Emerging Biomarkers in Acute Coronary Syndromes - A Pathophysiologic Perspective.

Diagnosis and prognostication in acute coronary syndromes (ACS) is achieved using a combination of clinical factors and biomarkers, notably cardiac troponin and B type natriuretic peptide and its N terminal fragment NT-proBNP. However, there are numerous biomarkers that have been shown to be associated with ACS, with variable incremental utility. This brief review focusses on some promising emerging biomarkers in ACS, discussed according to pathophysiologic mechanism, as well as diagnostic and prognostic utility.

Clinical Characteristics and Burden of Risk Factors Among Patients With Early Onset Acute Coronary Syndromes: The ANZACS-QI New Zealand National Cohort (ANZACS-QI 17).

BACKGROUND: Cardiovascular (CV) risk factor profiles of people experiencing acute coronary syndromes (ACS) vary with age, and in New Zealand (NZ), Maori and people of Pacific Island descent typically present with ACS at a younger age. We aimed to explore age- and ethnicity-related differences in CV risk factors in a large NZ cohort with first-time ACS. METHODS: The All NZ Acute Coronary Syndrome Quality Improvement program (ANZACS-QI) registry collects comprehensive data for patients admitted with ACS at NZ hospitals. This analysis includes patients with no prior atherosclerotic CV disease enrolled from 1 July, 2012 to 30 June, 2015. RESULTS: 14,190 patients had confirmed ACS, 8493 (60%) patients with no prior CVD comprised the study cohort. The mean age was 64 years, 25% were aged <55years, and 66% were male. Those aged <55years were more likely than older patients to be current smokers (48% vs 19%), have higher body mass index (BMI) (48% vs 34% with BMI≥30kg/m2), and higher total cholesterol:HDL ratios (≥4.0, 70% vs 50%), all p<0.001. Sixteen per cent of those <55years had diabetes; these patients often had a BMI≥30kg/m2 (67%) and higher median HbA1c than older patients with diabetes (69mmol/mol vs 55mmol/mol). Maori and people of Pacific Island descent were overrepresented in the younger age group; these patients had a very high risk factor burden. CONCLUSIONS: A quarter of NZ patients admitted to hospital with a first-time CV disease event are aged <55years. Younger patients have a very high risk factor burden: half are current smokers, half have a BMI≥30kg/m2, and 16% have diabetes.

Correcting bias in cardiac geometries derived from multimodal images using spatiotemporal mapping.

Cardiovascular imaging studies provide a multitude of structural and functional data to better understand disease mechanisms. While pooling data across studies enables more powerful and broader applications, performing quantitative comparisons across datasets with varying acquisition or analysis methods is problematic due to inherent measurement biases specific to each protocol. We show how dynamic time warping and partial least squares regression can be applied to effectively map between left ventricular geometries derived from different imaging modalities and analysis protocols to account for such differences. To demonstrate this method, paired real-time 3D echocardiography (3DE) and cardiac magnetic resonance (CMR) sequences from 138 subjects were used to construct a mapping function between the two modalities to correct for biases in left ventricular clinical cardiac indices, as well as regional shape. Leave-one-out cross-validation revealed a significant reduction in mean bias, narrower limits of agreement, and higher intraclass correlation coefficients for all functional indices between CMR and 3DE geometries after spatiotemporal mapping. Meanwhile, average root mean squared errors between surface coordinates of 3DE and CMR geometries across the cardiac cycle decreased from 7 ± 1 to 4 ± 1 mm for the total study population. Our generalised method for mapping between time-varying cardiac geometries obtained using different acquisition and analysis protocols enables the pooling of data between modalities and the potential for smaller studies to leverage large population databases for quantitative comparisons.

Prognostic modelling of clinical outcomes after first-time acute coronary syndrome in New Zealand.

