The Association of Obstructive Sleep Apnea in Ischemia with No Obstructive Coronary Artery Disease - A Pilot Study.

Obstructive sleep apnea (OSA) is increasingly recognized to be a risk factor for cardiovascular disease. This pilot study assessed the association of OSA and invasive coronary microvascular function in patients with ischemia with no obstructive coronary artery disease (INOCA). Forty-two patients with angina, were prospectively screened at a single tertiary centre covering the northern metropolitan area of South Australia, from February 2018 to December 2020 (ACTRN12618000149268). Forty patients were invited into to this observational study after coronary angiography demonstrated INOCA and functional coronary vasomotor disorder (n = 40). Twenty one participants subsequently underwent a sleep study for OSA diagnosis while 9 participants had prior formal diagnosis of OSA (ACTRN12618000227291). Of the 30 participants with OSA data, 87% (n = 26) had a diagnosis of OSA. Accordingly, 11 with mild severity, 7 with moderate severity and 8 with severe OSA. No OSA was observed in 4 participants. Participants with OSA were older [61.4±8.7 vs 49.9±9.7, P = 0.002] with similar clinical characteristics for the pattern and severity of angina and other co-morbidities. 73.3% (n = 22) had abnormal functional disorders of the epicardial coronary arteries and/or coronary microcirculation. On multivariate analysis, OSA was the only statistically significant association with functional coronary microvascular disorders [OR 53.95, 1.41 -2065.01, P = 0.032]. This study provided an observation of a significant correlation between INOCA with abnormal coronary vasomotor function and OSA in an Australian cohort. This correlation supports a possible pathophysiological interplay between these two conditions that needs to be further evaluated. The benefit of treatment of OSA in this subset remains unknown.

Obstructive Sleep Apnea in Coronary Artery Disease.

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, characterized by obstruction of upper airways during sleep, resulting in repetitive breathing pauses accompanied by oxygen desaturation and arousal from sleep. OSA patients commonly suffers from poor sleep quality and reduced quality of life. Further, OSA is associated with cardiovascular risk factors and linked independently to both structural coronary artery disease (CAD) as well as functional CAD. Structural CAD is depicted by atherosclerosis (either obstructive or non-obstructive) of the epicardial coronary arteries, while functional CAD, encompasses the spectrum of coronary vasomotor disorders. There are multiple factors including intermittent hypoxia (IH), sleep fragmentation, and intra-thoracic pressure swings leading to altered cardiopulmonary vascular hemodynamic. IH and its downstream maladaptive responses has the most robust evidence for OSA's role in atherogenesis. CPAP therapy has been linked with reduction in major adverse cardiovascular events in meta-analyses, however, pivotal randomized controlled trials failed to demonstrate its significance.

Predictors of Obstructive Sleep Apnoea (OSA) Population in the Coronary Angiogram Database of South Australia (CADOSA).

Obstructive sleep apnoea (OSA) is increasingly recognized to be a risk factor for cardiovascular disease. This study assessed the prevalence and clinical predictors of OSA in patients undergoing coronary angiography. Consecutive patients undergoing coronary angiography in South Australian public hospitals from 2015 to 2018 were included. Clinical details for consecutive patients undergoing coronary angiography in South Australian public hospitals were captured by the Coronary Angiogram Database of South Australia (CADOSA) registry staff, with OSA identified by patient report. Among the 9,885 patients undergoing coronary angiography for the investigation of chest pain, 11% (n = 1,089) were documented as having OSA. Independent clinical predictors of OSA included male gender (OR 2.22, 1.86-2.65, P < 0.001), diabetes mellitus (OR 1.84, 1.58-2.14, P < 0.001), depression (OR 1.81, 1.55-2.12, P < 0.001), prior heart failure (OR 1.63, 1.22-2.18, P = 0.001), hypertension (OR 1.61, 1.32-1.95, P ≤ 0.001), asthma (OR 1.61, 1.34-1.93, P < 0.001), not a current smoker (OR 1.60, 1.30-1.96, P < 0.001), dyslipidaemia (OR 1.46, 1.22-1.76, P < 0.001), non-acute coronary syndrome presentation (OR 1.45, 1.25-1.69, P < 0.001), chronic lung disease (OR 1.40, 1.12-1.73, P = 0.003), cerebrovascular disease (OR 1.36, 1.07-1.73, P = 0.012), non-obstructive coronary artery disease (NOCAD) (OR 1.30, 1.10-1.55, P = 0.003) and atrial fibrillation/flutter (OR 1.30, 1.06-1.60, P = 0.012). Finally, stable angina (32.1% vs 22.7%) and NOCAD (29.1% vs 26.3%, P = 0.051) were trended more common in patients with OSA versus no OSA. In addition to established risk factors for OSA, this study found NOCAD to be independent predictor of OSA; especially in those presenting with a stable angina presentation. This suggests that coronary vasomotor disorders may be associated with OSA, although further detailed studies are required.

