Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analysesBMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f1378 (Published 04 April 2013) Cite this as: BMJ 2013;346:f1378
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Re: Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses
This century dietary approach (Addison W)1 has not been properly addressed in the pathogenesis and treatment of hypertension and cardiovascular diseases (CVD). In effect, low potassium (K) intake has been associated with elevated BP, hypertension and stroke, and higher levels of this ion in human and animal models protects against these conditions.2,3 However, since K is the main intracellular ion and our foods come from animal or plant cells, it is difficult to explain body K deficits in hypertensives or CVD patients, except for the non-sodium dependent hereditable defect in red-blood-cell (RBC) K-uptake,4-6 drugs affecting RBC-K content and transport (β-blockers, diuretics, potassium-proton pump inhibitors, NSAIDs),7-9 or body K declining with age (0.23 to 0.26 mmol/kg per year).10
This hereditable defect in RBC-K uptake is critical for K and O2-binding to human oxyhemoglobin11 and other RBC functions including Pyruvate-Kinase potassium dependent ATP synthesis12 and ATP release by RBC during low PO2 or pH, the most powerful regulator of vascular tone and tissue blood flow and oxygenation.13
In this context, the recent crystal structure of the Na/K ATPase14 further support that this Intermediate phenotype in essential hypertension represents a hereditable defect unrelated to cell Na exchange, independent of drugs, dietary Na/K intake, sex, race or age, and expressed in all hypertensive subjects and 52% of their normotensive adolescents offspring (Fig. 1, Bimodal expression).5 BP and plasma aldosterone in these adolescents were higher (167±58 vs 105±17 pg/ml, p<0.001) and RBC-K lower (88.2±4 vs 92.3±5 mmol/lc, p<0.005) than those from normotensive parents (Delgado-Almeida A, unpublished observation, 2010).
Such RBC-K depletion serially recorded in essential hypertension implies a genetic mechanism from erythropoietic cells, in which the increased plasma aldosterone could be a non-classical feedback for cell K depletion, as the rapidly increased plasma aldosterone in athletes subjects during prolonged hypokinesis or astronauts in zero-gravity space flights.15,16
The above considerations apply to broader aspects in evaluation and treatment of hypertension, in which a different and novel approach is necessary for the understanding the role of aldosterone in body Na/K physiology and disorders that occur in hypertensive subjects or that may follow the administration of most comon antihypertensive drugs. Unfortunately, clinical physiology and pharmacology of intracellular K have been virtually ignored in cardiovascular medicine.17 In this scenario, it should not be surprising that despite the large number of life style modifications and dietary advices, the number of hypertensives is rising in this century,18 with an estimated world population of 1.5 billion hypertensives in 2020.
However, other phenotypes associated to this genetic defect (electrocardiographic, vascular and central aortic phenotypes) could be easily recognized in hypertension or other CVD. First, the ST-T changes and LV straight pattern, recently considered to be a non-specific ST-T alterations (AHA, ACC), a critical point since these ECG alterations are not reversed by current anti-hypertensive treatment,19 whereas a T wave inversion may carry an elevated risk for ischemic heart disease, whether in conjunction with ST depression or increased QRS voltages. Such “minor” alterations, often discarded as clinically meaningless and receiving little attention, provide some explanation for the increasing number of coronary heart disease reported in hypertensive subjects despite improved BP control. In this context, we have documented how the ST-T alterations in hypertensive subjects with LVH or CAD can be improved and reversed in a large number of subjects within the first 6 months of treatment, when RBC-K content and functions are improved by low doses of Amiloride HCl.20
Second, Heritability (h2) in vascular phenotypes include the increased Systemic vascular resistance (59±6) in twins studies ,21 decreased brachial artery distensibility and increased augmentation aortic index in pre-hypertensives as compared with normotensive gropus;22 and third, changes in morphology, pressure and timing of central aortic pulse waveform reflection (Fig. 2), along with a decreased systemic and brachial artery compliances in normotensive individuals with family history of hypertension compared with controls without hypertensive parents.23
Other research findings supporting a different physiological approach might probably replace our current concept on dietary potassium in hypertension and cardiovascular diseases for that of Intramolecular K-binding and intracellular K-functions.24 In this context, the specific identity of K-binding sites in all enzymes or proteins structures activated by this ion, the activation of ADP/ATP energy phosphates, RNA and DNA stabilization and the regulation of mitochondrial matrix volume,25 now considered critical in living systems, including the β-Cell mitochondria insulin secretion and K fluxes in the electrophysiology of glucose and amino acid metabolism,26 critically imply that K ion may be involved on Metabolic Syndrome and in most cardiovascular diseases.
In brief, this new paradigm should make us view the RBC functions in a very different way and more fascinating approach for the management of hypertension, coronary artery diseases and other CVD, while the primary objective of the research laboratory would be to assess the probably roles of these blood cells in plasma K regulation, inter-organ K exchange and renal ammonia excretion by Rh glycoproteins, the first recognized gas-transport proteins in living cells.27
1. Addison WL. The Use of Sodium Chloride, Potassium Chloride, Sodium Bromide, and Potassium Bromide in Cases of Arterial Hypertension which are Amenable to Potassium Chloride. Can Med Assoc J. 1928;18:281-85.
