Spectrum Of Ischemic Heart Disease Research Articles

[Cardiovascular magnetic resonance in clinical practice: who, when and why?]

Cardiovascular magnetic resonance (CMR) is an imaging modality with growing indications in cardiology. The purpose of this article is to illustrate the current clinical applications of CMR across the spectrum of ischemic heart disease, non-ischemic cardiomyopathies, cardiac arrhythmias and valvular or vascular heart disease. The strengths of CMR lie in its ability to comprehensively image, without the need for ionizing radiation, cardiac and vascular anatomy, function, perfusion, viability and physiology, providing a powerful non-invasive tool for patient diagnosis and prognostication.

The Relationship/Association of Triglyceride and Severity of Coronary Artery Disease: Is Triglyceride Really a Risk Factor for Coronary Artery Disease?

Worldwide, the major cause of mortality and morbidity is coronary artery disease (CAD). In the pathogenesis and progression of atherosclerosis, lipid and its metabolites play an important role. The aim of the study was to find out the association of triglyceride (TG) level on the severity of coronary artery disease (CAD) in patients with ischemic heart disease (IHD). In this cross-sectional study, 431 patients with ischemic heart disease were enrolled after taking informed written consent. TG level were categorized into normal (< 150 mg/dl), borderline (150-199 mg/dl) and high (³200 mg/dl). Patients with ischemic heart disease (IHD) were stratified according to TG level. Severity of CAD was assessed by the Gensini score. Most of the patients (33.4%) belonged to the age group 51–60 years. The mean age was 51.31±10.30 years. The majority (74.5%) of patients were male. Among risk factors, 205 (47.6%) patients were smokers, followed by hypertension 190 (44.1%) and diabetes mellitus 175 (40.5%). The association of TG with the whole spectrum of IHD was found statistically significant (p < 0.05). Moderate to severe CAD was found to be higher in the high TG level group compared with the other groups and was statistically significant.
 University Heart Journal 2022; 18(2): 101-105

Gender-differences in antithrombotic therapy across the spectrum of ischemic heart disease: Time to tackle the Yentl syndrome?

The incidence and clinical presentation of ischemic heart disease (IHD), as well as thrombotic and bleeding risks, appear to differ between genders. Compared with men, women feature an increased thrombotic risk, probably related to an increased platelet reactivity, higher level of coagulation factors, and sex-associated unique cardiovascular risk factors, such as pregnancy-related (i.e., pre-eclampsia and gestational diabetes), gynecological disorders (i.e., polycystic ovary syndrome, early menopause) and autoimmune or systemic inflammatory diseases. At the same time, women are also at increased risk of bleeding, due to inappropriate dosing of antithrombotic agents, smaller blood vessels, lower body weight and comorbidities, such as diabetes and chronic kidney disease. Pharmacological strategies focused on the personalization of antithrombotic treatment may, therefore, be particularly appealing in women in light of their higher bleeding and ischemic risks. Paradoxically, although women represent a large proportion of cardiovascular patients in our practice, adequate high-quality clinical trial data on women remain scarce and inadequate to guide decision-making processes. As a result, IHD in women tends to be understudied, underdiagnosed and undertreated, a phenomenon known as a "Yentl syndrome." It is, therefore, compelling for the scientific community to embark on dedicated clinical trials to address underrepresentation of women and to acquire evidence-based knowledge in the personalization of antithrombotic therapy in women.

Comparison of high sensitivity troponin I and NT pro BNP as prognostic markers of major adverse cardiac events across spectrum of ischemic heart disease

Background: In an era of a cardiovascular epidemic an imminent search for highly sensitive and specific markers for prognostication in ischemic heart disease have been sought. This study attempted to assess how high sensitive troponin I and NT pro BNP fare as prognostic markers for major adverse cardiac events across the spectrum of ischemic heart disease and hence estimate cardiovascular risk.Objective: To compare high sensitivity Troponin I and NT pro BNP as prognostic markers of major adverse cardiac events across the spectrum of ischemic heart diseases including SIHD, USA/NSTEMI and STEMI. Methods:112 subjects were chosen across the spectrum of ischemic heart disease with equal number of STEMI, USA/NSTEMI AND SIHD. Patients were recruited after satisfying the inclusion criteria and standard definitions as per recommendations and guidelines. Hs trop I and NT pro BNP values were obtained for all patients apart from other parameters. The patients in the study underwent treatment as per standard recommendations.. RESULTS: Hs Troponin I was a poor prognostic marker of overall/ cardiovascular mortality if the entire study population was taken into context with a P value=0.954 and 0.765 respectively for baseline and third hour values. 

