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(Stroke. 1996;27:7-9.)
© 1996 American Heart Association, Inc.

Articles

Hypertension, Stroke, and Coronary Heart Disease in Relatives of Patients With Subarachnoid Hemorrhage

J.E.C. Bromberg, MD; G.J.E. Rinkel, MD; A. Algra, MD; U.A.C. van den Berg, MD; M.L.R. Tjin-A-Ton, MD J. van Gijn, MD, FRCPE

From the University Department of Neurology, Utrecht, Netherlands.

Correspondence to Jacoline E.C. Bromberg, MD, University Department of Neurology, PO Box 85500, 3508 GA Utrecht, Netherlands.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose First-degree relatives of patients with subarachnoid hemorrhage (SAH) have a three to seven times greater risk of SAH than second-degree relatives and than the general population. If hypertension, which is in part genetically determined, contributes to this increased risk, the frequency of hypertension and its sequelae would be expected to be higher in first- than in second-degree relatives of patients with SAH.

Methods We compared the reported frequency of hypertension, stroke, and coronary heart disease between 1290 first- and 3588 second-degree relatives of a prospective series of patients with SAH.

Results The relative risk adjusted for age and survival status in first-degree relatives was 2.3 (95% confidence interval [CI], 1.9 to 2.9) for hypertension, 1.8 (95% CI, 1.3 to 2.4) for stroke, and 1.9 (95% CI, 1.5 to 2.3) for coronary heart disease.

Conclusions Hypertension is a familial factor contributing to the risk of SAH. Hypertension should be sought and treated in first-degree relatives of patients with SAH to reduce the increased risk of cerebrovascular and cardiovascular diseases.

Key Words: subarachnoid hemorrhage • hereditary disease • hypertension

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hereditary and degenerative disorders of blood vessels may play a role in the pathogenesis of intracranial aneurysms.¹ In a recent study, we found an increased risk of SAH in first-degree relatives compared with second-degree relatives of patients with SAH,² which suggests a familial factor in at least some patients. This familial factor could be a genetically determined defect in the structure of the arterial wall or a secondary effect of another familial trait such as hypertension; in 20% to 60% of hypertensive patients, the disorder is genetically determined.^{3 4} Population studies suggest that hypertension is a risk factor for SAH,^{5 6 7} although a causal relationship has not been universally accepted.⁸ If hypertension is indeed a familial factor contributing to an increased risk for SAH in first-degree relatives, the frequency of hypertension among first-degree relatives of patients with SAH should also be higher than among second-degree relatives. As a result, other diseases for which hypertension is a risk factor, such as cerebrovascular and cardiovascular diseases, would also be expected to occur more frequently in first-degree relatives.

We therefore studied the frequency of hypertension, as well as of the related disorders stroke and CHD, in first- and second-degree relatives of a prospective series of patients with SAH.

	Subjects and Methods

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From September 1991 through October 1992 we prospectively collected a series of patients with SAH admitted to the Academic Medical Centre, Amsterdam, and the University Hospitals of Rotterdam and Utrecht. The diagnosis of SAH was based on history, neurological examination, and a CT scan showing extravasated blood in the basal cisterns. Informed consent was obtained from the patient or next of kin. Pedigrees were made up for 163 patients (61 men and 102 women). In 123 patients, one or more aneurysms were proven by angiography, operation, or autopsy; 15 patients had perimesencephalic hemorrhage with a negative angiogram; and angiography was otherwise negative in 5 patients and was not performed because of a poor clinical condition in 20. No patients with coagulation disorders or an arteriovenous malformation were encountered in the series. All living relatives of the 163 patients with SAH were interviewed over the telephone. The standard questionnaire included questions regarding episodes of SAH or of sudden severe headache; the occurrence of stroke, cardiovascular disease, or hypertension; and the use of antihypertensive medication. For deceased relatives, a next of kin was interviewed about the cause of death. When stroke or any other brain disease was reported, medical documents were obtained if available.

We compared the frequency of self-reported hypertension, stroke other than SAH (ischemic stroke or transient ischemic attack, intracerebral hemorrhage, unspecified stroke), and CHD (myocardial infarction, angina pectoris, cardiac failure) in first- and second-degree relatives of the index patients. Because the age distribution of first-degree relatives differed from that of second-degree relatives (Figure), we used RRs with matching 95% CIs adjusted for age according to the Poisson regression model.⁹ In addition, we compared the frequency of hypertension, stroke, and CHD in deceased and living relatives and adjusted for survival status to control for reporting bias related to the occurrence of fatal diseases.

View larger version (61K): [in this window] [in a new window]   Figure 1. Bar graph shows age distribution of first- and second-degree relatives.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The 163 patients with SAH included in the study had 1290 first-degree relatives and 3588 second-degree relatives. Eighteen (1%) first-degree and 238 (7%) second-degree relatives could not be included in the analysis because age at death or at completion of the study was unknown. The age distribution of relatives is shown in the Figure. Of second-degree relatives, 44% had died versus only 25% of first-degree relatives.

The frequency of hypertension, stroke (excluding SAH), and CHD is shown in Table 1. The RR for self-reported hypertension adjusted for age and survival status in first-degree relatives compared with second-degree relatives was 2.3 (95% CI, 1.9 to 2.9). For stroke, this RR was 1.8 (95% CI, 1.3 to 2.4), and for CHD the RR was 1.9 (95% CI, 1.5 to 2.3). We excluded SAH from the analysis for stroke, since in families of a patient with SAH the risk of SAH may differ from that of other cerebrovascular diseases, but inclusion of SAH only marginally changes the RR for stroke in general to 1.6 (95% CI, 1.3 to 2.1).