OBJECTIVE: The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) was established to investigate the drivers of secondary events after first-time acute coronary syndrome (ACS), including addressing inequitable outcomes by ethnicity. Herein, the first clinical outcomes and prognostic modelling approach are reported. METHODS: First, in 28 176 New Zealanders with first-time ACS from a national registry, a clinical summary score for predicting 1-year death/cardiovascular readmission was created using Cox regression of 20 clinical variables. This score was then calculated in the 2015 participant MENZACS study to represent clinical risk. In MENZACS, Cox regression was used to assess N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a prognostic marker for death/cardiovascular readmission in four models, adjusting for (1) age and sex; (2) age, sex, ethnicity; (3) clinical summary score; (4) clinical summary score and ethnicity. RESULTS: Of the 2015 MENZACS participants (mean age 61 years, 79% male, 73% European, 14% Maori, 5% Pacific people), 2003 were alive at discharge. Of the 2003, 416 (20.8%) experienced all-cause death/cardiovascular readmission over a median of 3.5 years. In a simple model, age, male sex, Maori ethnicity and NT-proBNP levels were significant predictors of outcome. After adjustment for the clinical summary score, which includes age and sex, NT-proBNP and ethnicity were no longer statistically significant: log2(NT-proBNP) hazard ratio (HR) 1.03, 95% confidence interval (95% CI) 0.98 to 1.08, p=0.305; Maori ethnicity HR 1.26, 95% CI 0.97 to 1.62, p=0.084. CONCLUSIONS: In 2015 patients with first-time ACS, recurrent events were common (20.8%). Increasing NT-proBNP levels and Maori ethnicity were predictors of death/cardiovascular readmission, but not after adjustment for the 20 clinical risk factors represented by the clinical summary score. TRIAL REGISTRATION NUMBER: ACTRN12615000676516.

MITEA: A dataset for machine learning segmentation of the left ventricle in 3D echocardiography using subject-specific labels from cardiac magnetic resonance imaging.

Segmentation of the left ventricle (LV) in echocardiography is an important task for the quantification of volume and mass in heart disease. Continuing advances in echocardiography have extended imaging capabilities into the 3D domain, subsequently overcoming the geometric assumptions associated with conventional 2D acquisitions. Nevertheless, the analysis of 3D echocardiography (3DE) poses several challenges associated with limited spatial resolution, poor contrast-to-noise ratio, complex noise characteristics, and image anisotropy. To develop automated methods for 3DE analysis, a sufficiently large, labeled dataset is typically required. However, ground truth segmentations have historically been difficult to obtain due to the high inter-observer variability associated with manual analysis. We address this lack of expert consensus by registering labels derived from higher-resolution subject-specific cardiac magnetic resonance (CMR) images, producing 536 annotated 3DE images from 143 human subjects (10 of which were excluded). This heterogeneous population consists of healthy controls and patients with cardiac disease, across a range of demographics. To demonstrate the utility of such a dataset, a state-of-the-art, self-configuring deep learning network for semantic segmentation was employed for automated 3DE analysis. Using the proposed dataset for training, the network produced measurement biases of -9 ± 16 ml, -1 ± 10 ml, -2 ± 5 %, and 5 ± 23 g, for end-diastolic volume, end-systolic volume, ejection fraction, and mass, respectively, outperforming an expert human observer in terms of accuracy as well as scan-rescan reproducibility. As part of the Cardiac Atlas Project, we present here a large, publicly available 3DE dataset with ground truth labels that leverage the higher resolution and contrast of CMR, to provide a new benchmark for automated 3DE analysis. Such an approach not only reduces the effect of observer-specific bias present in manual 3DE annotations, but also enables the development of analysis techniques which exhibit better agreement with CMR compared to conventional methods. This represents an important step for enabling more efficient and accurate diagnostic and prognostic information to be obtained from echocardiography.

Left ventricular systolic and diastolic function assessed by tissue Doppler imaging and outcome in asymptomatic aortic stenosis.