Assessing the Impact of Colchicine on Coronary Plaque Phenotype After Myocardial Infarction with Optical Coherence Tomography: Rationale and Design of the COCOMO-ACS Study.

INTRODUCTION: Recurrent event rates after myocardial infarction (MI) remain unacceptably high, in part because of the continued growth and destabilization of residual coronary atherosclerotic plaques, which may occur despite lipid-lowering therapy. Inflammation is an important contributor to this ongoing risk. Recent studies have shown that the broad-acting anti-inflammatory agent, colchicine, may reduce adverse cardiovascular events in patients post-MI, although the mechanistic basis for this remains unclear. Advances in endovascular arterial wall imaging have allowed detailed characterization of the burden and compositional phenotype of coronary plaque, along with its natural history and responsiveness to treatment. One such example has been the use of optical coherence tomography (OCT) to demonstrate the plaque-stabilizing effects of statins on both fibrous cap thickness and the size of lipid pools within plaque. METHODS: The Phase 2, multi-centre, double-blind colchicine for coronary plaque modification in acute coronary syndrome (COCOMO-ACS) study will evaluate the effect of colchicine 0.5 mg daily on coronary plaque features using serial OCT imaging in patients following MI. Recruitment for the trial has been completed with 64 participants with non-ST elevation MI randomized 1:1 to colchicine or placebo in addition to guideline recommended therapies, including high-intensity statins. The primary endpoint is the effect of colchicine on the minimal fibrous cap thickness of non-culprit plaque over an 18-month period. The COCOMO-ACS study will determine whether addition of colchicine 0.5 mg daily to standard post-MI treatment has incremental benefits on high-risk features of coronary artery plaques. If confirmed, this will provide new mechanistic insights into how colchicine may confer clinical benefits in patients with atherosclerotic cardiovascular disease. TRIAL REGISTRATION: ANZCTR trial registration number: ACTRN12618000809235. Date of trial registration: 11th of May 2018.

Cardiologists appropriately exclude resuscitated out-of-hospital cardiac arrests from emergency coronary angiography.