The Potential of F-18 Flurpiridaz PET/CT Myocardial Perfusion Imaging for Precision Imaging.

Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) has been the main method for assessing patients with known or suspected coronary artery disease (CAD) for decades. Based on a strong and growing evidence base, positron emission tomography (PET) MPI is increasingly favored when it is available. However, currently available PET perfusion tracers have limitations that have hampered broad utilization. F-18 flurpiridaz is a novel PET MPI agent that is nearing completion of studies necessary to obtain regulatory approval. It has unique capabilities that will facilitate further expansion of PET MPI utilization. In addition, it has characteristics that may define it as the best MPI agent to date, in terms of the potential to equalize accuracy independent of patient size, gender, complexity, or ability to perform exercise stress. The combination of excellent image quality and accurate absolute blood flow quantification hold the potential of its being an ideal precision tool for non-invasive assessment of myocardial blood flow and entire spectrum of ischemic heart disease.

Impact of Serum Uric Acid Level on Systemic Endothelial Dysfunction in Patients with a Broad Spectrum of Ischemic Heart Disease.

Previous studies indicated that serum uric acid (SUA) level is a marker of endothelial function in subsets of ischemic heart disease (IHD). In the present study, we aimed to evaluate the relation between the SUA level and endothelial function in patients with a broad spectrum of IHD, including obstructive coronary artery disease (CAD) and ischemia with no obstructive CAD (INOCA). Three prospective studies and one retrospective study were pooled, in which the SUA level was measured, and systemic endothelial function was assessed using the reactive hyperemia index (RHI). The primary endpoint of the present study was a correlation of the SUA level with RHI. A total of 181 patients with a broad spectrum of IHD were included, among whom, 46 (25%) had acute coronary syndrome presentation and 15 (8%) had INOCA. Overall, the SUA level was negatively correlated with the RHI (r = −0.22, p = 0.003). Multivariable analysis identified the SUA level and INOCA as significant factors associated with RHI values. In conclusion, in patients with a broad spectrum of IHD, including obstructive epicardial CAD (chronic and acute coronary syndromes) and INOCA, the SUA level was significantly and negatively correlated with systemic endothelial function assessed with the RHI. INOCA, rather than obstructive CAD, was more associated with endothelial dysfunction.

Association of C- Reactive Protein and HbA1c in the Severity of Coronary Artery Disease in Patients with Ischemic Heart Disease

Background: C-reactive protein (CRP) and glycohemoglobin (HbA1c) are established risk factors for the development of cardiovascular disease. We investigated the joint effects of these parameters on the severity of coronary artery disease (CAD) in patients with ischemic heart disease.Methods: This cross sectional study was performed on 668 patients of ischemic heart disease. CRP value were divided into normal (<6 mg/L), borderline (6-10 mg/L) and high (>10 mg/L) and HbA1c was divided <6.5% and ≥ 6.5%. After performing Coronary angiography the extent of disease was divided into insignificant CAD of (<50% stenosis), significant CAD considered as >50% stenosis and single vessel, double vessel, triple vessel CAD and normal coronaries.Results: Most (65.0%) of the patients belonged to age 41-60 years. The mean age was found 51.4±10.7 years. Majority (82.3%) of patients were male. Among risk factors, highest (40.0%) patients had hypertension followed by 209 (31.3%) diabetes mellitus and 204 (30.5%) smoker. The relationship of CRP with the whole spectrum of ischemic heart disease was found statistically significant (p<0.05). The relationship of HbA1c and CRP were significantly associated with the severity of coronary artery disease. At HbA1c e”6.5 percent, severe CAD (double vessel and triple vessel) were found higher in high CRP than normal and borderline CRP group.Conclusion: Inflammation, presented by CRP, and hyperglycemia, presented by HbA1c, jointly contributes to the cardiovascular risk of patients. Patients with high CRP and elevated HbA1c are associated with severe coronary artery diseases.Cardiovasc. j. 2018; 11(1): 53-58