AIMS: Left ventricular (LV) hypertrophy and abnormal non-invasive measures of LV diastolic function are common in patients with severe aortic stenosis (AS) but their prognostic importance is uncertain. This study aimed to determine whether tissue Doppler measures of LV systolic and/or diastolic function or echocardiographic LV hypertrophy are useful for risk stratifying asymptomatic patients with severe calcific AS. METHODS AND RESULTS: One hundred and eighty-three initially asymptomatic patients with moderate or severe AS (valve area mean 0.96 ± SD 0.3 cm(2)) and a normal LV ejection fraction were followed for median 31 (IQR 14-40) months. Peak systolic (S') and diastolic (E') mitral annular velocities and LV mass were measured by echocardiography at baseline and during follow-up. During follow-up 106 (58%) patients suffered symptomatic deterioration, including three sudden deaths and one resuscitated cardiac arrest. Peak aortic velocity (for 0.5 m/s increase HR = 1.43, 95% CI 1.25, 1.64, P < 0.0001) and aortic valve area (-0.1 cm(2)/m(2) HR = 1.23, 95% CI 1.12, 1.35, P = 0.004) at baseline were most strongly associated with symptomatic deterioration. After peak aortic velocity adjustment neither LV mass index nor any measure of LV systolic or diastolic function was associated with symptomatic deterioration (P > 0.2 for all). CONCLUSION: In patients with calcific AS who have a normal LV ejection fraction the severity of stenosis is the most important correlate of symptomatic deterioration. Tissue Doppler measures of LV systolic and diastolic function and LV mass provide limited predictive information after accounting for the severity of stenosis.

Outcomes for working age patients after first-time acute coronary syndrome - ANZACS-QI 35.

BACKGROUND: Acute coronary syndrome (ACS) events and the ongoing burden of disease can have a significant impact on the subsequent life-course of working age people. METHODS: We report 12-month clinical outcomes for 10,822 patients hospitalized with first-time ACS between 2015-2016 and enrolled in the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry, with a focus on people of working age (defined as <65 years). RESULTS: Nearly half (48%) of first-time ACS occurred in people of working age. Compared to those >65 years, these patients had a high burden of cardiovascular risk factors, and were more likely to be male (75% vs 60%), to be of non-European ethnicity (36% vs 15%), and to be living in areas of high deprivation. Subsequent clinical events were common in the younger patients, with 15% dying or being readmitted for cardiovascular causes within 12 months despite high rates of angiography (96%), revascularization (74%) and evidence-based medical therapy at the time of the index ACS event. CONCLUSIONS: The high risk factor burden and subsequent high rate of clinical events in working age patients reinforces the need for a longer-term focus on strategies to improve clinical outcomes following first-time ACS.

Systematic Comparison of Left Ventricular Geometry Between 3D-Echocardiography and Cardiac Magnetic Resonance Imaging.

Aims: Left ventricular (LV) volumes estimated using three-dimensional echocardiography (3D-echo) have been reported to be smaller than those measured using cardiac magnetic resonance (CMR) imaging, but the underlying causes are not well-understood. We investigated differences in regional LV anatomy derived from these modalities and related subsequent findings to image characteristics. Methods and Results: Seventy participants (18 patients and 52 healthy participants) were imaged with 3D-echo and CMR (<1 h apart). Three-dimensional left ventricular models were constructed at end-diastole (ED) and end-systole (ES) from both modalities using previously validated software, enabling the fusion of CMR with 3D-echo by rigid registration. Regional differences were evaluated as mean surface distances for each of the 17 American Heart Association segments, and by comparing contours superimposed on images from each modality. In comparison to CMR-derived models, 3D-echo models underestimated LV end-diastolic volume (EDV) by -16 ± 22, -1 ± 25, and -18 ± 24 ml across three independent analysis methods. Average surface distance errors were largest in the basal-anterolateral segment (11-15 mm) and smallest in the mid-inferoseptal segment (6 mm). Larger errors were associated with signal dropout in anterior regions and the appearance of trabeculae at the lateral wall. Conclusions: Fusion of CMR and 3D-echo provides insight into the causes of volume underestimation by 3D-echo. Systematic signal dropout and differences in appearances of trabeculae lead to discrepancies in the delineation of LV geometry at anterior and lateral regions. A better understanding of error sources across modalities may improve correlation of clinical indices between 3D-echo and CMR.

Digital devices for teaching cardiac auscultation - a randomized pilot study.

