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Essential hypertension is lymphatic: a working hypothesis
Medical Hypotheses (1998) 51, 101-103 © Harcourt Brace & Co. Ltd 1998
Essential hypertension is lymphatic: a working hypothesis J. E. MI~KARSKI 315-700 Sir J. A. MacDonald, Kingston, ON, K7M 1A4, Canada (e-mail: [email protected])
Abstract - - Lymphatics, a third component of the circulation, may be deranged by the same factors as veins and arteries. Malfunctioning through overload or dyscrasia, they may foster high blood pressure. It is hypothesized that essential hypertension is caused by lymphatic system aberrations.
Introduction
Controlling hypertension is important because it affects about a quarter of the world's population and is a risk factor for coronary heart disease, stroke, congestive heart failure and peripheral artery disease (1,2). Despite the need, 'we are missing something important in our understanding of hypertension' (3) and have to define over 90% of it as 'essential' because 'as much as 95% of all hypertension is of unknown cause' (4). The situation might be attributed to attention which has been riveted upon arterial and venous circulation, ever since hypertension was induced via renal artery clamps (5). This may have spurred research first to lowering peripheral resistance, then to dampening sympathetic neural activity blamed for driving a hyperkinetic circulation, but neglect of other etiologies. Considerations
It is important to recall that the circulation is not binary but triune. Positive arterial outflow to distal cells, and negative venous return therefrom, cannot
function properly without the third or neutralizing influence of a lymphatic system (6). Governed by wall distensibility and modulated by sympathetic neurons, an active lymph pump intrinsically contracts its vessels (7), increasing pressure from about 0.6 to > 40 mm Hg in order to drain connective tissue spaces of cells, protein constituents, proteolytic enzymes, etc., and return interstitial fluid to the bloodstream. Because of their intimate association with, and functional resemblance to blood vessels, the lymphatics may be subject to the same dysregulation as the cardiovasculature. Lymphocytes needed for defence and healing which migrate into lymph nodes enter the blood via the thoracic duct, while splenic lymphocytes enter the circulation via the splenic vein. This dynamic and highly organized lymphoid system guards the body against foreign antigens by recruiting lymphocytes at about 1% to 2% per hour between the blood, body tissues and secondary lymph organs (8). With reciprocal influence, malfunctions here might precipitate hypertension. Conversely, antihypertensive drugs such as the vasodilator hydrazine may derange lymphoid defences and induce autoimmune disease or haemolytic anaemia (9).
Received 4 April 1997 Accepted 13 May 1997
101
102
Hypothesis A priori, it is hypothesized that much of essential hypertension is caused by lymphatic system aberrations. For example, the lymphatics as an equilibrating component of the circulation, which functions analogously to a sewage and purification system, may suffer from overload or dyscrasia.
Tangential clues 1. Ability of the lymphatics to remove tissue filtrate is important to overall fluid balance, because without lymph flow, the tissue pressure increases. According to the Starling (10) equation, capillary filtrate is a function of differences in hydrostatic and colloidal pressure acting across the capillary wall. In principle, it is conceivable that hypertension could develop from this source. After ligation of the thoracic lymphatic duct, for example, pressure increases noticeably and alternate connections or shunts to blood vessels develop rapidly. 2. Pressure-regulating vasoactive substances (11,12) act as signals among all three components of the circulatory system. As an example, the heart myocytes, by means of atrial natriuretic peptide, modulate not only vasoconstriction (13) but influence the lymphatics. This suggests the lymphatics actively participate in blood pressure regulation. 3. One way in which hypertension might develop is through overtaxing of the lymphatic capacity to handle substances like animal protein which exert osmotic pressure. Further, it is known that methionine derived from animal protein is a precursor of homocysteine, which affects blood pressure by increasing formation of atherogenic oxycholesterols (14). Homocysteine also acts by modifying a genetic variant of LDL cholesterol, lipoprotein (a) (15). Finally, sugar-protein glycosylation might be implicated by exacerbating adhesive vessel blockage. 4. Backed by Virchow's thrombosis triad of vessel injury, altered blood flow and coagulability, lipoproteins and fats may induce injury leading to inflammation and progression toward atherosclerosis (16,17). There is indirect evidence of both humoral and cell-mediated immunity in essential hypertension (18). Degranulation of platelets at sites of injury, for example, attracts foam cells which store plasma lipids in arterial sclerosis. Such foam cells have been recognized as differentiated macrophages (19). As these constituents are associated with the lymphatics, the lymphatic defence system may actively participate in atherosclerosis and hypertension. For instance, cytotoxic T lymphocytes sensitized by antigens from
MEDICAL HYPOTHESES
animal proteins could turn against vascular endothelium. Helper T lymphocytes secreting cytokines may also overrecruit macrophages, or natural killer lymphocytes might attack tissues without antigenic stimulation (20).