Takotsubo is not a cardiomyopathy

Unraveling the mechanisms underlying Takotsubo (TTS) leads to question the current inclusion of the condition within the spectrum of cardiomyopathies. Indeed, the clinical presentation and pathophysiology of TTS clearly differ from cardiomyopathies, i.e. diseases of heart muscle unexplained by abnormal loading conditions or coronary artery disease, which cannot recover spontaneously and may cause sudden death often in minimally symptomatic individuals or result in a gradual deterioration in ventricular function and end-stage heart failure. Furthermore, the term ‘cardiomyopathy’ can no longer be applied when functional or morphologic abnormalities of the coronary arteries leading to acute myocardial ischemia are deemed responsible for left ventricular (LV) systolic dysfunction.After 27years of investigation, time has come to recognize that patients with TTS do suffer from severe myocardial ischemia and fulfill all criteria of acute coronary syndromes, i.e. acute chest pain, typical electrocardiographic changes, cardiac troponin rise, as well as LV wall motion abnormalities. Accordingly, we propose that TTS should be labeled as an acute ‘syndrome’ to be included more appropriately within the spectrum of ischemic heart disease. With regard to the term ‘stress’, it may imply that the catecholamine surge is essential to produce the typical transient myocardial injury. Thus, the terminology ‘Takotsubo (stress) syndrome’ would more accurately reflect recent advances in the pathophysiology.

Stable ischemic heart disease in the older adults.

Ischemic heart disease is caused by atherosclerotic and/or thrombotic obstruction of coronary arteries. Clinical spectrum of ischemic heart disease expands from asymptomatic atherosclerosis of coronary arteries to acute coronary syndromes (ACS) including unstable angina, acute myocardial infarction (non-ST elevation myocardial infarction and ST elevation myocardial infarction). Stable ischemic heart disease (SIHD) refers to patients with known or suspected SIHD who have no recent or acute changes in their symptomatic status, suggesting no active thrombotic process is underway. These patients include those with (1) recent-onset or stable angina or ischemic equivalent symptoms, such as dyspnea or arm pain with exertion; (2) post-ACS stabilized after revascularization or medical therapy; and (3) asymptomatic SIHD diagnosed by abnormal stress tests or imaging studies. This review summarizes clinical features and management of SIHD in the older adult. ACS in older adults is not considered in this review. Age is a strong independent risk factor for the development of atherosclerotic arterial disease. In the coming decades, tremendous increase of the prevalence of SIHD in the older adults is projected for the following reasons: (1) The world's population is aging, with those aged 80 and older expanding most rapidly. (2) The elderly population makes up the majority of new angina pectoris patients. In the USA, the annual rates per 1000 population of new episodes of angina pectoris of nonblack men were reported to be 28.3 for those 65 to 74 years of age, 36.3 for 75 to 84 years of age and 33.0 for ≥ 85 years of age; and 14.1, 20.0 and 22.0 for nonblack women in the same age groups; 22.4, 33.8 and 39.5 for black women; 15.3, 23.6 and 35.9 for black women, respectively.[1] (3) The acute myocardial infarction (AMI) survival rate has improved dramatically under current ACS care, so large numbers of AMI patients become SIHD patients. (4) The increased use of non-invasive (coronary artery calcium score, coronary CT angiography, etc) and invasive diagnostic modalities adds significantly to the number diagnosed with SIHD. SIHD in the older adult presents unique challenges to the healthcare community with predictable increasing burden but less clinical evidence to guide practice. In the older adults, SIHD has equal prevalence in men and women. Obstructive coronary artery disease (CAD) is often more diffuse and severe anatomically. These patients have higher prevalence of left main stenosis, multi-vessel disease and impaired left ventricular function than in younger patients. In this population, other pathophysiological mechanisms may also cause myocardial ischemia and contribute to SIHD clinical presentation. These include microvascular dysfunction, endothelial dysfunction, vascular spasm or micro-embolism, left ventricular hypertrophy associated microvascular insufficiency or other factors contributing to supply-demand imbalance.[2] Microvascular and endothelial dysfunction are common in the older adult population. Therefore, SIHD in the older adult requires a comprehensive approach, not only diagnosing and treating obstructive CAD, but also managing other potential etiologies.

