Melissa Leung

Significance and assessment of coronary microvascular dysfunction

The endothelium, although only a monolayer of cells, plays a pivotal role in vascular haemostasis by regulating vascular tone, thereby controlling blood flow to end organs.1 It also plays important roles in maintaining balance between anti- and pro-coagulant activities, contributing to thrombo-resistance and controlling cellular adhesion, underlying smooth muscle proliferation, and vessel wall inflammation. In addition to local conversion of angiotensin I to angiotensin II, endothelial cells produce and release a number of vasoactive substances, including nitric oxide, endothelium derived hyperpolarising factor, prostacyclin, endothelin, and vasoconstrictor prostanoids, that regulate vascular tone. Endothelial cells can also respond to circulating vasoactive substances such as bradykinins, serotonin, adenosine, and thrombin. Alterations in endothelial function precede the development of atherosclerotic changes in larger blood vessels, which are the common underlying pathogenetic mechanisms of a large number of diseases affecting all major organs. Endothelial dysfunction should actually be considered as endothelial activation, where there is a switch from nitric oxide mediated vasodilatation and silencing of cellular processes to activation by redox signalling. Prolonged and repeated exposure to vascular risk factors may eventually overwhelm the anti-inflammatory, vasodilatory and antiproliferative effects of normal endothelium and lead to endothelial activation and dysfunction, ultimately leading to loss of endothelial cell integrity, apoptosis and their release into the circulation. Changes in the microvasculature, through its pivotal roles in initiating and perpetuating atherosclerotic diseases in the larger conduit vessels, play an important part in the end organ damage from vascular diseases. Understanding the importance of the endothelium in health and disease not only affords the opportunity for early detection of diseases in at-risk patients, but also provides a means for risk stratification, development of interventions to prevent disease progression and to alleviate diseases subsequent in the pathophysiological process, and the development of novel techniques to assess response to treatment. It …

Prognostic implications of left atrial volume index in patients in sinus rhythm.

The maximum left atrial volume index (LAVI) has been shown to be of prognostic values, but previous studies have largely been limited to older patients with specific cardiovascular conditions. We examined the independent prognostic values of LAVI in a large unselected series of predominantly younger patients in sinus rhythm followed up for a long period. We evaluated 483 consecutive patients (mean age 47.3 years) using transthoracic echocardiography. The median LAVI was 24 ml/m(2). A primary combined end point of cardiovascular death, stroke, heart failure, myocardial infarction, and atrial fibrillation was sought. We had complete follow-up data for 97.3% of the 483 patients. During a median follow-up of 6.8 years, 86 patients (18.3%) reached the primary end point. Older age, male gender, diabetes, hypertension, hypercholesterolemia, chronic renal failure, a history of myocardial infarction or stroke, a mitral E deceleration time of </=150 ms, and LAVI of >/=24 ml/m(2) were univariate predictors of the primary end point. Event-free survival was significantly lower for patients with a LAVI of >/=24 ml/m(2). Age, a history of stroke, hypertension, chronic renal failure, and male gender were independent clinical predictors. A LAVI of >/=24 ml/m(2) was the only independent echocardiographic predictor (hazard ratio 1.72, 95% confidence interval 1.34 to 2.13, p = 0.018), with the chi-square of the Cox model increased significantly with the addition of the LAVI (p <0.001). The LAVI independently predicted an increased risk of cardiovascular death, heart failure, atrial fibrillation, stroke, or myocardial infarction during a median follow-up of 6.8 years. In conclusion, the prognostic values were incremental to the clinical risks and were valid in a younger, general patient population.

Impact of Improved Glycemic Control on Cardiac Function in Type 2 Diabetes Mellitus.

