Correspondence
Plasma Renin Activity and Ischemic Heart Disease
N Engl J Med 1994; 330:506-507February 17, 1994
- Article
To the Editor:
The recent report by Meade et al. (Aug. 26 issue)1 relating plasma renin activity to ischemic heart disease in primarily normotensive subjects is consistent with and extends our previous investigation2 in which a high renin-sodium profile was associated with an increased rate of myocardial infarction among subsequently treated patients with hypertension. This association was confirmed by Meade et al.,1 who also found an increase in the incidence of myocardial infarction among their hypertensive subjects with elevated plasma renin activity.
The inability of these authors to detect this association in their normotensive subjects suggests that both high plasma renin activity and high blood pressure are necessary to produce ischemic vascular disease. This is consistent with the inverse relation between plasma renin activity and blood pressure in normal people and animal models (the higher the pressure, the lower the plasma renin activity). In this context, virtually any plasma renin activity in a hypertensive subject can be considered inappropriate3. This may be due to the failure (as we believe) of the elevated pressure to suppress renin secretion in such patients, as it always does in normal subjects, possibly because of incipient or occult renal disease in hypertensive subjects.
In our study of patients with hypertension, the rate of myocardial infarction was significantly greater in the group with a high renin-sodium profile than in all other equally hypertensive patients. In the authors' study, too,1 plasma renin activity was higher in their hypertensive subjects who had an infarction within five years than in those who did not (964.0 vs. 674.6 pmol per liter per hour). Unfortunately, the significance of this difference was not reported.
The report by Meade et al. differs from our study in two important ways. First, they studied mostly normotensive subjects, and not just those who would have met our criteria for blood pressure2. Second, we compared the 12 percent of patients who had the highest profiles with all other patients, not just the 33 percent with the lowest profiles. Perhaps a similar analysis of the authors' data would yield further statistical confirmation of the association of high plasma renin activity with an increased rate of myocardial infarction among hypertensive subjects.
The association of elevated plasma renin activity and myocardial infarction in hypertensive subjects also might have been found to be more significant in the study of Meade et al. if plasma renin activity had not been routinely measured in plasma that had been chilled, which might have resulted in unpredictable cryoactivation of prorenin -- a methodologic flaw recognized only after the blood samples were collected for their study4. This event would inevitably mute the association between a high profile and infarction by misclassifying subjects with truly low plasma renin activity in higher categories. Short of drawing more blood samples, there is no post hoc statistical approach to correct for this methodologic error5.
Finally, we do not believe the renin assay used by Meade et al. is a “standard method” for measuring plasma renin activity. In fact, when renin incubation is carried out at pH 6 most renin assays routinely add a serine protease inhibitor, such as diisopropyl fluorophosphate or phenylmethylsulfonyl fluoride, to inhibit angiotensinases that are not blocked at this pH by the inhibitors used by Meade et al.
5 ReferencesMichael H. Alderman, M.D.
Albert Einstein College of Medicine, Bronx, NY 10461Jean E. Sealey, D.Sc.
John H. Laragh, M.D.
New York Hospital-Cornell Medical Center, New York, NY 100211
Meade TW ,Cooper JA ,Peart WS . Plasma renin activity and ischemic heart disease. N Engl J Med 1993;329:616-619
Full Text | Web of Science | Medline2
Alderman MH ,Madhavan S ,Ooi WL ,Cohen H ,Sealey JE ,Laragh JH . Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098-1104
Full Text | Web of Science | Medline3
Sealey JE ,Blumenfeld JD ,Bell GM ,Pecker MS ,Sommers SC ,Laragh JH . On the renal basis for essential hypertension: nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasoconstriction-volume relationship. J Hypertens 1988;6:763-777
CrossRef | Medline4
Sealey JE . Plasma renin activity and plasma prorenin assays. Clin Chem 1991;37:1811-1819
Web of Science | Medline5
Mertens TE . Estimating the effects of misclassification. Lancet 1993;342:418-421
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The comments by Alderman and colleagues are ambivalent, in that they claim that our findings support their conclusions while at the same time they question the laboratory method on which our results were based.
In our analyses we had the advantage of considerably more episodes of myocardial infarction than Alderman et al.,1 and none of our analyses confirmed an association between plasma renin activity and ischemic heart disease. We drew attention to some findings suggesting that the results of the two studies are not necessarily incompatible, although these came from subgroup analyses to be interpreted only cautiously, as we ourselves pointed out. We referred to the nonsignificant (P = 0.32) relation between levels of renin activity and the occurrence of myocardial infarction according to interval between entry and event. There was, however, a marginally significant trend (P = 0.04) for systolic blood pressure. Table 3 of the study by Alderman et al.1 shows the rate ratio for their high-renin and low-renin groups (accounting for about 11 percent and 31 percent of the person-years of follow-up, respectively). A similar analysis of our data gave the nonsignificant results we referred to. We reiterate, however, that the most appropriate analyses are those based on all available data rather than data from subgroups, and none of these showed relations between plasma renin activity and ischemic heart disease. In other studies, the elevated levels of renin activity expected in patients taking thiazide diuretics are associated with a reduction in the incidence of stroke and ischemic heart disease2,3.
As we also pointed out, our laboratory method establishes the same association between plasma renin activity and a range of characteristics, such as age, sex, ethnic group, and blood pressure, as the assay used by Alderman et al.,1 so that any differences between the two methods cannot account for the differences between the results of the two studies.
3 ReferencesT.W. Meade, D.M.
J.A. Cooper, M.Sc.
W.S. Peart, M.D.
Medical College of St. Bartholomew's Hospital, London EC1M 6BQ, United Kingdom1
Alderman MH ,Madhavan S ,Ooi WL ,Cohen H ,Sealey JE ,Laragh JH . Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098-1104
Full Text | Web of Science | Medline2
Medical Research Council Working Party
CrossRef | Web of Science | Medline3
MRC Working PartyMedical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992;304:405-412
CrossRef | Web of Science
- Citing Articles (2)
Citing Articles
1
Jens Jordan, Italo Biaggioni. (2002) Diagnosis and Treatment of Supine Hypertension in Autonomic Failure Patients With Orthostatic Hypotension. The Journal of Clinical Hypertension 4:2, 139-145
CrossRef2
A H. Jan Danser, Frans H.M. Derkx, Maarten A.D.H. Schalekamp, Hans-Werner Hense, Günter A.J. Riegger, Heribert Schunkert. (1998) Determinants of interindividual variation of renin and prorenin concentrations. Journal of Hypertension 16:6, 853-862
CrossRef