View this table: [in this window] [in a new window]   Table 1. Frequency of Hypertension, Stroke, and CHD in First- and Second-Degree Relatives

We found no difference in the reported frequency of hypertension between deceased relatives and relatives who were still alive at the time of the study (Table 2). The RR for hypertension in living first-degree relatives compared with living second-degree relatives was 2.2, and for deceased first-degree relatives it was 2.6; the probability value for the difference of RRs was .37. Similarly, there was no difference between living and deceased relatives in the occurrence of stroke (P=.69) or in the occurrence of CHD (P=.94).

View this table: [in this window] [in a new window]   Table 2. Difference in Risks of Hypertension, Stroke, and CHD in Living and Deceased First-Degree Compared With Second-Degree Relatives

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We found that hypertension had been diagnosed almost three times as often in first- as in second-degree relatives of patients with SAH. Because hypertension is genetically determined in 20% to 60% of hypertensive subjects³ and linkage of the angiotensinogen gene to hypertension has recently been demonstrated,^{10 11 12} this association suggests that hypertension explains at least part of the increased risk for SAH in first-degree relatives of index patients.² In accordance with this higher frequency of hypertension in first-degree relatives, strokes and CHD also occurred significantly more often in first- than in second-degree relatives. Our data therefore support the notion that SAH belongs to the category of atherosclerotic diseases for which hypertension is a risk factor.

However, hypertension occurred only three times more often, and stroke and CHD one and one-half times more often, in first- than in second-degree relatives, whereas SAH occurs three to seven times more often in first- than in second-degree relatives.² This suggests that a familial factor other than hypertension, such as a structural abnormality of the arterial wall, also contributes to the risk of SAH in first-degree relatives of patients with SAH. Comparison of the RR for hypertension in first- versus second-degree relatives in families with familial SAH with that in families with truly sporadic SAH could perhaps shed more light on the existence of a second etiologic factor, but even in our series of 163 families groups were too small for statistical testing to be meaningful.

Relatives were classified as hypertensive when they themselves reported hypertension. The diagnosis was not verified, and this naturally causes misclassification to a certain extent. However, since this will occur in first- and second-degree relatives alike, nondifferential misclassification will result, which leads to bias toward the null condition and an underestimation of the difference.¹³ Thus, the actual RR for hypertension in first- compared with second-degree relatives may be even greater than 2.3.

Moreover, although more second-degree than first-degree relatives had died (44% versus 25%), there was no difference in the frequency of hypertension between living relatives and deceased relatives.

In conclusion, our study provides evidence that hypertension is a familial factor contributing to the increased risk of SAH in first-degree relatives but that the association is not powerful enough to explain the entire excess risk of SAH in first-degree relatives of index patients. Moreover, first-degree relatives of patients with SAH are at risk not only for SAH² but also for hypertension and for stroke and other CHD. Detection and treatment of hypertension in first-degree relatives of patients with SAH may prevent a proportion of these cerebrovascular and cardiovascular diseases.

	Selected Abbreviations and Acronyms

 

SAH = subarachnoid hemorrhage CHD = coronary heart disease RR = relative risk CI = confidence interval

	Acknowledgments

 
This study was partially supported by the Dutch Heart Foundation (grant 90.321).

Received August 3, 1995; revision received September 19, 1995; accepted September 29, 1995.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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2. Bromberg JEC, Rinkel GJE, Algra A, Greebe P, van Duyn CM, Hasan D, Limburg M, ter Berg HWM, Wijdicks EFM, van Gijn J. Subarachnoid haemorrhage in first and second degree relatives of patients with subarachnoid haemorrhage. BMJ. 1995;311:288-289. [Free Full Text]

3. Kurtz TW, Spence MA. Genetics of essential hypertension. Am J Med. 1993;94:77-84. [Medline] [Order article via Infotrieve]

4. Pickering G. Hyperpiesis: high blood-pressure without evident cause: essential hypertension. Brit Med J. 1965;2:1021-1026.

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6. Knekt P, Reunanen A, Aho K, Helivaara M, Rissanen A, Aromaa A, Impivaraa O. Risk factors for subarachnoid hemorrhage in a longitudinal population study. J Clin Epidemiol. 1991;44:933-939. [Medline] [Order article via Infotrieve]

7. Sacco RL, Wolf PA, Bharucha NE, Meeks SL, Kannel WB, Charette J, McNamara PM, Palmer EP, D'Agostino R. Subarachnoid and intracerebral hemorrhage: natural history, prognosis, and precursive factors in the Framingham study. Neurology. 1984;34:847-854. [Abstract/Free Full Text]

8. Mayberg MR, Batjer HH, Dacey R, Diringer M, Haley EC, Heros RC, Sternau LL, Torner J. Guidelines for the management of aneurysmal subarachnoid hemorrhage. Stroke. 1994;25:2315-2328. [Medline] [Order article via Infotrieve]

9. Breslow NE, Day NE. Statistical Methods in Cancer Research, II: The Design and Analysis of Cohort Studies. Lyon, France: IARC Scientific Publications; 1987:131-135.

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13. Rothman KJ. Modern Epidemiology. Boston, Mass: Little, Brown & Co; 1986:85-87.

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