Background—Patients with type 2 diabetes mellitus are at risk of heart failure. Specific therapeutic interventions for diabetic heart disease are still elusive. We aimed to examine the impact of improved glycemic control on left ventricular (LV) function in these patients. Methods and Results—A total of 105 subjects with type 2 diabetes mellitus (aged 54±10 years) and poor glycemic control received optimization of treatment for blood glucose, blood pressure, and cholesterol to recommended targets for 12 months. LV systolic and diastolic function, measured by LV global longitudinal strain (GLS) and septal e′ velocities, were compared before and after optimization. At baseline, patients had impaired LV systolic (GLS −14.9±3.2%) and diastolic function (e′ 6.2±1.7 cm/s). After 12 months, glycated hemoglobin (HbA1c) decreased from 10.3±2.4% to 8.3±2.0%, which was associated with significant relative improvement in GLS of 21% and septal e′ of 24%. There was a progressively greater improvement in GLS as patients achieved a lower final HbA1c. Patients achieving an HbA1c of <7.0% had the largest improvement. The 15 patients whose HbA1c worsened experienced a decline in GLS. Patients who improved their HbA1c by ≥1.0% had a significantly higher relative improvement in e′ than those who did not (32% versus 8%; P=0.003). Baseline GLS, decrease in body mass index, and treatment with metformin were additional independent predictors of GLS improvement. Conclusions—Improvements in glycemic control over a 12-month period led to improvements in LV systolic and diastolic function. This may have long-term prognostic implications.

Integrated imaging of echocardiography and computed tomography to grade mitral regurgitation severity in patients undergoing transcatheter aortic valve implantation

Aims Quantitative mitral regurgitation (MR) grading remains challenging. This study evaluated the concept of integrating echocardiography and computed tomography for grading MR severity. Specifically, an integrated parameter was developed that combines the true cross-sectional mitral regurgitant orifice area (ROA) assessed with multi-detector row computed tomography (MDCT) with flow data from echocardiography. Methods and results Systolic MDCT data of 73 patients, referred for transcatheter aortic valve implantation (TAVI) who also had MR, were evaluated. The MDCT systolic phase with the smaller left ventricular volume and the largest mitral regurgitant orifice was selected. Using planimetry, the mitral ROA was measured. The mitral ROA was multiplied with the velocity time integral of the MR jet on echocardiography for the calculation of the integrated regurgitant volume (RVol). MDCT analysis showed a mean mitral ROA of 11.3 ± 7.4 mm2 and a mean integrated RVol of 21.4 ± 14.7 mL/beat, whereas echocardiography showed a mean effective ROA and RVol of MR of 13.3 ± 8.2 mm2 and 23.9 ± 13.6 mL/beat, respectively. Compared with echocardiography, grading based on integrated mitral RVol resulted in reclassification of 10% of the patients from severe to non-severe MR and 14% of the patients from non-severe to severe MR. Conclusions Integrated mitral RVol is a quantitative parameter of MR severity by combining the true cross-sectional mitral ROA assessed with MDCT and Doppler mitral haemodynamics which resulted in a significant reclassification of MR grade in patients with severe aortic stenosis undergoing TAVR.

Evaluation of Troponin T Criteria for Periprocedural Myocardial Infarction in Patients With Acute Coronary Syndromes

In patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI), the diagnosis of periprocedural myocardial infarction is often problematic when the pre-PCI levels of cardiac troponin T (TnT) are elevated. Thus, we examined different TnT criteria for periprocedural myocardial infarction when the pre-PCI TnT levels were elevated and also the associations between the post-PCI cardiac marker levels and outcomes. We established the relation between the post-PCI creatine kinase-MB (CKMB) and TnT levels in 582 patients (315 with acute coronary syndromes and 272 with stable coronary heart disease). A post-PCI increase in the CKMB levels to 14.7 μg/L (3 × the upper reference limit [URL] in men) corresponded to a TnT of 0.23 μg/L. In the 85 patients with acute coronary syndromes and normal CKMB, but elevated post peak TnT levels before PCI (performed at a median of 5 days, interquartile range 3 to 7), the post-PCI cardiac marker increases were as follows: 21 (24.7%) with a ≥ 20% increase in TnT, 10 (11.8%) with an CKMB level >3 × URL, and 12 (14%) with an absolute TnT increase of >0.09 μg/L (p <0.005 for both). In the patients with stable coronary heart disease and post-PCI cardiac markers > 3× URL compared to those without markers elevations, the rate of freedom from death or nonfatal myocardial infarction was 88% for those with TnT elevations versus 99% (p <0.001, log-rank) and 84% for those with CKMB elevations versus 98% (p <0.001, log-rank). Of the patients with acute coronary syndromes, the post-PCI marker levels did not influence the outcomes. In conclusion, in patients with acute coronary syndromes and elevated TnT levels undergoing PCI several days later, ≥20% increases in TnT were more common than absolute increments in the TnT or CKMB levels of >3× URL. Also, periprocedural cardiac marker elevations in patients with acute coronary syndromes did not have prognostic significance.

Evaluation of coronary microvascular function by left ventricular contractile reserve with low-dose dobutamine echocardiography

AIMS Coronary microvascular function has important diagnostic and prognostic implications but routine assessment is difficult. The index of microcirculatory resistance (IMR) is a reliable but invasive measure. We evaluated whether left ventricular contractile reserve (CR), measured with strain imaging on dobutamine echocardiography (DSE), is a reliable non-invasive measure of coronary microvascular function. METHODS AND RESULTS Forty-five patients underwent low-dose DSE and invasive coronary angiography with IMR measurement in the left anterior descending artery. Global mean peak systolic longitudinal strain was measured in three apical views at rest, and with low-dose DSE. CR was the difference between the resting and low-dose values. Mean IMR was 19.8 (range 6-104): mean peak global systolic strain at rest was -17.90% and at low-dose was -21.46%, giving a mean CR of +3.6% (20% relative increase). IMR and CR were significantly correlated, IMR(-1)=(0.0014×CR+0.05), r=0.64, p<0.001. CR of ≥10% relative increase identified IMR <25 (100% sensitivity and specificity) and <16 (93% sensitivity, 50% specificity [AUC=0.84]). CR ≥20% identified IMR of <16 (78% sensitivity, 82% specificity) with CR ≥ 41% having 100% specificity. CONCLUSIONS LV CR with low-dose DSE may be used to estimate IMR non-invasively. An impaired CR indicates coronary microvascular dysfunction.

Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression

Severe cytopenias in patients with autoimmune conditions treated with azathioprine are well‐recognized. Thiopurine methyltransferase (TPMT) enzymatic activity is subject to individual and ethnic variability. Patients with low TPMT activity (poor metabolizers) are at high risk of developing severe and potentially fatal haematopoietic toxicity. Studies have shown that essentially all TPMT‐deficient patients will develop haematopoietic toxicity on administration of conventional thiopurine dosages (6‐mercaptopurine, azathioprine). Therefore, screening for TPMT polymorphisms in patients before prescribing thiopurine drugs has been proposed. However, despite normal in vitro enzymatic activity, cytopenia may still occur in vivo. This is the case report of an Asian patient with Crohn disease harbouring a rare TPMT mutation on DNA sequencing, who developed neutropenic sepsis and anaemia after a flare of Crohn disease. The report illustrates the importance of monitoring for cytopenia in the setting of active inflammatory disease despite prior normal phenotyping, the role of predictive pharmacogenetics and the limitations of TPMT phenotype assays that may result in misclassification of at‐risk patients.

Left ventricular diastolic reserve in patients with type 2 diabetes mellitus.