BACKGROUND: Competent cardiac auscultation is a declining skill. Digital stethoscopes and hand-held echocardiography (HHE) are modern devices which may improve the accuracy of heart murmur recognition and diagnosis. Their incremental value compared to conventional examination has not been evaluated in depth. OBJECTIVES: Our aim was to quantify the utility of digital stethoscopes and HHE as teaching aids to improve medical students' diagnostic accuracy in the evaluation of heart murmurs using a novel clinically weighted scoring system. DESIGN: This pilot study involved eight medical students and eight patients with heart murmurs. Four patients were examined at 2 sessions, 1 week apart. Medical students were randomised into two groups: the 'intervention group' examined patients with a standard and digital stethoscope, and then received demonstration of the valvular lesion with HHE to illustrate the diagnosis. The 'control group' used a standard stethoscope only and were taught using traditional methods. Students' scores were compared to a 'gold standard' derived from a consensus of auscultation findings of three cardiologists. RESULTS: Overall the mean percent correct of total possible score was 65.4% (SD8.4). Using a mixed models ANOVA approach to repeated measures, the mean [95% CI] increase from training to validation period for the control group was 2.5% [-11.5, 16.5] P(Tukey) = 0.95 and 15.8% [1.7,29.8] P(Tukey) = 0.027 for the intervention group. Between the validation and training sessions for both groups, there was an increase of 9.1% [1.82, 16.4] in scores (p = 0.018). The mean [95% CI] difference in scores of the control and intervention groups was 1.9% [-5.4, 9.2] (p = 0.59). The Cohen's effect size estimate was 0.9. CONCLUSION: Digital stethoscopes and hand-held echo may be useful devices for teaching cardiac auscultation. This pilot study provides a novel study design, a heart murmur grading system, and data that will help develop definitive studies to assess new teaching techniques for cardiac auscultation using digital technology.

Extra-aortic balloon counterpulsation: an intraoperative feasibility study.

BACKGROUND: Current methods of counterpulsation or ventricular assistance have significant vascular and limb complications. The aim of this study was to determine the safety and performance of a new method of non-blood-contacting counterpulsation using an inflatable cuff around the ascending aorta (extra-aortic balloon [EAB]). METHODS AND RESULTS: In 6 patients undergoing first time off-pump coronary bypass surgery via sternotomy, the EAB was secured around the ascending aorta and attached to a standard counterpulsation console. At baseline and with 1:2 and 1:1 augmentation, hemodynamic and echocardiographic parameters of ventricular function and coronary flow were measured. High-intensity transient signals were measured using transcutaneous Doppler over the right common carotid artery. No complications occurred. With EAB there was no significant change in heart rate or blood pressure and no increase in high-intensity transient signals. There was a 67% increase in diastolic coronary blood flow (mean left-main diastolic velocity time integral 15.3 cm unassisted versus 25.1 cm assisted, P<0.05). Measurements with transesophageal echocardiography at baseline and with 1:1 counterpulsation demonstrated a 6% reduction in end-diastolic area (P=NS), a 16% reduction in end-systolic area (P<0.01), a 31% reduction in left ventricular wall stress (P<0.05), and a 13% improvement in fractional area change (P<0.005). CONCLUSIONS: EAB counterpulsation augments coronary flow and reduces left ventricular afterload. Further testing is warranted to assess the use of the EAB for chronic non-blood-contacting support of the failing heart.

Increased plasma natriuretic peptide levels reflect symptom onset in aortic stenosis.

BACKGROUND: The onset of symptoms is a critical point in the natural history of aortic stenosis and the cardinal indication for valve replacement. This study assessed the associations between natriuretic peptide levels, disease severity, and cardiac symptoms in aortic stenosis. METHODS AND RESULTS: Seventy-four patients with isolated aortic stenosis underwent independent assessment of symptoms, transthoracic echocardiography, and measurement of plasma levels of atrial natriuretic peptide, brain natriuretic peptide (BNP), and N-BNP. Natriuretic peptide levels were also measured in 100 clinically normal control subjects. The aortic valve area was smaller in symptomatic patients (n=45) than in asymptomatic patients (n=29; mean, 0.71+/-0.23 cm2 and 0.99+/-0.31 cm2, respectively; P<0.0001). Plasma natriuretic peptide levels were higher in symptomatic patients than in asymptomatic patients (for N-BNP: median, 112 versus 33 pmol/L; interquartile range, 70 to 193 versus 16 to 58 pmol/L, respectively; P=0.0002). After adjustment for age, sex, serum creatinine, aortic valve area, and left ventricular ejection fraction, N-BNP levels were 1.74 times higher (95% confidence interval, 1.12 to 2.69) for symptomatic than asymptomatic patients with aortic stenosis (P=0.014). Natriuretic peptide levels increased with the New York Heart Association class (for N-BNP median values were 13, 34, 105, and 202 pmol/L for normal control subjects, class I, class II, and class III/IV patients, respectively; interquartile ranges for the same patients were 8 to 21, 16 to 58, 57 to 159, and 87 to 394 pmol/L; P<0.0001). Similar associations were observed for BNP and atrial natriuretic peptide. CONCLUSIONS: Plasma natriuretic peptide levels are elevated in symptomatic patients with aortic stenosis. Measurement of natriuretic peptides may complement clinical and echocardiographic evaluation of patients with aortic stenosis.