OBJECTIVE: Emergency coronary angiography after resuscitated out-of-hospital cardiac arrest as a selective or non-selective diagnostic procedure with or without intervention continues to be the subject of debate. This study sought to determine if cardiologists reliably select patients using clinical judgement for emergency coronary angiography without missing acutely ischemic cases requiring revascularization. METHODS: Presenting clinical details and ECGs (within 2 hours) from 52 consecutive out-of-hospital cardiac arrest patients who underwent non-selective coronary angiography were compiled retrospectively. Three out-of-hospital cardiac arrest-experienced interventional cardiologists, blinded to patient outcome, independently determined working diagnosis, and decision for emergency coronary angiography using clinical judgement. Sensitivity of the cardiologists' decision was assessed with respect to the outcome of acute revascularization. Inter-rater differences, consensus in clinical assessment, and influence of working diagnosis were also investigated. RESULTS: Sensitivity of individual cardiologist's decision for emergency coronary angiography with respect to acute revascularization was very high (adjusted overall sensitivity = 95.8%, 95% CI = 89-100, cardiologist range = 93%-100%), and perfect for the consensus of 2 or more cardiologists (100%, 95% CI = 79.4-100). There was no statistical difference in the sensitivity of this decision between cardiologists (P < 0.05), and inter-rater agreement was moderate (78% overall agreement, Κ = 0.56). CONCLUSIONS: Experienced cardiologists recommend emergency coronary angiography in all resuscitated out-of-hospital cardiac arrest requiring acute revascularization and appropriately excluded one-third of patients. Rather than advocating a non-selective, or conversely, a restrictive strategy with respect to coronary angiography after out-of-hospital cardiac arrest, the findings support an individualized approach by a multidisciplinary emergency team that includes experienced cardiologists. The results should be confirmed in a larger prospective study.

Non-invasive Risk Stratification for Coronary Artery Disease: Is It Time for Subclassifications?

PURPOSE OF REVIEW: Coronary artery disease (CAD) is the leading contributor to cardiovascular disease; it is the most prevalent non-communicable disease globally and has high morbidity, mortality and health care cost. Risk stratification is defined as prevention or containment of disease prior to it occurring or progressing, and non-invasive surrogates include history, examination, biomarkers and non-invasive imaging. This review aims to highlight advancement in current diagnostic strategies and explores gaps for CAD secondary to atherosclerosis and non-obstructive vascular diseases. RECENT FINDINGS: Cardiac risk scores have largely proven inadequate in risk stratifying heterogeneous patient populations. Greater emphasis should also be provided to posttest risk stratification. Non-invasive imaging with MRI is the most accurate but least cost efficacious presently due to availability and expertise. Echocardiography and nuclear imaging have good accuracy, but radiation limits the latter. Novel echocardiographic technologies may increase its appeal. Cardiac CT angiography is increasingly promising. Non-invasive and minimally invasive imaging has significantly influenced the cost-efficacy trajectory of coronary artery disease diagnosis and management. Recent studies suggest that future guidelines will incorporate more subclassifications from the findings of these novel technologies and for more diverse patient demographics.

Clinical and coronary haemodynamic determinants of recurrent chest pain in patients without obstructive coronary artery disease - A pilot study.

BACKGROUND: Coronary haemodynamic testing frequently identifies abnormal pathophysiological parameters in patients with angina and non-obstructed coronaries on angiography (NoCAD) but the clinical utility of these measures has received limited attention. OBJECTIVE: This study aims to identify the clinical and coronary haemodynamic determinants of recurrent chest pain at one month in patients with NoCAD. METHODS: Patients with angina, NoCAD (<50% stenosis) and normal LV systolic function underwent invasive coronary haemodynamic testing involving: (1) angiographic TIMI frame and opacification rate, (2) microvascular functional measures including coronary flow reserve (CFR) and hyperaemic microvascular resistance (HMR), (3) coronary endothelial function assessment with low dose intracoronary acetylcholine (IC-ACh) infusions (0.18 µg/min & 1.8 µg/min over 2 min), and (4) Provocative spasm testing with high dose IC-ACh boluses (25, 50 and 100 µg). Clinical and health status were assessed at baseline and one month. RESULTS: In the 49 NoCAD patients (78% female, mean age of 54 ±â€¯11) undergoing comprehensive coronary haemodynamic testing, 33 (67%) continued to experience chest pain at one month. Determinants of recurrent chest pain on univariate analysis included baseline chest pain status or a HMR > 1.9. Multivariate logistic regression analysis identified frequent angina at baseline (OR: 68.9 [4.1, 1165.0], p = 0.003), previous unstable angina admission (OR: 43.9 [3.5, 547.9], p = 0.003) and a HMR > 1.9 (OR: 15.6 [2.1, 114.0], p = 0.007) as independent predictors of recurrent chest pain. CONCLUSION: In this small pilot study, an abnormal HMR was the only coronary haemodynamic parameter that was a determinant of ongoing angina at short-term follow-up.