Conclusion Suggestive data warrant examination of essential hypertension etiology based on the lymphatic hypothesis. Three starting questions for research might be: (i) Does chronic physical overload disturb lymphatic homeostasis toward increasing blood pressure? (ii) Could dyscrasia due to varied animal proteins, etc., precipitate hypertension? (iii) What factors might activate lymphoid immune mechanisms against vascular beds?
Acknowledgment This work is dedicated to the memory of Jerzy Kazimierz and W'rodzimierzM~karski who died in defence of our freedom in the mass graves of Kharkov and Katyn. Thanks are due Teresita Mfkarski, BScN/RN, for critical discussions of hypertension.
References 1. Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report (JNC V). Arch Intern Med 1993; 153: 154-183. 2. Lenfant C. High blood pressure: some answers, new questions, continuingchallenges.J Am Med Assoc 1996;275: 1604-1606. 3. Dimsdale J E. Symptoms of anxiety and depression as precursors of hypertension. J Am Med Assoc 1997; 277: 574-575. 4. Kaplan N M. Clinical Hypertension, 6th edn. Baltimore, MD: Williams and Wilkins, 1994: 47. 5. GoldblattH, Lynch J, Hanzal R F, Summerville W W. Studies of experimental hypertension, I: The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 1934; 59: 347-378. 6. Abramson D I, Dobrin P B. Blood vessels and lymphatics in organ systems. Toronto: AcademicPress, 1984. 7. McHale N G. Role of the lymph pump and its control. News in PhysiologicalSciences 1995; 10:112-117. 8. Reeves G, Todd I. Lectures on Immunology, 3rd edn. New York: Blackwell Science, 1996. 9. CanadianPharmaceuticalAssociation.Compendiumof pharmaceuticals and specials, 35th edn. Ottawa: author, 1996. 10. Starling E H. The fluids of the body. The Herter lectures. Chicago, IL, 1909. 11. Elias R M, Johnson M G. Modulation of lymphatic pumping by lymph-borne factors after endotoxin administration in sheep. J Appl Physiol 1990; 68: 199-208. 12. Schad H, Brechtelsbauer H. Effect of ganglionic blockade and subsequent i.v. infusion of catecholamines and angiotensin II on the formation and transport of lymph: studies in
103
ESSENTIALHYPERTENSIONIS LYMPHATIC
13.
14. 15.
16.
anesthesized dogs and a review of the literature. J Lymphol 1986; 10: 46-54. Lewicki J A, Protter, A A. Physiological studies of the natriuretic peptide family. In: Laragh J H, Brenner B M, eds. Hypertension: Pathology, Diagnosis, and Management, 2nd edn. New York: Raven Press, 1995. McCully K S. Homoeysteine and vascular disease. Nature Med 1996; 2: 386-398. Scanau A M. Lipoprotein (a) a genetic risk factor for premature coronary heart disease. J Am Med Assoc 1992; 267: 3326-3329. Berliner A J, Navab M, Fogelman A Met al. Atherosclerosis:
17. 18. 19.
20.
basic mechanisms - - oxidation, inflammation, and genetics. Circulation 1995; 91: 2488-2496. Witzum J L. The oxidation hypothesis of atherosclerosis. Lancet 1994; 344: 793-795. Norman R A, Dzielak D J, Prost K L e t al. Immune system dysfunction contributes to aetiology of spontaneous hypertension. J Hypertens 1985; 3: 261-268. Schaffner T, Taylor K, Bartucci E J e t al. Arterial foam cells with distinctive immunologic and histochemical features of macrophages. Am J Pathol 1980; 100: 57-73. Liu C-C, Young L H Y, Young J D-E. Lymphocyte mediated cytolysis and disease. N Engl J Med 1996; 335: 1651-1659.
