Positive Health Online

The Causal Role of Autonomic Dysfunction and Lactic Acidosis in the Development of Hypertension

by Carlos ETB Monteiro

Abstract

In the present article is postulated a new hypothesis that may explain the basic causes of hypertension. It presents a list of common risk factors for hypertension which are associated to overactive sympathetic nervous system what may lead to autonomic dysfunction. Also, it discusses recent findings showing that hypertension is associated with increased lactate production getting worse the disease process.

The autonomic dysfunction may accelerate glycolysis, which results in increased lactate production in hypertension. Finally, it shows the potential use of digoxin (Digitalis Lanata), at daily low concentration dosages, for the management of hypertension. This by restoring the balance of the autonomic nervous system and reduction of lactate production in the body. Digitalis was used for the treatment of hypertension until the middle of the past century. Drew Luten have written in his book from 1936:

“By many physicians, hypertension, especially when associated with cardiac enlargement, is now regarded as an indication for the continuous use of digitalis”

Available on Amazon.co.uk and Amazon.com.

Introduction

The fundamental cause of hypertension remains in discussion. What is known are some risk factors associated with this condition.

The autonomic nervous system (ANS) is responsible for controlling many physiological functions like inducing the force of contraction of the heart, peripheral resistance of blood vessels and the heart rate. The ANS has both sympathetic and parasympathetic divisions that work together to maintain balance. Cardiovascular diseases, such as hypertension, acute myocardial infarction and heart failure, are diseases of the autonomic nervous system

We support the concept that autonomic dysfunction is the primary inductor for the development of the hypertensive process.

Autonomic Dysfunction in Hypertension

The autonomic nervous system plays an important role in the regulation of arterial pressure and, increased sympathetic nervous system (SNS) activity has been implicated as a primary precursor of hypertension in both humans and animal models of the disease.[1-3] Essential hypertension is significantly associated with higher mean fasting insulin levels and insulin resistance. Hyperinsulinemia plays a possible role in the pathophysiology of essential hypertension, with insulin resistance being the likely predominant mechanism.[4] Some studies advocate that insulin resistance might contribute to enhance the SNS activity.[5]

However, other studies advocate that the SNS may increase insulin resistance.[6,7]

We should emphasize that many risk factors leading to insulin resistance,[8] like obesity[9] and physical inactivity,[10] are associated with sympathetic activation.

A study published in 2019[11] demonstrated the evidence that an important factor driving at least some of the obesity-associated end-organ damage is over activity of the sympathetic nervous system (SNS), an observation that suggests that targeting SNS in obesity may help to reduce the cardiovascular risk associated with obesity. In their review, the authors highlighted the current knowledge of the potential role of SNS function in obesity-induced organ damage and examine whether interventions aimed at reducing cardiovascular risk in obesity may be mediated via alterations in SNS activity. While not discounting the important and prolific preclinical data on this subject, the authors pointed out their review is primarily focused on recent observations from human trials.

The results of a study from 2010 suggest that high fructose intake, in the form of added sugar, independently associates with higher blood pressure levels among US adults without a history of hypertension.[12] Excess fructose has been found to activate vasoconstrictors, inactivate vasodilators, and over-stimulate the SNS.[13] Other carbohydrate diets may also stimulate the SNS.[14]

Hypertension is common among patients with diabetes, with the prevalence depending on type and duration of diabetes, age, sex, race/ethnicity, BMI, history of glycemic control, and the presence of kidney disease, among other factors.[15]

On the causal role and triggers of diabetes mellitus, involving the autonomic dysfunction and increased lactate production, we have written an article which will be published soon.[16]

Other Risk Factors for Hypertension

There are many other risk factors leading to dysregulation of the autonomic nervous system in hypertension.

Some examples:

• Age[17,18]
• Tobacco consumption[19]
• High salt intake[20-22]
• Restricted salt intake[23,24]
• Depression[25,26]

According to our present postulation the autonomic dysfunction may lead to increased lactate production, which get worse the hypertensive process.

Increased Lactate Production in Hypertension

Two cross-sectional studies published in 1998[27, 28] have shown that lactate is associated with blood pressure.

In 2008 the ‘Atherosclerosis Risk in Communities - Carotid MRI Study’[29] found that high plasma lactate was independently associated with the odds of hypertension. The authors suggested that the decreased oxidative capacity may play an important role in hypertension prevalence.

Also, a study from 2008[30] demonstrated that lactate is associated with obesity and that change in lactate is associated with change in diastolic and mean arterial pressure after adjustment for weight loss and other factors. The authors told that although the cause of this association cannot be identified in the study, their results are consistent with the notion that insufficient oxidative capacity in muscle may be an important mechanism in obesity-related hypertension. They also said that several lines of evidence suggest that lactate is also associated with other downstream complications of obesity including insulin resistance and type 2 diabetes

In 2014 researchers from the ‘Atherosclerosis Risk in Communities Study’[31] hypothesized that lactate would be positively associated with incident hypertension even after accounting for traditional hypertension risk factors.

A study published in 2016[32] concluded that plasma lactate level in non-dipping hypertension is significantly higher than dipping hypertension, and this difference may be the potential mechanism non-dipping hypertension contributes to greater targeted organ damage.

On the other hand, a study from 2016[33] found that plasma lactate is independently associated with incident atrial fibrillation, and its contribution to AF may be, at least in part, mediated by diabetes and/or hypertension. Sugars in excess may raise lactic acid production in the body.[34,35]

How Autonomic Dysfunction Leads to Lactic Acidosis

The chronic elevated release of catecholamine, precipitated by the sympathetic nervous system, may accelerate glycolysis, which results in a significant increase in lactate production.

The influence of adrenaline on lactic acid production was observed in the early 1920s by the Coris. They have discussed about these findings in a study published in 1929.[36] Carl Ferdinand Cori and his wife Gerty Cori received a Nobel Prize in1947 for their discovery of how glycogen – a derivative of glucose – is broken down and resynthesized in the body.

A 1982 article by David S. Schade[37] provided further support for the direct participation of catecholamines in the development and/or maintenance of lactic acidosis as follows:

1. The common association of stress and lactic acidosis;
2. The rise in plasma lactate concentration during adrenaline infusion;
3. The precipitation of lactic acidosis by adrenaline intoxication and pheochromocytoma;
4. The vasoconstrictor effects of catecholamines leading to tissue anoxia and lactic acid production.

A study from John R Williamson confirmed in 1964 the effects of adrenaline infusion on the increased production of lactate in isolated heart tissue, up to five times the normal production.[38]

Digitalis for Hypertension

Drew Luten has written about digitalis on hypertension in his book ‘The Clinical Use of Digitalis’, from 1936:[39]

“It is well known that hypertension is associated with heart strain, and that perhaps its chief danger is ultimate heart failure. By many physicians, hypertension, especially when associated with cardiac enlargement, is now regarded as an indication for the continuous use of digitalis. There is much to comment this conception of the value of what might be called the prophylactic use of digitalis. It appears to be based on sound theory. It is applied in practice by physicians of authority. Its reasonableness is further augmented by the fact that the cases to which it applies merge almost imperceptibly with cases in which digitalis is used with known benefit…... The evidence so far available indicates that the drug in proper dosage may be of considerable value in some cases”

Charles C Wycoff cited the following studies about the beneficial effects of digitalis on hypertension, in his paper from 1969:[40]

a. In 1908 and 1929 Cloetta found that digitalis prevented the chronically stressed rabbit heart from enlarging as much as the undigitalized stressed heart. He avulsed a single aortic valve in the animals and maintained half of the group on digitalis. At the end of one year, the untreated animals had an increase of heart size 80 percent above the normal unstressed rabbit heart and the digitalis-treated animals had only a 38 percent increase of heart size above normal. In addition, acute performance tests of the hearts were made, and the results were summarized: ". . . one finds that the crippled digitalis treated heart is almost equal to the normal while the defective heart without digitalis treatment is much more rapidly exhausted. The capacity of the former is nearly double that of the latter, a fact of great importance in practice. This should be sufficient to induce prophylactic treatment with digitalis in all early cases of endocarditis which are apt to terminate in valvular lesions." Williams and Braunwald in 1965, studied chronic heart strain in rats by constricting the abdominal aorta, which resulted in hypertension. Some of the rats were maintained on digitalis. Their results were similar to those of Cloetta. Fewer of the digitalized rats died from heart failure and the weight gain of the digitalized hearts was less than the undigitalized hearts;

b. Reindell and Konig in 1967 reported on studies of several hundred volunteers and patients during which, they determined the myocardial reserve by doing exercise tests. During the exercise tests, they measured the heart rate, the heart size and the oxygen uptake. They found that patients who were not in failure but who had fixed hypertension, coronary insufficiency, or branch blocks, or who had had myocardial infarction, showed performance tests that were well below the normal for their ages. In other words, a "loading insufficiency" developed. These patients were shifted to the normal or near normal status by digitalization;

c. Mason in 1968 told in his article: “Digitalis may be of potential clinical value in preventing the development of ventricular hypertrophy in patients with aortic valvular disease or hypertension without heart failure, since the drug reduces the degree of mortality from heart failure and the degree of ventricular hypertrophy resulting from a chronic pressure load in experimental animals, further, the belief that the administration of digitalis in special situations may be helpful in certain cardiac patients without failure is gaining in prevalence”.

Several investigators have reported that digitalis administration reduces cardiac hypertrophy in rats with experimental hypertension. A study from 1990 found that the comparison of hypertensive rats receiving to those not receiving digoxin revealed no differences in arterial pressure or aortic water content, but aortic growth was significantly attenuated (-41%, P = 0.02) in the hypertensive rats receiving digoxin. These results provide evidence that digoxin reduces hypertensive arterial growth by a mechanism that does not affect normal growth.[41]

Although, even with the support of many studies, the use of digitalis (like digoxin), for the treatment of hypertension, was abandoned and forgotten.

A study from 2015[42] found that in hypertensive patients with ECG left ventricular hypertrophy with existing or new atrial fibrillation, digoxin use was not associated with a significantly increased risk of all-cause mortality after adjusting for other independent predictors of death and for the factors associated with the propensity to use digoxin in this population. These findings suggested to the authors that factors other than digoxin use may account for the increased mortality found with digoxin use in some studies.

Most probable, the increased mortality using digoxin in studies related to hypertension, or other diseases, were due to inadequate dosages of this drug.

As Wycoff told in his paper from 1969:[40] “It is now recognized that even small doses of digitalis have a positive inotropic effect on the heart and produce an increase in the contractile force. Therefore, it is possible to get a beneficial effect from digitalis in a dose much lower than that which was considered a digitalizing dose in the past.”

The retrospective analysis of data from Rathore and colleagues in 2003[43] and Adams and colleagues in 2005[44] on the DIG (Digitalis Investigation Group) trial, published in 1997,[45] confirms Wycoff’s prediction.[40] Their retrospective analysis has indicated a beneficial effect of digoxin on morbidity and no excess mortality at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentrations > or =1.2 ng/ml seemed harmful.

Moreover, taking in view that digoxin and other cardiac glycosides, at daily low concentration dosages, can restore the balance of the autonomic nervous system and reduce the production of lactic acid in the body.

“Although there is not total agreement on the nature and clinical significance of the effects of digitalis on the autonomic nervous system, the following points seem well established and generally accepted: I) the actions of digitalis on the autonomic nervous system are very important clinically and play a major role in determining the clinical pharmacodynamic effects of the drug; 2) with therapeutic concentrations of the drug, the predominant effect is activation of vagal tone; and 3) with toxic concentrations of the drug there may be activation of sympathetic tone.” August M. