastolic timing in a subgroup of women with chest pain (Women's Ischemia Syndrome Evaluation, WISE) and no obstructive coronary artery disease (CAD). METHODS: Radial artery BP waveforms were recorded by applanation tonometry, and aortic BP waveforms derived. Data from WISE participants were compared with data from asymptomatic women (reference group) without chest pain matched for age, height, BMI, mean arterial BP, and heart rate. RESULTS: Compared with the reference group, WISE participants had higher aortic SBP and pulse BP and ejection duration. These differences were associated with increased augmentation index and reflected pressure wave systolic duration. These modifications in wave reflection characteristics were associated with increased SPTI and wasted LV energy (Ew) and a decrease in pulse pressure amplification, myocardial viability ratio, and diastolic pressure time fraction. CONCLUSION: WISE participants with no obstructive CAD have changes in systolic wave reflections and diastolic timing that increase LV afterload, MVO2 demand, and Ew with the potential to reduce coronary artery perfusion. These alterations in cardiovascular function contribute to an undesirable mismatch in the MVO2 supply/demand that promotes ischemia and chest pain and may contribute to, or increase the severity of, future adverse cardiovascular events.

Detailed analysis of polymer response to delivery balloon expansion of drug-eluting stents versus bare metal stents.

AIMS: We sought to describe the response of the polymer surface of drug-eluting stents (DES) to delivery balloon expansion, including quantitation of any resulting detached microparticles. METHODS AND RESULTS: We expanded the US Food and Drug Administration (FDA)-approved first- and second-generation DES in a vacuum filtration system and used optical and scanning electron microscopy to image the polymer surface, filters and delivery balloons. DES were expanded under a range of conditions, from in vitro conditions used for FDA regulatory submissions to human in vivo conditions. Dispersive Raman spectroscopy was used for definitive identification of microparticles. All polymer surfaces were topographically disturbed over an average of 4.6%-100% of the surface area imaged. Disturbances ranged from deformation (including peeling) to complete delamination. The dimensions of detached microparticles were 2-350 µm. The extent and nature of surface disturbances and microparticles were primarily a function of polymer composition (p<0.001 for 8/10 disturbance types/locations) and were independent of expansion condition (p=0.100 to 0.989 for 9/10 disturbance types/locations). CONCLUSIONS: Balloon expansion of first- and second-generation DES disturbs the polymer surface and can cause detachment of microparticles; each is functionally related to the specific polymer but not to expansion condition. Disturbance "roughness" and detached microparticles may contribute to DES limitations.

Effect of phosphodiesterase type 5 inhibition on microvascular coronary dysfunction in women: a Women's Ischemia Syndrome Evaluation (WISE) ancillary study.

BACKGROUND: Microvascular coronary dysfunction (MCD) is associated with symptoms and signs of ischemia, and also adverse outcomes in women without macrovascular obstructive coronary artery disease (M-CAD). Although MCD can be quantified using coronary flow reserve (CFR), treatment is poorly defined. HYPOTHESIS: Phosphodiesterase type 5 (PDE-5) inhibition acutely improves MCD in these women. METHODS: The subjects were 23 symptomatic women (age 54 ± 11 y) participating in an ancillary study of the Women's Ischemia Syndrome Evaluation with baseline CFR ≤3.0 (Doppler flow wire and intracoronary adenosine) and without M-CAD. Coronary flow reserve was remeasured 45 minutes after PDE-5 inhibition (100 mg oral sildenafil). The primary measure of interest was change in CFR adjusted for baseline variables. RESULTS: The relationship between log(2)-transformed CFR post-PDE-5 inhibition (adjusted) and baseline was different from the line of identity (slope: 0.55 vs 1.0, P = 0.008; intercept: 0.73 vs 0.0, P = 0.01), indicating that PDE-5 inhibition improves CFR and the lower the baseline CFR, the greater the response. Among women with baseline CFR ≤2.5 (n = 11), CFR increased from 2.1 ± 0.2 to 2.7 ± 0.6 (P = 0.006). For women with baseline CFR >2.5 (n = 12), CFR did not change (3.1 ± 0.3 to 3.0 ± 0.6; P = 0.70). CONCLUSIONS: For women with symptoms and signs of ischemia and no M-CAD, PDE-5 inhibition is associated with acute improvement in CFR, and the effect concentrates among those with CFR ≤2.5. If these acute effects are sustained, then PDE-5 inhibition would provide a rational strategy for management of MCD in symptomatic women without M-CAD. The longer-term effects warrant study in a randomized trial using a sustained-acting PDE-5 inhibitor.

Pulse wave analysis of the aortic pressure waveform in severe left ventricular systolic dysfunction.

BACKGROUND: The effect of moderate left ventricular systolic dysfunction (LVSD) on ventricular/vascular coupling and the aortic pressure waveform (AoPW) has been well described, but the effect of severe LVSD has not. METHODS AND RESULTS: We used noninvasive, high-fidelity tonometry of the radial artery and a mathematical transfer function to generate the AoPW in 25 treated patients with LVSD (mean LV ejection fraction, 24+/-8.8%; range, 11% to 40%; 21 patients <30%). Pulse wave analysis of the AoPW was used to characterize ventricular/vascular coupling and compared with pulse wave analysis performed in 25 normal subjects matched for age, gender, height, body mass index, and heart rate. Measurements obtained using pulse wave analysis in LVSD patients indicated features of poor LV stroke performance and also reduced indices of arterial stiffness: increased travel time of the pressure wave (147+/-10 ms versus 132+/-21 ms; P<0.001); decreased systolic duration of reflected wave (134+/-24 ms versus 167+/-26 ms; P<0.001); ejection duration (277+/-22 ms versus 299+/-25 ms; P<0.008); percent systolic duration (32+/-5.3% versus 35+/-4.0%; P<0.02); aortic systolic pressure (100+/-16 mm Hg versus 121+/-16 mm Hg; P<0.001); unaugmented pressure (24+/-6.3 mm Hg versus 32+/-6.4 mm Hg; P<0.001); augmented pressure (4.8+/-3.1 mm Hg versus 9.6+/-4.5 mm Hg; P<0.001); pulse pressure (28+/-7.4 mm Hg versus 42+/-9.5 mm Hg; P<0.001); augmentation index (12+/-6.6% versus 23+/-7.6%; P<0.006); wasted LV effort (5.3+/-2.8x10(2) dyne sec/cm(2) versus 17+/-10x10(2) dyne sec/cm(2); P<0.001); systolic pressure time index (17+/-4.1x10(2) mm Hg-sec/min versus 23+/-4.2x10(2) mm Hg sec/min; P<0.001); and pressure systolic area (383+/-121 mm Hg sec/min versus 666+/-150 mm Hg sec/min; P<0.001). CONCLUSIONS: Severe LVSD causes measurable changes in the AoPW. Standardization of AoPW findings in LVSD patients may allow for the clinical use of radial artery pulse wave analysis to noninvasively determine the severity of dysfunction and aid in logical therapy.

Blood pressure and outcomes in very old hypertensive coronary artery disease patients: an INVEST substudy.

BACKGROUND: Our understanding of the growing population of very old patients (aged >or=80 years) with coronary artery disease and hypertension is limited, particularly the relationship between blood pressure and adverse outcomes. METHODS: This was a secondary analysis of the INternational VErapamil SR-Trandolapril STudy (INVEST), which involved 22,576 clinically stable hypertensive coronary artery disease patients aged >or=50 years. The patients were grouped by age in 10-year increments (aged >or=80, n=2180; 70-<80, n=6126; 60-<70, n=7602; <60, n=6668). Patients were randomized to either verapamil SR- or atenolol-based treatment strategies, and primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: At baseline, increasing age was associated with higher systolic blood pressure, lower diastolic blood pressure, and wider pulse pressure (P <.001). Treatment decreased systolic, diastolic, and pulse pressure for each age group. However, the very old retained the widest pulse pressure and the highest proportion (23.6%) with primary outcome. The adjusted hazard ratio for primary outcomes showed a J-shaped relationship among each age group with on-treatment systolic and diastolic pressures. The systolic pressure at the hazard ratio nadir increased with increasing age, highest for the very old (140 mm Hg). However, diastolic pressure at the hazard ratio nadir was only somewhat lower for the very old (70 mm Hg). Results were independent of treatment strategy. CONCLUSION: Optimal management of hypertension in very old coronary artery disease patients may involve targeting specific systolic and diastolic blood pressures that are higher and somewhat lower, respectively, compared with other age groups.

Outcomes Among hypertensive patients with concomitant peripheral and coronary artery disease: findings from the INternational VErapamil-SR/Trandolapril STudy.

Hypertension is a common risk factor for peripheral arterial disease (PAD). Guidelines suggest treating PAD patients to a blood pressure <130/80 mm Hg; therefore, our objective was to explore whether attainment of this target blood pressure is associated with improved outcomes. We performed a post hoc analysis of the INternational VErapamil-SR/Trandolapril STudy, a randomized clinical trial, which included hypertensive patients with concomitant PAD and coronary artery disease. There were 2699 PAD patients followed for a mean of 2.7 years (60 970 patient-years). The primary outcome, all-cause death, nonfatal myocardial infarction, or nonfatal stroke, occurred in 16.3% of PAD patients versus 9.2% without PAD (adjusted hazard ratio: 1.26 [95% CI: 1.13 to 1.40]; P<0.0001). The primary outcome occurred least frequently among PAD patients treated to an average systolic blood pressure of 135 to 145 mm Hg and an average diastolic blood pressure of 60 to 90 mm Hg. PAD patients displayed a J-shape relationship with systolic blood pressure and the primary outcome, although individuals without PAD did not. PAD patients may require a different target blood pressure than those without PAD.