2. Young DB. Quantitative analysis of aldosterone’s role in potassium regulation. Am J Physiol. 1988;255:F811–F822.
3. Tobian L, Lange J, Ulm K, Wold L, Iwai J. Potassium reduces cerebral hemorrhage and death rate in hypertensive rats, even when blood pressure is not lowered. Hypertension 1985;7:110-114.
4. Delgado-Almeida A, Delgado MC. Hereditable Defect in Red-Blood-Cell K in Hypertension. FASEB J. 2008;22:968.8 Experimental Biology 2008.
5. Delgado MC, Delgado-Almeida A. Abnormal Potassium. In: Mohler III ER, Townsend RR (eds). Advanced Therapy in Hypertension and Vascular Disease. BC Decker Inc. Publisher, Ontario, Canada.2006, Chapter 35:291-99.
6. Delgado MC, Delgado-Almeida A. Red blood cell K+ could be a marker of K+ changes in another cells involved in blood pressure regulation. J Human Hypertens.2003;17: 313-318.
7. Agostoni A, Berfasconi C, Gerli GC, Luzzana M, Rossi-Bernardi L. Oxygen affinity and electrolyte distribution of human blood: changes induced by propranolol. Science.1973: 182(4109):300-1.
8. Heitzmann D, Warth R. No potassium, no acid: K+ channels and gastric acid secretion. Physiology (Bethesda) 2007; 22: 335-41.
9. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal antiinflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121:289-300.
10. He Q, Heo M, Heshka S, Wang J, Pierson RN Jr, Albu J et al. Total body potassium differs by sex and race across the adult age span. Am J Clin Nutr. 2003;78:72-7.
11. Delgado-Almeida A. From Bohr Effect to the Electrical Regeneration of the Heart FASEB J. 2012; 26:1126.7.Experimental Biology2012.
12. Kachmar JF, Boyer PD. Kinetic analysis of enzyme reactions. II. The potassium activation and calcium inhibition of pyruvic phosphoferase. J Biol Chem 1953; 200: 669-82.
13. Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The erythrocyte as a regulator of vascular tone. Am J Physiol.1995; 269:H2155-61.
14. Toyoshima C, Kanai R, Cornelius F. First crystal structure of Na+, K+ ATPase: new light on the oldest ion pump”. Structure.2011;19:1732-9.
15. Zorbas YG, Kakurin VJ, Afonin VB, Charapakhin KP, Denogradov SD. Potassium supplements' effect on potassium balance in athletes during prolonged hypokinetic and ambulatory conditions. Biol Trace Elem Res.2000;78(1-3):93-112.
16. Johnston RS, Dietlein LF (eds). Biomedical results from Skylab. NASA SP-377. Washington, DC: National Aeronautics and Space Administration, 1977.
17. Delgado-Almeida A. Assessing cell K physiology in hypertensive patients. A new clinical and methodologic approach. Am J Hypertens. 2006;19:432-436.
18. Fang J, Ayala C, Loustalot F, Dai S. Self-Reported Hypertension and Antihypertensive Medication Among Adults-United States, 2005–2009. Div for Heart Disease and Stroke Prevention, National Center for Chronic Disease Prevention and Health Promotion, CDC. 2013/62(13):237-244.
19. Delgado-Almeida A, Schneider MP, Schmieder RE, and Fagard RH on behalf of the Syst-Eur investigators. Critical Value of the Electrocardiogram in LVH: From Predictive Index to Therapeutic Reassessment. Hypertension.2005;45:e6-e7.
20. Delgado-Almeida A. Improving Red Blood Cell K-Uptake and Its Impact on O2/CO2 Exchange, and NO-Generation in Microvascular CHD: A Novel Therapeutic Approach. Recent Patent on Cardiovasc. Drug Discovery.2010:5:227-238.
21. Seasholtz TM, Wessel J, Rao F, Rana BK, Khandrika S, Kennedy BP et al. Rho kinase polymorphism influences blood pressure and systemic vascular resistance in human twins: role of heredity.Hypertension.2006;47:937-47.
22. Urbina EM, Khoury PR, McCoy C, Daniels SR, Kimball TR, Dolan LM. Cardiac and vascular consequences of pre-hypertension in youth. J Clin Hypertens (Greenwich). 2011;13:332-342.
23. Delgado-Almeida A, Delgado CL, Delgado-León A (Eds). Recent Advances on DynaPulse Technology in Cardiovascular Diseases. Punto Laser Co. Valencia, Venezuela. 2011:1-58.
24. Delgado-Almeida A. Intracellular Potassium or Intramolecular Potassium-binding and Dependent Function. TM’s 2nd world drug discovery online conference. October 16-18, 2012.
25. Garlid KD, Paucek P. Mitochondrial potassium transport: the K (+) cycle. Biochim Biophys Acta.2003;1606(1-3):23-41.
26. Salvucci M, Neufeld Z, Newsholme P. Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line. PLoS One.2013;8(3):e52611.
27. Gruswitz F, Chaudhary S, Ho JD, Schlessinger A, Pezeshki B, Ho CM. Function of human Rh based on structure of RhCG at 2.1 A. Proc Natl Acad Sci. 2010. 25;107: 9638-43.
Competing interests: No competing interests