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Cancer and Hypertension

An Unresolved Issue
Originally published1 Sep 1996https://doi.org/10.1161/01.HYP.28.3.321Hypertension. 1996;28:321–324

    Abnormalities in proliferative pathways have been noted in hypertension for over half a century. They have been proposed by Folkow1 to be a hallmark of hypertension, leading to increased peripheral resistance. Heightened proliferation, characterized by a higher organ-to–body weight ratio, has been observed early in hypertension, at least in genetic models, even at birth.234 The increased proliferation of vascular smooth muscle cells (VSMCs) in spontaneously hypertensive rats persists in culture, responds exaggeratedly to growth stimuli,5678 and is characterized by shortening of the cell cycle.910

    The physiological balance between cell growth and death is at present believed to be governed by the interplay between cell replication and apoptosis (ie, genetically programmed cell death).11121314 We have recently summarized evidence that cell death by apoptosis can control the growth of VSMCs and that significant abnormalities can be observed in cardiovascular diseases.12131415 Some examples are depicted in Table 1. Many pathways thought to be abnormal in hypertension were actually more intensely studied in relation to neoplastic growth, where it was originally described.161718 Indeed, apoptosis received much attention in the field of cancer.1920 In this context, it is relevant that the index word “cancer” is absent in most textbooks dealing with hypertension, and the subject was only briefly dealt with in a philosophical manner.21 Is that justified?

    Certainly not on the basis of epidemiological evidence. A simple MedLine survey teaches us that solid evidence points to the possibility that hypertension is actually a significant risk factor for cancer. At least seven prospective studies22232425262728 highlighted in Table 2 have demonstrated clearly that hypertension is a risk factor. Yet unresolved differences persist, mainly concerning cancer site specificity, sex, age, duration of the disease, and interactions with other risk factors, including obesity and smoking. Thus, the organ most frequently related to preexisting hypertension, even in long-term prospective studies, is the kidney,2930 but the colon2225 and even the endometrium3132 have been cited. Some studies have confined the risk to men, yet others have demonstrated hypertension to be a risk factor for cancer in women as well.2530 Other risk factors, mainly obesity,33 diabetes,3132 and smoking,28 appear to be related in a complex fashion to hypertension as a risk for cancer. Most studies that address this question have found that risk increases with the duration of hypertension, particularly when diagnosed before the age of 50 years.283435 A complication in the assessment of hypertension as a risk factor is actually the possibility that hypertension of short (<5 years) duration may even procure a protective effect, while a positive association is observed with prolonged exposure to hypertension (usually >10 years).2834 This increased risk of cancer in hypertension cannot be simply explained as a consequence of detection bias,36 since in many studies mentioned, the outcome is not only the diagnosis of cancer but also death caused by it.222425

    But how did it all get started? Actually, the first prospective type of study was reported by Dyer et al22 in 1975, from an analysis of the relationship of systolic (SBP) and diastolic (DBP) blood pressure at entry into the study and a 14-year mortality follow-up. Both SBP and DBP appeared to be significantly associated with subsequent mortality from lung, colon, and other cancers, even after appropriate adjustment for age, cholesterol, and smoking.22 It is relevant that this prospective study was antedated by three retrospective investigations,35373839 all relating the use of reserpine (the antihypertensive drug of choice in those days) with breast cancer. Careful analysis by Dyer et al22 helped to exclude reserpine and implicated hypertension as a culprit in cancer association.

    Since then, many retrospective cohorts, some simply based on questionnaires, others carefully related to records of patients in prepaid health plans, have linked the use of other antihypertensive agents with cancer. Most frequent associations have been reported between the use of thiazide diuretics and the incidence of renal cancer, but again, only in retrospective case/control studies.35404142434445 Actually, half a dozen trials have reported the association from various parts of the globe, including large multinational efforts.42 It has to be mentioned that here most of the studies have recognized that it is difficult to disentangle the separate effects due to potential misclassification of highly correlated events,3540 ie, to exclude hypertension per se as a cause because the use of diuretics is highly correlative with it. Again, the duration (of diuretic use/hypertension) has been frequently noted.35 Other drugs, including β-blockers, have been reported to be a significant risk factor for kidney cancer.46 It is of interest that in a large cohort from the Glasgow Clinic, which helped to clear β-blockers from their association with kidney cancer, actually remained significantly more relevant among hypertensives independent of the medication used.47 It is also of interest that in studies demonstrating the danger of diuretics, other antihypertensive drugs are usually considered to be without risk.3541 Although the fact was largely unnoticed, even ACE inhibitors appeared to be related to increased death (38 gastrointestinal cancers in the enalapril group compared with 22 in the placebo group; odds ratio, 1.7) in a double-blind trial.48 The relevance of the above-mentioned studies will also have to be evaluated, keeping in mind the reality of competing risk of death phenomenon (cardiovascular versus cancer)49 ; yet let us mention that the increased relative risk of cancer death in hypertension was observed in both treated and untreated patients.22