Essential hypertension is lymphatic: a working hypothesis J. E. MI~KARSKI 315-700 Sir J. A. MacDonald, Kingston, ON, K7M 1A4, Canada (e-mail: [email protected])
Abstract - - Lymphatics, a third component of the circulation, may be deranged by the same factors as veins and arteries. Malfunctioning through overload or dyscrasia, they may foster high blood pressure. It is hypothesized that essential hypertension is caused by lymphatic system aberrations.
Introduction
Controlling hypertension is important because it affects about a quarter of the world's population and is a risk factor for coronary heart disease, stroke, congestive heart failure and peripheral artery disease (1,2). Despite the need, 'we are missing something important in our understanding of hypertension' (3) and have to define over 90% of it as 'essential' because 'as much as 95% of all hypertension is of unknown cause' (4). The situation might be attributed to attention which has been riveted upon arterial and venous circulation, ever since hypertension was induced via renal artery clamps (5). This may have spurred research first to lowering peripheral resistance, then to dampening sympathetic neural activity blamed for driving a hyperkinetic circulation, but neglect of other etiologies. Considerations
It is important to recall that the circulation is not binary but triune. Positive arterial outflow to distal cells, and negative venous return therefrom, cannot
function properly without the third or neutralizing influence of a lymphatic system (6). Governed by wall distensibility and modulated by sympathetic neurons, an active lymph pump intrinsically contracts its vessels (7), increasing pressure from about 0.6 to > 40 mm Hg in order to drain connective tissue spaces of cells, protein constituents, proteolytic enzymes, etc., and return interstitial fluid to the bloodstream. Because of their intimate association with, and functional resemblance to blood vessels, the lymphatics may be subject to the same dysregulation as the cardiovasculature. Lymphocytes needed for defence and healing which migrate into lymph nodes enter the blood via the thoracic duct, while splenic lymphocytes enter the circulation via the splenic vein. This dynamic and highly organized lymphoid system guards the body against foreign antigens by recruiting lymphocytes at about 1% to 2% per hour between the blood, body tissues and secondary lymph organs (8). With reciprocal influence, malfunctions here might precipitate hypertension. Conversely, antihypertensive drugs such as the vasodilator hydrazine may derange lymphoid defences and induce autoimmune disease or haemolytic anaemia (9).
Received 4 April 1997 Accepted 13 May 1997
101
102
Hypothesis A priori, it is hypothesized that much of essential hypertension is caused by lymphatic system aberrations. For example, the lymphatics as an equilibrating component of the circulation, which functions analogously to a sewage and purification system, may suffer from overload or dyscrasia.
Tangential clues 1. Ability of the lymphatics to remove tissue filtrate is important to overall fluid balance, because without lymph flow, the tissue pressure increases. According to the Starling (10) equation, capillary filtrate is a function of differences in hydrostatic and colloidal pressure acting across the capillary wall. In principle, it is conceivable that hypertension could develop from this source. After ligation of the thoracic lymphatic duct, for example, pressure increases noticeably and alternate connections or shunts to blood vessels develop rapidly. 2. Pressure-regulating vasoactive substances (11,12) act as signals among all three components of the circulatory system. As an example, the heart myocytes, by means of atrial natriuretic peptide, modulate not only vasoconstriction (13) but influence the lymphatics. This suggests the lymphatics actively participate in blood pressure regulation. 3. One way in which hypertension might develop is through overtaxing of the lymphatic capacity to handle substances like animal protein which exert osmotic pressure. Further, it is known that methionine derived from animal protein is a precursor of homocysteine, which affects blood pressure by increasing formation of atherogenic oxycholesterols (14). Homocysteine also acts by modifying a genetic variant of LDL cholesterol, lipoprotein (a) (15). Finally, sugar-protein glycosylation might be implicated by exacerbating adhesive vessel blockage. 4. Backed by Virchow's thrombosis triad of vessel injury, altered blood flow and coagulability, lipoproteins and fats may induce injury leading to inflammation and progression toward atherosclerosis (16,17). There is indirect evidence of both humoral and cell-mediated immunity in essential hypertension (18). Degranulation of platelets at sites of injury, for example, attracts foam cells which store plasma lipids in arterial sclerosis. Such foam cells have been recognized as differentiated macrophages (19). As these constituents are associated with the lymphatics, the lymphatic defence system may actively participate in atherosclerosis and hypertension. For instance, cytotoxic T lymphocytes sensitized by antigens from
MEDICAL HYPOTHESES
animal proteins could turn against vascular endothelium. Helper T lymphocytes secreting cytokines may also overrecruit macrophages, or natural killer lymphocytes might attack tissues without antigenic stimulation (20).