Cardiac troponin in cerebral injury: understanding your laboratory reports

Biomarkers in MedicineVol. 2, No. 5 EditorialFree AccessCardiac troponin in cerebral injury: understanding your laboratory reportsDavid C GazeDavid C GazeDepartment of Chemical Pathology, Clinical Blood Sciences, St George’s Healthcare NHS Trust, Blackshaw Road, Tooting, London, SW17 0QT, UK. Search for more papers by this authorEmail the corresponding author at david.gaze@stgeorges.nhs.ukPublished Online:7 Nov 2008https://doi.org/10.2217/17520363.2.5.433AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Cardiac troponin (cTn) is now the ‘gold standard’ biochemical test for the diagnosis of acute coronary syndrome (ACS). This clinical spectrum of ischemic heart disease includes stable and unstable angina through to acute myocardial infarction (AMI). The growing evidence base for the diagnostic and prognostic use of cTn in ACS has resulted in the redefinition of AMI [1].With increasing popularity owing to ease of measurement, the presence of a tick box on a laboratory request form and a reduction in test price, cTn is a common request in many clinical scenarios outside the remit of ACS. This has resulted in the identification of a plethora of elevated cTn in other conditions, often creating clinical confusion. With the redefinition of AMI, many emergency physicians could not adequately distinguish between a primary acute coronary syndrome and secondary ischemic or nonischemic disease states [2], plainly from ignoring the clinical history. A common misconception is that elevated cTn indicates AMI. It does not. All cTn elevations indicate myocardial cell necrosis [3] but not the pathological mechanism of release. Anecdotal data from a London teaching hospital demonstrate as many as 30% of all medical noncardiac admissions with elevated serum cTn do not have a final diagnosis of ACS [2].Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are expressed in the cardiac myocyte. A small circulating pool exists in the cytosol, but greater than 90% is bound to the thin filament of the contractile apparatus. The cardiac isoforms are distinctly different in amino acid sequence from those expressed in skeletal muscle. Monoclonal antibodies have been raised against cTnT and cTnI and form the basis of immunoassay tests that have been in commercial use since the early 1990s [4].Patients presenting to the emergency department with an acute cerebral injury may be cognitively impaired or exhibit severe speech impediments. This hampers obtaining a full clinical history, including concomitant chest pain symptoms. Many of the risk factors for cardiovascular disease also contribute heavily towards the risk of developing acute cerebral ischemic disease states. The economic consequences of cerebral ischemia are extensive, consuming approximately 3% of total healthcare budgets [5] and a more crippling wider financial burden, with strokes costing the UK economy £7–8 billion in 2005 [6].Cerebral injury commonly manifests as stroke, of which 87% are ischemic [7]. Elevated cTn occurs in approximately 10–30% of stroke patients [8–12]. Generally, elevated cTn during stroke episodes is prognostic; however, there is a lack of consensus between studies. This probably reflects the inappropriate cut-off used to define a positive cTn. Many studies quote an AMI cut-off value for cTn. This was based on the epidemiologically derived WHO definition of AMI, where ‘enzyme’ concentrations were deemed positive if they were twice the upper limit of normal. Many noncardiology-based studies adopting cTn since 2000 have continued to use this concentration to define a positive cTn.Myocardial damage (myocytolysis) during stroke may result from intense activation of the sympathoadrenal system [13], resulting in cardiac arrhythmia [14]. cTn-positive patients demonstrate statistically higher blood adrenaline concentrations [12]. However, the increases in cTn are not correlated with the extent of insular damage [9,12]. This is contradictory to the findings of Ay and colleagues who demonstrated a correlation between cTnT and insular infarctions found in the right posterior insular cortex and inferior parietal lobule [15]. In this study, imaging was performed using diffusion-weighted magnetic resonance, which is superior to conventional CT; however, they also adopted a high cTn cut-off value derived from the WHO-derived definition.The dogma has been that the concentration of cTn in the healthy individual was effectively zero, given the intracellular location of the molecule within the myocyte and its release from tissue during cellular necrosis. The ‘normal’ concentration of cTn in a healthy person theoretically could be truly undetectable or at best below the detection limit of the assay employed. Recently an ultra-sensitive flow-based microparticle immunoassay with single-molecule counting has been developed. Using this assay, a normal distribution of cTnI in a healthy population has been observed [16]. This assay has determined the 99th percentile of 100 healthy subjects to be 8 ng/l. With the most sensitive commercial immunoassay on the market to date, the 99th percentile value can range from 0.02 to 0.04 ng/ml (µg/l), which is a number of orders of magnitude higher than the ultra-sensitive method. Therefore, current cTnI assay performance characteristics are determined by the limit of the detection methodology.cTnT is manufactured by a single supplier owing to patent ownership, therefore direct comparison between studies is possible. However, cTnI is available from a number of manufacturers. The use of different antibodies directed against different epitope-binding regions does not allow direct comparison. A standardization program is currently underway and a reference material has been assigned to act as the calibrator for all cTnI methods [17]. Even with the success of the ongoing standardization program, each troponin assay should be validated in terms of its analytical performance as well as its diagnostic and prognostic clinical utility.An updated universal definition