Comparative effects of glucose and water drinks on blood pressure and cardiac function in older subjects with and without postprandial hypotension.

Postprandial hypotension (PPH) occurs frequently and is thought to reflect an inadequate increase in cardiac output to compensate for the rise in splanchnic blood flow after a meal. Gastric distension by water attenuates the postprandial fall in blood pressure (BP). Cardiac hemodynamics (stroke volume (SV), cardiac output (CO), and global longitudinal strain (GLS)) have hitherto not been measured in PPH We sought to determine the comparative effects of water and glucose drinks on cardiac hemodynamics in healthy older subjects and individuals with PPH Eight healthy older subjects (age 71.0 ± 1.7 years) and eight subjects with PPH (age 75.5 ± 1.0 years) consumed a 300 mL drink of either water or 75 g glucose (including 150 mg 13C-acetate) in randomized order. BP and heart rate (HR) were measured using an automatic device, SV, CO, and GLS by transthoracic echocardiography and gastric emptying by measurement of 13CO2 In both groups, glucose decreased systolic BP (P < 0.001) and increased HR, SV, and CO (P < 0.05 for all). The fall in systolic BP was greater (P < 0.05), and increase in HR less (P < 0.05), in the PPH group, with no difference in SV or CO Water increased systolic BP (P < 0.05) in subjects with PPH and, in both groups, decreased HR (P < 0.05) without affecting SV, CO, or GLS In subjects with PPH, the hypotensive response to glucose and the pressor response to water were related (R = -0.75, P < 0.05). These observations indicate that, in PPH, the hypotensive response to oral glucose is associated with inadequate compensatory increases in CO and HR, whereas the pressor response to water ingestion is maintained and, possibly, exaggerated.

Troponin-positive chest pain with unobstructed coronary arteries: incremental diagnostic value of cardiovascular magnetic resonance imaging.

AIMS: Troponin-positive chest pain patients with unobstructed coronaries represent a clinical dilemma. Cardiovascular magnetic resonance (CMR) imaging has an increasingly prominent role in the assessment of these patients; however, its utility in addition to expert clinical judgement is unclear. We sought to determine the incremental diagnostic value of CMR and the heterogeneity in diagnoses by experienced cardiologists when presented with blinded clinical and investigative data in this population. METHODS AND RESULTS: A total of 125 consecutive patients presenting to a tertiary centre between 2010 and 2014 with cardiac chest pain, elevated troponin (>29 ng/L), and unobstructed coronaries were enrolled and underwent CMR. A panel of three experienced cardiologists unaware of the CMR diagnosis and blinded to each other's assessment provided a diagnosis based on clinical and investigative findings. A consensus panel diagnosis was defined as two or more cardiologists sharing the same clinical diagnosis. Findings were classified into acute myocarditis, Takotsubo cardiomyopathy, acute myocardial infarction (AMI), or indeterminate. CMR provided a diagnosis in 87% of patients. Consensus panel diagnosis and CMR were concordant in 65/125 (52%) patients. There was an only moderate level of agreement between the three cardiologists (k = 0.47, P < 0.05) and a poor level of agreement between the consensus panel and CMR (k = 0.38, P < 0.05) with the most disagreement seen in patients with AMI diagnosed on CMR. CONCLUSION: The clinical diagnosis of patients with non-obstructive coronaries and positive troponin remains a challenge. The concordance between CMR and clinical diagnosis is poor. CMR provides a diagnosis in majority of these patients.

A South Australian registry of biphasic cardioversions of atrial arrhythmias: efficacy and predictors of success.