    With what we have discussed, it came as a surprise that in a recent retrospective case/control study by Pahor et al,50 none of the above was considered. There was no suggestion or reference to prospective investigations demonstrating hypertension as a risk factor for cancer, and no mention of all other drugs related in remote and recent history with the risk for cancer in the study or accompanying editorials.5152 What is most surprising is the discussed pathophysiological mechanism proposing an explanation for the association between use of calcium channel blockers and cancer, ie, their putative effects on apoptosis. The latter is a complex process, leading to DNA fragmentation via calcium-dependent as well as calcium-independent pathways, and so is DNA synthesis and repair.535455

    At present, we do not know of any potential mechanisms of hypertension as a risk factor for cancer. Alas, we have done very little in this area. A single brief report in 1975 as a reaction to the milestone paper of Dyer et al22 suggested abnormalities of carcinogen binding to DNA in lymphocytes of hypertensive subjects.56 Very little is also known in extensively studied spontaneously hypertensive rats, with a few reports indicating an increased but variable response to carcinogens.575859

    Is any class of antihypertensive agents safe? All are, if we stand by targeted studies. Are retrospective case/control studies useful, perhaps as stimulants for debate and thoughts? We have to recognize that we have not done much, and in view of what our epidemiology colleagues are telling us about hypertension as a risk for cancer in humans, few understand it. It is time to change that.

    Table 1. Conditions Associated With Cardiovascular Apoptosis In Vivo

    TissueEvidenceComments on ApoptosisReference
    Smooth muscle cells from genetically hypertensive rats and miceb, cGreater in smooth muscle cells cultured from hypertensive animals. Also increased in heart, kidney, and brain in vivo.14
    Abdominal aortas of newborn sheepb, c, dInduced in vivo by a decrease in blood flow after birth.60
    Rat aortic intimal thickeninga, b, c, dRestricted to areas with high cell proliferation rates.61, 62
    Advanced human atheromaa, b, c, dColocalized with ICE expression; more frequent in atheroma cells versus arterial media cells.62-64
    Human primary and restenotic coronary atherectomy specimencMore frequent in restenotic specimens.65
    Intima in human vein graftsaMore frequent in intima versus media.66
    Human retinal microvascular endothelial cellsa, cIncreased in diabetic subjects in vivo.67
    Postnatal heartcPeaks in myocytes and fibroblasts early after birth. More prominent in right versus left ventricle.68
    Arrhythmic myocardiuma, c69
    Pressure-overloaded heartb, cPeaks at 4 days postbanding of aortic arch, then subsides.13
    Kidney in AIDS patientsa, cIncreased in tubular cells.70
    Polycystic kidneya, b, c, dIncreased in glomeruli, cyst walls, and tubular cells.71
    Atrophied kidney undergoing regenerationcTransient increase preceeding epithelial hyperplasia.72
    Kidney with glomerulonephritisb, cIncreased in glomeruli and mesangium.73

    a, Cellular/nuclear morphology.

    b, “DNA laddering” by gel electrophoresis.

    c, In situ cell labeling with terminal deoxynucleotide transferase.

    d, In vivo nuclear staining with propidium iodine.

    Table 2. Highlights of Prospective Studies Evaluating Hypertension as a Risk for Cancer

    Odds Evaluation as Reported
    StudyPublication YearNumber of PatientsDuration of Observation, yOrgan
    Dyer et al221975123314BPRRLung, colon, other
    >1482.02
    >1603.05
    Svardsudd and Tibblin23197997313.5Trend P>.05All
    Raynor et al241981539717SBPRRKidney
    <1251.00
    <1391.40
    <2501.90
    Rate, %
    Khaw and Barrett-Connor25198428529SBPM F
    <1304.4 4.1
    130-1448.2 4.3
    145-1597.3 4.9
    >1607.7 5.3
    Goldbourt et al26198610 05915RRCIDigestive, adenocarcinoma,
    1.201.03-1.39genitourinary
    1.191.04-1.37
    1.260.99-1.59
    Buck and Donner2719874067 HBP5All hypertensivesRR 1.34Abdominal, lung, kidney, ovary
    CI 1.03-1.74
    10 366 NormotensiveNew hypertensive with DBP>95RR 2.29
    CI 1.42-3.68
    Filipovsky et al331993731215-20DBP>96More in lean subjects
    RR 1.66CI 1.45-1.90
    Wannamethee and Shaper281996773512.75SBP>161CI 1.04-2.38Only in smokers
    RR 1.56

    RR indicates relative risk; CI, confidence interval.

    The author thanks Drs Jacques Lelorier, Denis de Blois, and Johanne Tremblay for their helpful comments and gratefully acknowledges the help of Josée Bédard-Baker as well as Ovid Da Silva in preparing this manuscript.

    Footnotes

    Correspondence to Pavel Hamet, Laboratory of Molecular Pathophysiology, Centre de Recherche Hôtel-Dieu de Montréal, 3850 St Urbain St, Montréal, Québec H2W 1TS, Canada.

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