of AMI was published in October 2007 with the aim of eliminating the clinical confusion surrounding diagnosis [18]. The use of cTn remains integral to the diagnosis, with a rise and/or fall in the kinetics. At least one value in the sequence of measurement should exceed the 99th percentile of the upper reference limit, but this should occur in the appropriate clinical context, that is, in conjunction with evidence of myocardial ischemia.Studies have demonstrated that patients with serum values above the 99th percentile confer a poor outcome for both cTnT [19] and cTnI [20]. These studies have been performed in chest pain populations. It is crucial that the 99th percentile value is adopted as the cut-off point to define a positive cTn assay in favor of the redundant WHO-derived AMI cut-off. This translation from the cardiology world to other clinical disciplines is essential in order to truly assess myocardial cell necrosis in patients with non-ACS primary pathology. Further studies of such patient groups are required using the sensitive cTn methods, adopting the appropriate cut-off points to assess the prognostic value of such elevations.Financial & competing interests disclosureDC Gaze is or has been a consultant for Diagnostic Products Corporation, Ischemia Technologies Inc, Roche Diagnostics, Olympus Life Science Research Europa GmbH and Siemens Healthcare Diagnostics Ltd and received honoraria for educational presentations from Beckman Coulter. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Alpert JS, Thygesen K, Antman E, Bassand JP: Myocardial infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J. Am. Col. Cardiol.36(3),959–969 (2000).Crossref, Medline, CAS, Google Scholar2 Collinson PO, Stubbs PJ: Are troponins confusing? Heart89,1285–1287 (2003).Crossref, Medline, CAS, Google Scholar3 Gaze DC, Collinson PO: Cardiac troponins as biomarkers of drug- and toxin-induced cardiotoxicity and cardioprotection. Expert Opin. Drug Metab. Toxicol.1,715–725 (2005).Crossref, Medline, CAS, Google Scholar4 Collinson PO, Boa FG, Gaze DC: Measurement of cardiac troponins. Ann. Clin. Biochem.38,423–449 (2001).Crossref, Medline, CAS, Google Scholar5 Flynn RWV, MacWalter RSM, Doney ASF: The cost of cerebral ischaemia. Neuropharmacology55,250–256 (2008).Crossref, Medline, CAS, Google Scholar6 National Audit Office and Department of Health. Reducing brain damage: faster access to better stroke prevention.Google Scholar7 Rosamond W, Flegal K, Friday G et al.: Hear disease and stroke statistics 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation115,e69–e110 (2007).Crossref, Medline, Google Scholar8 Chalela JA, Ezzeddine MA, Davis L, Warach S: Myocardial injury in acute stroke: a troponin I study. Neurocrit. Care1,343–346 (2004).Crossref, Medline, Google Scholar9 Christensen H, Johannesen HH, Christensen AF, Bendtzen K, Boysen G: Serum cardiac troponin I in acute stroke is related to serum cortisol and TNF-α. Cerebrovasc. Dis.18,194–199 (2004).Crossref, Medline, CAS, Google Scholar10 James P, Ellis CJ, Whitlock RM, McNeil AR, Henley J, Anderson NE: Relation between troponin T concentration and mortality in patients presenting with an acute stroke: observational study. Br. Med. J.320,1502–1504 (2000).Crossref, Medline, CAS, Google Scholar11 Apak I, Iltumur K, Tamam Y, Kaya N: Serum cardiac troponin T levels as an indicator of myocardial injury in ischemic and hemorrhagic stroke patients. Tohoku J. Exp. Med.205,93–101 (2005).Crossref, Medline, CAS, Google Scholar12 Barber M, Morton JJ, Macfarlane PW, Barlow N, Rodti G, Stott DJ: Elevated troponin levels are associated with sympathoadrenal activation in acute ischaemic stroke. Cerebrovasc. Dis.23,260–266 (2007).Crossref, Medline, CAS, Google Scholar13 Myers MG, Norris JW, Achinski VC, Weingert ME, Sole MJ: Cardiac sequelae of acute stroke. Stroke13,838–842 (1982).Crossref, Medline, CAS, Google Scholar14 Hachinski VC, Smith KE, Silver MD, Gibson CJ, Cirello J: Acute myocardial and plasma catecholamine changes in experimental stroke. Stroke17,387–390 (1986).Crossref, Medline, CAS, Google Scholar15 Ay H, Koroshetz WJ, Benner T et al.: Neuroanatomic correlates of stroke-related myocardial injury. Neurology66,1325–1329 (2006).Crossref, Medline, CAS, Google Scholar16 Todd J, Freese B, Lu A, Held D, Morey J, Livingston R, Goix P: Ultrasensitive flow-based immunoassays using single-molecule counting. Clin. Chem.53,1990–1995 (2007).Crossref, Medline, CAS, Google Scholar17 Bunk DM, Welch MJ: Characterization of a new certified reference material for human cardiac troponin I. Clin. Chem.52,212–219 (2006).Crossref, Medline, CAS, Google Scholar18 Thygesen K, Alpert JS, White HD; On behalf of the Joint ESC/ACC/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal Definition of Myocardial Infarction. Eur. Heart J.28,2525–2538 (2007).Crossref, Medline, Google Scholar19 James S, Armstrong P, Califf R, Simmons ML, Venge P, Wallentin L, Lindahl B: Troponin T levels and risk of 30-day outcomes in patients with acute coronary syndrome: prospective verification the GUSTO-IV trial. Am. J. Med.115,178–184 (2003).Crossref, Medline, CAS, Google Scholar20 Apple FS, Smith SW, Pearce LA, Ler R, Murakami MM: Use of the Centaur TnI-Ultra assay for detection of myocardial infarction and adverse events in patients presenting with symptoms suggestive of acute coronary syndrome. Clin. Chem.54,723–728 (2008).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 2, No. 5 Follow us on social media for the latest updates Metrics History Published online 7 November 2008 Published in print October 2008 Information© Future Medicine LtdFinancial & competing interests disclosureDC Gaze is or has been a consultant for Diagnostic Products Corporation, Ischemia Technologies Inc, Roche Diagnostics, Olympus Life Science Research Europa GmbH and Siemens Healthcare Diagnostics Ltd and received honoraria for educational presentations from Beckman Coulter. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Amino-Terminal Pro–B-Type Natriuretic Peptides in Stable and Unstable Ischemic Heart Disease

