Transfer function-derived central pressure and cardiovascular disease events: the Framingham Heart Study.

W e write in relation to the article of Mitchell et al. [1], describing analysis of the Framingham data, and the accompanying editorial by Laurent et al. [2]. Dr Dan Levy as Framingham Director was kind enough to share the data with us, but we had many reservations and could not agree on the manuscript, and so declined to act as coauthors. We had initially approached Dr Levy in 1987 offering to use SphygmoCor (AtCor Medical, Sydney, New South Wales, Australia) in a study of outcome, on the basis of previous articles [3,4] from Framingham, which had shown a relationship between peripheral pressure pulse waves and cardiovascular outcomes. Dr Levy chose to conduct the planned study using local resources. This was published in 2010 [5]. Our concerns were expressed in journal correspondence [6], and we were given the opportunity by Dr Levy to reanalyse the de-identified data. As part of our arrangement with Framingham, it was agreed that only data that met quality control standards that Atcor (Sydney, New South Wales, Australia) recommends for all its tonometry studies would be analysed. It was felt that this quality standard was important as the Framingham tonometry data were collected using a system that was not cleared by the US Food and Drug Administration (FDA) and for which there were no published validation, reproducibility, or repeatability data. We were, in fact, surprised at the variability of data. On reviewing the reports of each patient, we saw a pattern of apparent errors on the same day and in clusters suggesting that supervision of data, possibly of one of the operators, was incomplete during the full study. Of the 2183 individual records, 1262 met the quality control standards for inclusion into the study. We feel that it was inappropriate to include records that did not meet quality control standards. Use of the smaller number of records would be expected to significantly reduce the statistical power of the analysis and may call into question the conclusions drawn from the analysis. Although the authors acknowledged this smaller dataset, the authors state that the correlation between central and radial systolic pressure is very high and thus central pressure would not be expected to provide a benefit in risk prediction of cardiovascular disease beyond that of brachial pressure. However, considering the correlation between systolic radial and central pressures is unrealistic in that such correlation is dominated by the mean pressure. This is analogous to viewing a rough surface from afar, in which case the surface looks smooth. The appropriate correlation to consider is between central and radial pulse pressure (PP), which is the component altered by the transfer function. Also, the authors consider the correlation over the entire range of pressure in which the extremes of pressure dominate the correlation. At the extremes the difference between brachial and central PP (CPP) is greatly reduced. However, if one considers the mid-range of systolic pressure (i.e. normal, high normal, and prehypertensive categories), the range for which central pressure measurements are potentially of greatest clinical interest, the correlation is significantly reduced. Since Framingham only provided us with uncalibrated waveforms, we investigated the dataset of McEniery et al. [7] to determine the correlation between brachial systolic pressure (BSP) and central systolic pressure (CSP) for the different blood pressure (BP) categories. For the dataset of approximately 6000 patients, the correlation between CBP and BBP over the entire data range is quite high (0.92). However, the correlation is much lower in the normal, high normal, and prehypertensive brachial BP categories (0.47, 0.40, and 0.65, respectively). Individual patients with the same BSP can have more than 30 mmHg difference in their CSP; the different levels of risk and therapeutic requirements cannot be discerned simply from BSP. We wished to include reference to the previous work of Framingham directors Kannel et al. [4] and Dawber et al. [3] who had shown correlation of plethysmographic distal pulse recordings with clinical events, but this was not retained by the authors. The accompanying editorial by Laurent et al. [2] noted limitations but did not mention that the US FDA in accepting SphygmoCor for use in the United States of America required calibration to BSP and brachial diastolic pressure as the ‘gold standard’ for outcome measures. This is mandated by FDA so that central aortic pressure would represent what central pressure would be if the cuff sphygmomanometer were correct, and so that brachial and central pressures could be appropriately compared. The FDA is well aware of large and unexplained differences between invasively and noninvasively measured brachial pressures. The criticism by the authors of major studies, including Vlachopoulos et al. [8], is based on a method of calibrating to mean brachial pressure that contravenes the theoretic requirements for applanation [9], and that provides values of aortic systolic pressure greater than that recorded in the arm – which is not in accord with the SphygmoCor process as approved by the FDA. Analyses which use this method of calibration [10] do not show correlation with cardiovascular events. This was pointed out by Vlachopoulos et al. [8] in journal correspondence regarding the meta-analysis [10], and in a similar report by Roman and Devereux [11], who used the SphygmoCor system in accordance with FDA (and AtCor) requirements. Neither is cited by authors. We attach a copy of Dawber’s Framingham recordings (Fig. 1) [3] and their analysis (Fig. 2) [12]. We are quite unable to reconcile these with Mitchell’s 2010 article [5] or the 2016 Framingham analysis in Journal of Hypertension [1].