Conclusion Suggestive data warrant examination of essential hypertension etiology based on the lymphatic hypothesis. Three starting questions for research might be: (i) Does chronic physical overload disturb lymphatic homeostasis toward increasing blood pressure? (ii) Could dyscrasia due to varied animal proteins, etc., precipitate hypertension? (iii) What factors might activate lymphoid immune mechanisms against vascular beds?
Acknowledgment This work is dedicated to the memory of Jerzy Kazimierz and W'rodzimierzM~karski who died in defence of our freedom in the mass graves of Kharkov and Katyn. Thanks are due Teresita Mfkarski, BScN/RN, for critical discussions of hypertension.
References 1. Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report (JNC V). Arch Intern Med 1993; 153: 154-183. 2. Lenfant C. High blood pressure: some answers, new questions, continuingchallenges.J Am Med Assoc 1996;275: 1604-1606. 3. Dimsdale J E. Symptoms of anxiety and depression as precursors of hypertension. J Am Med Assoc 1997; 277: 574-575. 4. Kaplan N M. Clinical Hypertension, 6th edn. Baltimore, MD: Williams and Wilkins, 1994: 47. 5. GoldblattH, Lynch J, Hanzal R F, Summerville W W. Studies of experimental hypertension, I: The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 1934; 59: 347-378. 6. Abramson D I, Dobrin P B. Blood vessels and lymphatics in organ systems. Toronto: AcademicPress, 1984. 7. McHale N G. Role of the lymph pump and its control. News in PhysiologicalSciences 1995; 10:112-117. 8. Reeves G, Todd I. Lectures on Immunology, 3rd edn. New York: Blackwell Science, 1996. 9. CanadianPharmaceuticalAssociation.Compendiumof pharmaceuticals and specials, 35th edn. Ottawa: author, 1996. 10. Starling E H. The fluids of the body. The Herter lectures. Chicago, IL, 1909. 11. Elias R M, Johnson M G. Modulation of lymphatic pumping by lymph-borne factors after endotoxin administration in sheep. J Appl Physiol 1990; 68: 199-208. 12. Schad H, Brechtelsbauer H. Effect of ganglionic blockade and subsequent i.v. infusion of catecholamines and angiotensin II on the formation and transport of lymph: studies in
103
ESSENTIALHYPERTENSIONIS LYMPHATIC
13.
14. 15.
16.
anesthesized dogs and a review of the literature. J Lymphol 1986; 10: 46-54. Lewicki J A, Protter, A A. Physiological studies of the natriuretic peptide family. In: Laragh J H, Brenner B M, eds. Hypertension: Pathology, Diagnosis, and Management, 2nd edn. New York: Raven Press, 1995. McCully K S. Homoeysteine and vascular disease. Nature Med 1996; 2: 386-398. Scanau A M. Lipoprotein (a) a genetic risk factor for premature coronary heart disease. J Am Med Assoc 1992; 267: 3326-3329. Berliner A J, Navab M, Fogelman A Met al. Atherosclerosis:
17. 18. 19.
20.
basic mechanisms - - oxidation, inflammation, and genetics. Circulation 1995; 91: 2488-2496. Witzum J L. The oxidation hypothesis of atherosclerosis. Lancet 1994; 344: 793-795. Norman R A, Dzielak D J, Prost K L e t al. Immune system dysfunction contributes to aetiology of spontaneous hypertension. J Hypertens 1985; 3: 261-268. Schaffner T, Taylor K, Bartucci E J e t al. Arterial foam cells with distinctive immunologic and histochemical features of macrophages. Am J Pathol 1980; 100: 57-73. Liu C-C, Young L H Y, Young J D-E. Lymphocyte mediated cytolysis and disease. N Engl J Med 1996; 335: 1651-1659.