Usefulness of serial measurement of N-terminal pro-brain natriuretic peptide plasma levels in asymptomatic patients with aortic stenosis to predict symptomatic deterioration.

In 29 initially asymptomatic patients with aortic stenosis followed for an average of 18 months, patients with a N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level above the normal range at baseline were more likely to develop symptoms during follow-up compared with patients with NT-pro-BNP within normal limits. The average increase in NT-pro-BNP per year was greater for patients who developed symptoms compared with patients who remained asymptomatic. Aortic valve area, peak aortic velocity, and the ejection fraction were less reliable predictors of symptom onset. Measurement of NT-pro-BNP in addition to clinical assessment and echocardiography may allow more reliable follow-up and timing of valve replacement for aortic stenosis.

Effect of aortic valve replacement on c-reactive protein in nonrheumatic aortic stenosis.

Plasma levels of C-reactive protein were higher in 20 patients with bicuspid or trileaflet degenerative aortic stenosis than in 31 normal controls and in 19 patients with pure aortic regurgitation. C-reactive protein decreased from before to 6 months after aortic valve replacement for aortic stenosis. These observations suggest that aortic stenosis is an inflammatory disease.

Associations between plasma natriuretic peptide levels, symptoms, and left ventricular function in patients with chronic aortic regurgitation.

In 40 patients with chronic moderate to severe aortic regurgitation, brain natriuretic peptide, N-brain natriuretic peptide, and atrial natriuretic peptide were higher in symptomatic patients compared with asymptomatic patients after adjustment for age, gender, and ejection fraction, but each natriuretic peptide correlated weakly with echocardiographic measures of left ventricular size and function. In patients with chronic aortic regurgitation, measurement of natriuretic peptide levels may provide information on left ventricular function in addition to echocardiography.

Pointwise assessment of three-dimensional computer reconstruction of mitral leaflet surfaces from rotationally scanned echocardiograms in vitro.

Three-dimensional transesophageal echocardiography offers promise for improved understanding of mitral leaflet pathology, but it has not been validated quantitatively, nor has the minimum number of imaging planes for satisfactory reconstruction been determined with a rotational scanning geometry. This study assessed its accuracy in vitro by comparing, on a 1 x 1-mm grid, the surfaces of mitral leaflets derived from 5-degree rotational ultrasonic scans with those derived from laser scans of casts of the atrial side of the leaflets. Overall, the ultrasonically derived surface had a mean absolute deviation of 0.65 +/- 0.12 mm from the laser-derived surface. Using only alternate imaging planes (10-degree increments) made no significant difference in the overall distribution of deviations (P =.56), although the distributions on some individual specimens differed markedly. We conclude that 5-degree rotational scanning in vitro can reconstruct the mitral valve leaflets with sufficient accuracy and detail to render clinically important features.

Usefulness of Parameters of Left Ventricular Wall Stress and Systolic Function in the Evaluation of Patients with Aortic Stenosis.

Left ventricular function and myocardial contractility in aortic stenosis have been intensely studied over the past 40 years. The underlying impetus for a good deal of this work has been to define the interaction between the ventricle and the valve, to predict in an individual patient the clinical course and outcome after aortic valve replacement. Furthermore, the relationship between afterload (wall stress) and contractility has been closely examined. Although wall stress has been shown to be inversely correlated to ejection fraction or fiber shortening, there is wide individual variability for a similar degree of valvular stenosis, which renders interpretation of data regarding left ventricular function and myocardial contractility difficult. A number of other factors affect the response of the left ventricle to chronic pressure overload. The use of stress-shortening relationships in patients with aortic stenosis requires further study before these measures can be advocated for clinical use. This review examines the usefulness of left ventricular wall stress and parameters of left ventricular function in aortic stenosis, dealing with basic concepts, echocardiographic approach, and clinical usefulness.