Across the entire spectrum of ischemic heart disease, amino-terminal pro-B-type natriuretic peptides (NT-proBNP) are a strong and independent prognostic indicator, representing a particularly strong predictor of heart failure or death. This risk is independent of all other variables, including renal function or troponin, and is proportional to the magnitude of NT-proBNP release, with higher risk observed among those with a more marked elevation of the marker. Although prospective studies on the effect of NT-proBNP measurement in guiding therapy in ischemic heart disease are lacking, among patients presenting with acute coronary syndromes, it is recommended to measure NT-proBNP on (or near) the time of admission. An elevated initial NT-proBNP concentration should prompt consideration of an early invasive management approach. Consideration should be given to repeating the NT-proBNP measurement after 24-72 hours and again at 3-6 months because these follow-up measurements provide more long-term prognostic information than single measures at presentation. In acute ischemic heart disease, an NT-proBNP value >250 ng/L is associated with an adverse prognosis. In patients with stable coronary artery disease, measurement may be performed for prognostication purposes at 6- to 18-month intervals. In the case of clinical suspicion of disease progression, a new sample may be warranted.

Functional Mitral Regurgitation Predicts Prognosis Independent of Left Ventricular Systolic and Diastolic Indices in Patients with Ischemic Heart Disease

The purpose of this study was to investigate the prognostic impact of functional mitral regurgitation (FMR) and tissue Doppler-derived index of left ventricular filling pressure, E/E', on long-term clinical outcome in a broad spectrum of ischemic heart disease. FMR has been shown to predict prognosis in patients with myocardial infarction. A total of 524 patients with ischemic heart disease were enrolled. Patients were categorized according to the presence (n = 58) or absence (n = 466) of severe FMR. Patients with severe FMR were significantly older. By echocardiography, ejection fraction was significantly lower (43.0% +/- 14.6% vs. 56.4% +/- 12.8%, P < .01) and E/E' was significantly higher (21.3 +/- 9.0 vs. 14.6 +/- 6.4, P < .01) in patients with FMR than without FMR. Event-free (death and congestive heart failure) survival was significantly lower in patients with FMR than in those without (log-rank P < .0001). By multivariate logistic regression analysis, E/E' greater than 15 (relative risk [RR] 3.49; 95% confidence interval [CI] 2.08-5.88, P < .0001), ejection fraction less than 50% (RR 3.33; 95% CI 1.96-5.64, P < .0001), and severe FMR (RR 2.34; 95% CI 1.22-2.48, P = .01) were independent echocardiographic predictors of cardiac events. In further analysis of 116 patients matched by a propensity score, severe FMR remained associated with reduced event-free survival (log-rank P = .004). FMR is a strong predictor of cardiac events independently of left ventricular systolic and diastolic indices in patients with ischemic heart disease.