BACKGROUND: Restoration of sinus rhythm by biphasic cardioversion is an established strategy for patients in atrial arrhythmias. This study aimed to investigate the real-life practice of cardioversions throughout a local hospital to determine frequency and predictors of success and use of high energy (> 200 joules). METHODS: Prospective analysis of consecutive biphasic cardioversions from 2009-2013. Patient demographics, medical history and cardioversion data were collected. RESULTS: 484 cardioversions from 379 patients were included in the final analysis. The majority (73%) of cardioversions were immediately successful after a single shock; overall success was 88% (1-5 shocks). Exploratory analyses revealed that single-shock success was significantly associated with lighter weight (OR 1.19, 95% CI 1.0-1.4, p<0.05). If a second shock was required, energy escalation was significantly associated with success (OR 3.11, 95% CI 1.43-6.77, p<0.05). Increasing weight was the strongest predictor of receiving high energy (10kg increase OR 1.43, 95% CI 1.13-1.81, p<0.05). CONCLUSIONS: This prospective analysis reflects the real-life heterogeneous practice of biphasic cardioversions of atrial arrhythmias throughout a local hospital. These findings highlight the importance of first shock energy selection with careful consideration of patient weight. We emphasise the recommendation to escalate energy, highlighting the need for high-energy defibrillators in 'hard-to-cardiovert' patients.

Premature aging of cardiovascular/platelet function in polycystic ovarian syndrome.

OBJECTIVE: The objective of this study was to compare the impact of aging on nitric oxide (NO) modulation of platelet and vascular function in healthy women and women with polycystic ovary syndrome. METHODS AND RESULTS: A case-control study of women ages 18 to 60 years, comparing women with polycystic ovarian syndrome against age-matched healthy controls, was performed. A total of 242 women, of whom 109 had polycystic ovarian syndrome (based on Rotterdam criteria), participated in the study. Women who were pregnant or on clopidogrel were excluded from the study. Inhibition of platelet aggregation by nitric oxide (primary outcome measure), vascular endothelial function, plasma concentrations of N(G), N(G)-dimethyl-L-arginine (ADMA), endothelial progenitor cell count, and high-sensitivity C-reactive protein (markers of endothelial dysfunction and inflammation) were assessed. With increasing age in control women, there was progressive attenuation of platelet responses to NO, impairment of endothelial function, and elevation of ADMA levels (P ≤.001). Irrespective of age, women with polycystic ovarian syndrome exhibited greater impairment of all these parameters (all P <.05, 2-way analysis of variance) and demonstrated these anomalies earlier in life. CONCLUSIONS: Normal aging in women is associated with attenuation of NO-based signaling in platelets and blood vessels. In women with polycystic ovarian syndrome, these changes are present from early adult life and may contribute to premature atherogenesis.

In patients with chronic stable angina, secondary prevention appears better in the very old compared to younger patients: the Coronary Artery Disease in gENeral practiCE (CADENCE) Substudy.

BACKGROUND: With our aging communities and the increased prevalence of coronary heart disease (CAD) with age, the impact of this disease in the very old warrants further investigation. OBJECTIVE: To assess health outcomes and the attainment of guideline-based secondary prevention targets in the very old (>80 years, n=482) as compared to young (<65 years, n=582) and elderly (between 65 and 80 years, n=932) patients, all of whom had chronic stable angina. DESIGN: The coronary artery disease in general practice (CADENCE) study was a cluster-stratified cross-sectional survey. This study reports on health outcomes quantitated using the Seattle Angina Questionnaire and guideline targets achieved for blood pressure, smoking, lipids, diabetic control and body habitus. SETTINGS AND PARTICIPANTS: 2031 stable angina patients were recruited from 207 primary care practices. RESULTS: Despite similar angina frequency scores, the very old were more physically impaired by their angina than both the young and elderly [76±25 (Young) vs. 70±26 (Elderly) vs. 63±28 (Very old), p<0.05 for both comparisons]. However, the very old had better quality of life scores than young stable angina patients [72±24 vs. 65±25, p<0.05] and were similar to the elderly [72±24 vs. 72±23, p>0.05]. Also blood pressure, lipid, diabetic and body habitus targets were more often achieved in the very old and elderly patients compared to young stable angina patients. CONCLUSION: Despite similar symptomatic status and greater physical limitations, the very old reported a better quality of life and more often achieved treatment targets than young stable angina patients. Failure to improve secondary prevention measures in younger age groups may potentially contribute to increased morbidity in older age, and failure to achieve 'Healthy Ageing'.

