Author + information
- Mark Richards, MBChB, MD, PhD, DSc⁎ ()
- ↵⁎Reprint requests and correspondence:
Prof. Mark Richards, Christchurch School of Medicine and Health Sciences, Department of Medicine, Riccarton Avenue, P.O. Box 4345, Christchurch, Canterbury 8140, New Zealand
Forty percent of middle-aged and elderly persons in the United Kingdom are treated for hypertension and/or dyslipidemia, aiming for primary prevention of adverse cardiovascular events (1). Despite treatment, rates of adverse cardiovascular events remain significant over long-term follow-up. This mandates efforts to improve risk stratification to guide deployment of resources for surveillance and proactive management and in fostering better adherence to therapy. At present, there is no generally accepted approach to refining risk stratification in those on appropriate therapy for primary prevention of cardiovascular events who have met accepted blood pressure and blood lipid targets. Asymptomatic changes in cardiac structure and function carry adverse prognostic significance (2,3). Awareness of the presence of such “silent” cardiac target organ damage (cTOD) may foster enhanced rates of optimized management. However, comprehensive cardiac testing in those receiving primary preventive therapy is economically and logistically challenging, and an initial screening with adequately sensitive and specific biomarkers may allow targeting of detailed assessments to those with an acceptably high yield of actionable findings.
In this issue of the Journal, Nadir et al. (4) report information obtained from biomarker and cardiac imaging studies in 300 patients recruited from a hospital-based cardiovascular risk factors clinic and neighboring general practices. Participants were 50 years of age or older, free of previous cardiovascular disease, stable on therapy for a year or more with attainment of blood pressure and lipid targets. All underwent electrocardiography, transthoracic and dobutamine stress echocardiography, and 24-h ambulatory blood pressure measurement. Biomarkers included plasma B-type natriuretic peptide (BNP), high-sensitivity cardiac troponin T (hscTnT), uric acid, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate.
Some 34% proved to harbor 1 or more forms of previously undetected cTOD including left ventricular hypertrophy (29.7%), diastolic left ventricular dysfunction (21.3%), left atrial enlargement (15.3%), systolic left ventricular dysfunction (6.3%), and inducible cardiac ischemia (6.3%). Strikingly, over 70% of those with cTOD had 2 or more forms present.
BNP and hscTnT proved discriminative for any form of cTOD with areas under the curve on receiver-operating characteristic analysis of 0.78 and 0.70, respectively. Microalbuminuria, uric acid, and estimated glomerular filtration rate lacked utility (areas under the curve: 0.49 to 0.61). The combination of BNP >15 pg/ml or hscTnT >5.93 ng/l had a sensitivity of 87%, negative predictive value of 90%, and both specificity and positive predictive value of about 65%. Applying this screen, about 2 in 3 of those subsequently tested would have had detectable cTOD at the cost of missing 13% of cases.
That cTOD is present in one-third of such patients is impressive especially in view of the exclusion of those with estimated glomerular filtration rate below 60 ml/m/min and the focus on those meeting treatment targets for control of blood pressure and blood lipids. Because mild-to-moderate renal impairment is both common and a known independent predictor of end organ disease among middle-aged and elderly persons harboring cardiovascular risk factors, and because failure to meet therapeutic targets is common, it is likely Nadir et al. (4) have examined a population with less cTOD than the average primary prevention population.
The data on BNP and hscTnT reflects an ongoing maturation of our understanding and application of these markers. Over a 20-year period, an initial focus on the use of BNP in the diagnosis of acute heart failure and in screening for reduced left ventricular ejection fraction has been superseded by studies demonstrating its prognostic utility across the spectrum of cardiovascular disease and now in the detection of multiple forms of cTOD in asymptomatic populations (5–7). Similarly, an increasing body of evidence indicates that hscTnT and other late-generation, highly sensitive cardiac troponin assays (with which plasma cardiac troponin T or I is measurable in two-thirds or more of the community-based normal population) provide information on structure, function, and cardiovascular prognosis beyond the long-appreciated and pivotal role of troponin measurements in immediate diagnosis of acute myocardial infarction (8). In this regard, it would be instructive to know what proportion of the 300 patients within the Nadir et al. (4) report had detectable plasma troponin values and whether simple detectability in its own right was predictive of cTOD.
Is the bold title of the Nadir et al. (4) report “Improving the Primary Prevention of Cardiovascular Events by Using Biomarkers to Identify Individuals With Silent Heart Disease” warranted? Outstanding issues to be resolved include, first, ascertainment of the rates of end-organ events presaged over what period of time by the single and combined forms of cTOD as found by these methods in this population. This can only be achieved by a longitudinal study in similar and larger populations. Whether the prevalence of cTOD and the attendant event rates can be extrapolated to other communities with differing prevalence of risk factors and varied ethnicity remains to be seen.
Second, the title presumes detection of cTOD will translate to improved care with reduced event rates. What proof is there of this? What number among the 102 (34%) with newly detected cTOD were eligible for immediate additions or alterations in treatment with evidence of benefit? There is some evidence that converting enzyme inhibitor therapy offers benefit in asymptomatic left ventricular dysfunction when left ventricular ejection fraction falls below 40% and the investigators suggest a finding of silent cardiac ischemia might mandate initiation of beta blockade, aspirin, and statins (9,10). Over 6% of the study population had each of these conditions. However, the number with left ventricular ejection fraction <40% (rather than <50%) is not given and is presumably much less than 6%. We are not informed how many were already on part or all of these suggested regimes and therefore what potential existed for rational changes in treatment. The suggestion of possible preventive coronary angioplasty is also raised, but notably the 2 references offered in support refer specifically to diabetic patients undergoing coronary grafting and to patients with silent ischemia after myocardial infarction undergoing angioplasty. As yet, it is far from proven that percutaneous coronary interventions for silent ischemia within the asymptomatic primary treatment population offer significant benefit over potential harm. With respect to the other forms of cTOD documented, in the presence of controlled blood pressure, there is no specific additional therapy indicated for left ventricular hypertrophy, diastolic dysfunction, or left atrial enlargement. It is a fundamental principle of biomedical screening that it should only be pursued when a proven beneficial response is available for those with positive findings. This is not convincingly the case in the current context.
In mitigation, new information on cTOD will improve risk stratification and therefore improve the quality of advice doctors can offer patients and it may enhance adherence to treatment among informed patients. The findings may become increasingly actionable as information from various therapeutic trials comes to hand and studies such as that from Nadir et al. (4) may inform the design of future therapeutic trials by facilitating better definition of treatment targets and better case selection for recruitment to trials. Is the combination of biomarkers and detailed cardiac phenotyping to aid better outcomes in primary prevention ready for prime time? For now the answer is “no,” but it is clear that validation and extension of these findings is necessary to set the scene for when therapeutic options do become available to render such an approach beneficial.
Dr. Richards is an adviser to Roche Diagnostics and Alere Diagnostics; and has received speakers' fees and research support from these companies.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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