Diagnostic Applications of Natriuretic Peptides in Ischemic Heart Disease

Early assessment of patients who have symptoms suggestive of an acute coronary syndrome (ACS) remains a challenge considering the heterogeneity of underlying pathologies and clinical outcomes. The purpose of the early evaluation of these patients is threefold: first, to diagnose or exclude acute myocardial infarction (AMI) second, to identify patients at different risks for future cardiac events; and third, to be able to select appropriate treatment. Currently the initial assessment of these patients is based on the patient’s history, clinical findings, ECG data, and serial testing of biochemical markers of myocardial necrosis, preferably troponin T or I. In the last few years, an increasing number of studies have evaluated the addition of the natriuretic peptides, NT-proBNP and BNP, in the diagnostic and prognostic arsenal for assessment of patients who have a suspected ACS. The studies of the value of natriuretic peptides have also been extended to patients who have stable angina pectoris for detection of significant coronary artery disease (CAD) and for assessment of the long-term risk. NT-proBNP and BNP in the different forms of ischemic heart disease The prognostic value of NT-proBNP and BNP has been evaluated in the full spectrum of ischemic heart disease in a large number of studies. It is striking that the increased mortality associated with elevation of NT-proBNP or BNP is of a similar degree, regardless of type of presentation of the ischemic heart disease.

Fluctuating Inflammatory Markers in Patients With Stable Ischemic Heart Disease

C-reactive protein (CRP), a marker of inflammation, is increasingly measured to stratify coronary artery disease risk and guide clinical management. However, little is known about how inflammatory markers fluctuate over time in patients with stable ischemic heart disease. We examined serial serum CRP values in 159 patients with histories spanning the clinical spectrum of ischemic heart disease. Two to 8 CRP measurements were made at intervals varying from 15 days to 6 years. Successive interleukin (IL)-6 values were examined in 1 subgroup. Blood samples were always taken when patients were clinically stable, in the absence of any potentially confounding inflammatory condition. C-reactive protein values in individual patients fluctuated considerably when examined in the following ranges: less than 1 mg/L, 1 to 3 mg/L, and greater than 3 mg/L, proposed to indicate low, average, and high risk. Sixty-four patients (40.3%) changed risk category between the first and the second measurement. Within-patient variances of CRP and IL-6 levels were 1.79 mg/L (95% confidence interval, 1.60-2.00) and 2.69 pg/mL (95% confidence interval, 2.29-3.18), respectively. The variability of CRP was consistent over different times and across clinical groups, and independent of body mass index, smoking status, medication, and clinical events. Relatively important fluctuations in CRP levels in patients with stable ischemic heart disease may be problematic for risk stratification and treatment monitoring. A similar IL-6 variability suggests that these patients have a dynamic inflammatory status whose kinetics may modulate acute coronary risk.

Spectrum of Ischemic Heart Disease and The Role of Biochemical Markers

An exciting era exists as a result of the introduction of novel markers of myocardial damage. The prognostic implications of troponins, even in the setting of "minor myocardial damage," are potentially of immense value to patient care. We need to take the next step and assess the outcomes of interventions in these settings. Use of new markers at triage will probably allow for more efficient and safe disposition of patients in this setting. There are many advantages and disadvantages to the current markers and many unanswered questions. Only through well-designed large clinical trials will we be able to realize the true potential of these markers.

Pathobiology of sudden death: coronary causes

The single most common cause of sudden death in the western world is coronary artery disease. Sudden death from coronary causes occurs equally in asymptomatic patients, patients with angina, and patients with a known history of myocardial infarction. The mechanism of sudden coronary death in most patients is ventricular fibrillation secondary to ischemia. Microthrombi in intramyocardial coronary arteries may also play a role. Instability of atherosclerotic plaques, in terms of thrombosis and vasoreactivity, underlies the syndrome of unstable angina as well as many cases of acute myocardial infarction. Sudden coronary death falls within this spectrum of ischemic heart disease. Development of these syndromes depends on the abruptness of onset and the completeness and duration of coronary occlusion. Thus a rapidly evolving coronary artery lesion, with plaque fissure, rupture, and luminal thrombosis, can lead to myocardial ischemia, with fatal electrical instability of the myocardium as the first clinical manifestation. The diagnosis of sudden coronary death in the absence of myocardial infarction is determined by the degree of coronary artery narrowing and the exclusion of other causes of death. The presence of acute coronary artery lesions, which may be present in a significant number of sudden coronary death patients, lends support to the pathologic diagnosis. Thus the coronary arteries in victims of sudden coronary death may exhibit established atherosclerotis or acute lesions, whereas the myocardium may appear normal or show healed or acute infarction or hypertrophy. Although less common, nonatherosclerotic coronary artery diseases can account for sudden death as well, particularly in younger patients. Therefore, when sudden death occurs in children and young adults, coronary causes related to congenital anomalies, fibromuscular dysplasia, arteritis, or metabolic diseases should be considered.