Ramipril sensitizes platelets to nitric oxide: implications for therapy in high-risk patients.

OBJECTIVES: Using 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) study-type patients, the aims of this study were: 1) to test the hypothesis that ramipril improves platelet nitric oxide (NO) responsiveness: and 2) to explore biochemical and physiological effects of ramipril in a cohort selected on the basis of platelet NO resistance. BACKGROUND: Ramipril prevents cardiovascular events, but the bases for these effects remain uncertain. NO resistance at both the platelet and vascular levels is present in a substantial proportion of patients with diabetes or ischemic heart disease and is an independent risk factor for cardiovascular events. METHODS: Study 1 was a double-blind, randomized comparison of ramipril (10 mg) with placebo in a cohort of patients (n = 119) with ischemic heart disease or diabetes plus additional coronary risk factor(s), in which effects on platelet responsiveness to NO were compared. Study 2 was a subsequent short-term evaluation of the effects of ramipril in a cohort of subjects (n = 19) with impaired platelet NO responsiveness in whom additional mechanistic data were sought. RESULTS: In study 1, ramipril therapy increased platelet responsiveness to NO relative to the extent of aggregation (p < 0.001), but this effect occurred primarily in patients with severely impaired baseline NO responsiveness (n = 41). In study 2, ramipril also improved platelet NO responsiveness (p < 0.01), and this improvement was correlated directly with increased NO-stimulated platelet generation of cyclic guanosine monophosphate (p < 0.02) but not with changes in plasma thrombospondin-1 levels. CONCLUSIONS: Ramipril ameliorates platelet NO resistance in HOPE study-type patients, with associated increases in soluble guanylate cyclase responsiveness to NO. This effect is likely to contribute to treatment benefit and define patients in whom ramipril therapy is particularly effective.

Lack of association between aortic sclerosis and left ventricular hypertrophy in elderly subjects.

BACKGROUND: The presence of aortic sclerosis has been associated with increased LV mass, particularly in hypertensive subjects. However, aortic sclerosis has also been associated with endothelial dysfunction, which may provide stimuli for development of left ventricular hypertrophy independent of afterload. Thus, we have sought to determine whether aortic sclerosis is a determinant of increased left ventricular mass in a non-hypertensive cohort of aging subjects. METHODS: 79 subjects, mean age 68 ± 6 years, without existing cardiovascular disease or previous antihypertensive therapy were studied. LV volumes were calculated from the short axis stack of cardiac MRI and LV mass was indexed to height(2.7). The presence of aortic sclerosis was assessed with echocardiography using backscatter from the aortic valve (AV(BS)) and visual scoring. Plasma asymmetric dimethylarginine levels and vascular responses to salbutamol were used to assess endothelial function. ANCOVA was used to test the relationship between LV mass index and afterload. Univariate and multivariate analyses were performed to find determinants of increased LV mass. RESULTS: 15 (19%) of subjects had aortic sclerosis on the basis of AV(BS); none had aortic valve areas <1.5 cm(2). There was no significant difference in LV mass between subjects with and without aortic sclerosis. While LV mass was directly related to systolic blood pressure, this relationship was independent of the presence/absence of aortic sclerosis. On multivariate analysis, significant correlates of increased LV mass were male gender, systolic blood pressure and increased BMI, but not presence of aortic sclerosis. CONCLUSIONS: In this aging normotensive population free of established cardiovascular disease, aortic sclerosis is not associated with left ventricular hypertrophy.

Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects.

Platelet hyporesponsiveness to the anti-aggregatory effects of nitric oxide (NO) occurs commonly in association with myocardial ischemia and coronary risk factors, often co-exists with endothelial dysfunction and represents an independent marker of long-term cardiovascular risk. We sought to determine whether polycystic ovary syndrome (PCOS), which has been postulated as a cardiovascular risk factor in women, is independently associated with this phenomenon. Twenty-four young women with PCOS (mean age 32.1+/-1.3) were evaluated in lean (n=12) and obese (n=12) subgroups, and compared with age-matched lean normals (n=12). Platelet aggregation and its inhibition by the nitric oxide donor sodium nitroprusside (SNP) were assessed and compared with vascular endothelial function. Plasma concentrations of malondialdehyde (MDA), N(G),N(G)-dimethyl-L-arginine (ADMA) and hs-CRP were measured as markers of oxidative stress, endothelial dysfunction and inflammation, respectively. Circulating endothelial progenitor cell (EPC) counts were also documented. In both PCOS subgroups, which demonstrated hyperaggregability to ADP, responses to SNP inhibition of aggregation (the principal end-point of the study) were significantly impaired (P<0.01 for both), as were their endothelium-dependent vascular responses to salbutamol (P<0.05 for both). However, vasomotor responses to nitroglycerin and circulating EPC counts did not vary between groups. PCOS subjects also had significantly elevated ADMA, MDA and hs-CRP levels relative to normals (all P<0.05). Impairment of SNP response remained unaltered after mean 30+/-2.4 months follow-up in PCOS subjects. We conclude that in PCOS subjects, independent of obesity and associated insulin resistance, profound and reproducible impairment of platelet responsiveness to NO is an additional component of cardiovascular homeostatic disturbance.

A universal classification system for chronic total occlusions.

Notwithstanding the advances in technology in the field of interventional cardiology, treatment of chronic total occlusions (CTOs) remains a challenging obstacle, posing a considerable barrier to achieving successful complete revascularization. We are proposing a new classification system for an antegrade approach to treat CTOs that will enable interventional cardiologists to assess the technical difficulties as well as procedural risks prior to attempting percutaneous treatment of this complex lesion subset. Furthermore, this classification may be a useful tool from the research standpoint, particularly in assessing the impact of this classification on clinical success rates.

Platelet hyperaggregability: impaired responsiveness to nitric oxide ("platelet NO resistance") as a therapeutic target.

Platelet hyperaggregability and associated thrombosis have been documented in a number of cardiovascular disease states. While one of the current mainstays of anti-thrombotic treatment (i.e. aspirin, clopidogrel, glycoprotein IIb/IIIa antagonists) has been directed at reducing platelet activation and aggregation, it is apparent that there are limitations to the effectiveness of these therapies. Nitric oxide (NO) plays an important role in platelet physiology. The ability of NO to regulate cyclic guanosine-3,'5'-monophosphate (cGMP), via activation of soluble guanylate cyclase, is the principal mechanism of negative control over platelet activity. NO is not only of the endothelial source, it is also released from activated platelets, providing a negative feedback. Studies in patients with symptomatic ischemia, chronic heart failure, diabetes and various risk factors for cardiovascular disease have demonstrated that platelets from these subjects exhibit reduced responsiveness to the anti-aggregating efficacy of NO: a phenomenon termed "platelet NO resistance". It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor or EDRF), and as such may contribute to the increased risk of ischemic events. NO resistance also accounts for reduced pharmaco-activity of exogenous NO donors, e.g. organic nitrates. Platelet NO resistance results largely from a combination of "scavenging" of NO by superoxide anion radical and inactivation of soluble guanylate cyclase. NO resistance has both diagnostic and prognostic implications. The current review examines the association of platelet NO resistance with pathological hyperaggregability and discusses potential therapeutic strategies targeting this abnormality.