Aims Diastolic reserve is the ability of left ventricular filling pressures to remain normal with exercise. Impaired diastolic reserve may be an early sign of diabetic cardiomyopathy. We aimed to determine whether diastolic reserve differs in type 2 diabetes (DM) compared with non-DM, and to identify clinical, anthropological, metabolic and resting echocardiographic correlates of impaired diastolic reserve in patients with DM. Methods and results 237 patients (aged 53±11 years, 133 DM, ejection fraction 68±9%) underwent rest and exercise echocardiography. Mitral E and septal e′ were measured at rest, immediately post, and 10 min into recovery. Analysis of covariance (ANCOVA) and binary regression with continuous outcomes were used to model e′ and E/e′ changes with exercise to identify impaired diastolic reserve defined as post-exercise E/e′ ≥15. After adjusting for baseline differences, patients with DM immediately post-exercise had a lower septal e′, a lower Δe′ (1.2 vs 2.3 cm/s, p=0.006) and a higher Δ septal E/e′ (1.7 vs 0.08, p<0.001) than patients without DM. In patients with normal resting E/e′ of ≤8 (n=130), DM had a significantly higher post-exercise septal E/e′ and a higher Δseptal E/e′ (2.63 vs 0.50, p<0.001). E/e′ in patients with DM remained significantly elevated up to 10 min post-exercise. Hypertension, longer duration of insulin therapy, poorer glycaemic control, worse renal function, larger left atrial volume and lower septal e′ were independent correlates of impaired diastolic reserve in patients with DM. Conclusions Patients with DM have impaired diastolic reserve manifest as a blunted e′ response with exercise, persisting into recovery. Clinical, anthropometric, metabolic and echocardiographic correlates of impaired diastolic reserve in patients with DM were identified. An impaired LV diastolic reserve may be the underlying pathophysiological mechanism in patients with DM with unexplained exertional dyspnoea and may allow earlier detection of DM cardiomyopathy.

Endothelial function and left ventricular diastolic functional reserve in type 2 diabetes mellitus

Background Endothelial dysfunction is an early feature of vascular disease. Left ventricular (LV) diastolic reserve is the ability of the left ventricle to augment diastolic function with exercise and may be impaired in patients with diabetes mellitus (DM). It is unclear if endothelial dysfunction is related to impaired LV diastolic reserve and diminished exercise capacity. Methods 96 patients with type 2 DM and 10 controls had brachial artery reactivity testing, followed by exercise echocardiography. The brachial artery diameter was measured at rest and during reactive hyperaemia. LV diastolic reserve was measured as Δe′ with exercise and diastolic reserve index (Δe′/rest e′). Exercise capacity was calculated by metabolic equivalents (METs). Results Compared with controls, patients with DM had lower rest e′ (7 vs 9 cm/s, p=0.002), lower Δe′(1 vs 4 cm/s, p=0.023), lower Δe′/rest e′ (0.20 vs 0.47, p=0.003) and reduced flow mediated dilation (FMD, 5 vs 15%, p<0.001). FMD was correlated with Δe′ (r=0.65, p<0.001), diastolic reserve index (r=0.61, p<0.001) and post-exercise septal E/e′ (r=−0.50, p<0.001), but not with rest e′ (r=0.13, p=0.177). FMD was an independent predictor of Δe′ (β=0.002, p<0.001, R2=0.47) and diastolic reserve index (β=0.030, p<0.001, R2=0.41). Younger age (p<0.001), male gender (p=0.014), lower body mass index (p<0.001), lower rest E/e′ (p=0.042) and higher FMD (p=0.025) were independent predictors of higher METs (R2=0.52, p<0.001). Conclusions Patients with DM had impaired endothelial function and LV diastolic dysfunction. LV diastolic reserve and exercise capacity are linked to endothelial function. Targeting vascular risk factors to improve endothelial function may improve LV diastolic reserve and exercise capacity.

Neonatal presentations to a Mixed Emergency Department

Aims:  To investigate the characteristics of neonates presenting to a metropolitan Mixed Emergency Department (MED). To examine whether there are maternal and neonatal characteristics which increase the risk of presentation to the ED in the neonatal period.