Coronary artery spasm: The pendulum continues swinging

Historical background. Those of us who have been interested in the concept of coronary artery spasm and re• search on it have witnessed a remarkable pattern of oscil• lation. The pendulum has swung from the enthusiasm of Sir William Osler (1), who in 1910 stated, I do not know of any better explanation of anginal pain ... , to the skep• ticism of Keefer and Resnick (2), who in 1928 wondered how rigid atherosclerotic coronary arteries could possibly constrict or go into spasm. The pendulum could not be stopped by Danielopolu (3), Gallavardin (4) and Kohn (5), who between 1924 and 1926 suggested that both spasm and atherosclerosis were involved in the pathophysiology of an• gina pectoris. With the influence of Blumgart et al. (6), not only the role of spasm, but its existence, was questioned. However, Blumgart himself (7) seemed to recognize some role for spasm when he stated, ., Some episodes, particularly those occurring in the absence of effort, or increased cardiac work, are best understood as the expression of vasocon• striction or absence of vasodilation leading to relatively insufficient coronary blood flow. Recent historical perspective. The advent of coronary arteriography in the late 1950s and the failure to demonstrate spontaneous spasm in a significant number of patients with angina focused attention on atherosclerosis as the sole phe• nomenon underlying ischemic heart disease. However, in the early 1970s it became clear that spasm could produce clinical myocardial ischemia in workers after withdrawal from long-term industrial exposure to nitroglycerin (8) and, in patients with Prinzmetal' s variant angina, during episodes of chest pain at rest (9). These observations were followed by a flurry of studies and reports documenting some role for spasm in the broad spectrum of ischemic heart disease ( 10) or proposing it as the key mechanism underlying myo• cardial infarction (II). However, in the early 1980s coro• nary angiography, performed in the acute phases of infarc-

Coronary Vasospasm

Patients with angina, myocardial infarction, and sudden death almost always have demonstrable coronary atherosclerosis. Furthermore, there is mounting evidence that coronary artery "spasm" is a contributing feature of these different coronary ischemic syndromes. Using quantitative angiography and two modes of alpha-adrenergic stimulation in patients with spontaneous most angina, vasomotor hyperreactivity was shown to be localized only to the region of a preexisting coronary atheroma. These observations support the hypothesis that a dynamic interaction between the histopathologic features of coronary atherosclerosis and "normal" amounts of coronary smooth-muscle shortening accounts for the clinical features in the great majority of cases in the spectrum of ischemic heart disease. There are stenosis, each with different therapeutic implications.

Coronary artery spasm: its role in the pathogenesis of myocardial ischemia.

The role of coronary artery spasm in the production of myocardial ischemia has recently become the focus of increased attention. This phenomenon is now well established as a causative mechanism underlying the resting chest pain attacks in Prinzmetal's variant angina. There is also evidence that coronary spasm may play a more significant role in the broad spectrum of ischemic heart disease than can be documented by current techniques. The autonomous nervous system constitutes a major element in the pathophysiology of spasm. Coronary arteriography, in spite of important limitations, remains the only technique for final documentation of this phenomenon, but radionuclide scintigraphy appears to be promising. Nitroglycerin is effective for the relief of the acute attack, while long acting nitrates and the calcium antagonists: nifedipine, perhexiline and verapamil are useful in the prevention of recurrences.

Medical Management of the Patient With Unstable Angina

SINCE 1937, a clinical syndrome intermediate between stable angina pectoris and classic myocardial infarction has been recognized.¹This syndrome has been called a variety of names. Terms such as "preinfarction angina" or "impending myocardial infarction" unfortunately carry prognostic implications that may lead cardiologists and surgeons to precipitate action that may not be warranted. Other terms that have been used include "intermediate coronary syndrome," "accelerated angina," "crescendo angina," and "unstable angina." "Unstable angina" is the preferred term.² Unstable angina is not an isolated entity but is part of the clinical spectrum of ischemic heart disease. The vast majority of patients have extensive obstructive coronary artery disease similar to that found in patients with stable angina. Of 100 consecutive patients with unstable angina who were hospitalized in The Johns Hopkins Hospital coronary care unit and underwent arteriography, 94% had greater than 70% narrowing of at least one major coronary artery.