High calcium scores in patients with a low Framingham risk of cardiovascular (CVS) disease: implications for more accurate CVS risk assessment in New Zealand.

AIMS: New Zealand (NZ) patients are recommended to undergo an 'adjusted' Framingham score to assess their cardiovascular (CVS) risk. The current (2009) NZ CVS Risk Guideline does not recommend the use of a 'calcium score' as an additional risk tool, although it has been shown to be powerfully predictive of CVS events above the predictive power of traditional Framingham risk factors. Calcium scores of >400 are very strongly predictive of a future CVS event and give direct evidence of atheromatous disease in the coronary circulation. Identification of people with advanced, premature coronary atheroma would allow early treatment of those who may benefit from more vigorous preventative strategies, including statin therapy. METHODS: Using a prospectively acquired, comprehensive database we audited the first 1000 patients (7 August 2006 to 28 November 2008) to undergo a 64-slice computed tomographic (CT) cardiac angiogram (GE Light Speed), which included a scan for a 'calcium score', at the Mercy Hospital, Auckland. We excluded 58 patients who had experienced one or more of a previous myocardial infarction (MI) (n=21), coronary artery bypass graft (CABG) surgery (n=15), percutaneous coronary intervention (PCI) (n=13) or stroke (n=21) and who therefore already had definite evidence of vascular disease and would be automatically placed in a high risk strata. We calculated each patient's Framingham risk from the original 'Anderson' equation, used by the 1996 NZ CVS risk Guideline, and the 'adjusted' Framingham 5-year CVS risk using the NZ Guidelines Group 2003/2009 recommendations, and then compared this with the observed calcium scores. RESULTS: The mean patient age was 56 (SD 9) years; 364 (39%) patients were female, 82% patients were Caucasian. 41% were current (4.6%) or previous (36%) cigarette smokers, 35% had a history of hypertension, 44% hyperlipidaemia and 5.6% had diabetes mellitus. The percentage of patients at 'low' 5-Year CVS risk (0-10% 5-year risk), using the 1996 and 2003/2009 guideline methods, was 78% and 58% respectively. Of patients in these Framingham 'low-risk' groups, 10% and 8.8% had a calcium score of >400 Agatston units, indicating that they were actually at very high CVS risk, and 203 (28%) and 147 (27%) respectively had a calcium score of >100 Agatston units, indicating that they were actually at 'high risk' and not 'low risk'. CONCLUSION: Approximately 10% to 27% of patients with a low CVS risk as assessed by the established Framingham equation have a markedly increased calcium score and hence a significantly increased risk of a CVS event. Currently promoted methods of risk assessment may be inadvertently, falsely re-assuring these patients. Clinicians managing patients may consider a calcium score as an additional tool to the standard risk assessment strategies.

Chronic extra-aortic balloon counterpulsation: first-in-human pilot study in end-stage heart failure.

BACKGROUND: Some patients continue to have significant heart failure symptoms despite optimal medical therapy. METHODS: We describe a first-in-human experience with an implantable non-blood-contacting extra-ascending aortic counterpulsation heart assist system (C-Pulse) in 5 end-stage heart failure patients, aged 54 to 73 years. RESULTS: All patients improved by 1 NYHA class and improvements in invasive hemodynamics were documented in 3 patients. Three of 5 patients (60%) had infectious complications. Two patients were explanted at 5 and 7 weeks, respectively, as a result of mediastinal infection related to the implant procedure. One patient was successfully transplanted at 1 month and 1 remained hemodynamically improved on the device at 6 months but suffered infective complications. The device and protocol have been modified as a result of this pilot study with a further multicenter safety study underway. CONCLUSIONS: Although feasibility of this device is suggested by this pilot study, safety and efficacy will need to be examined in a larger cohort with longer follow-up.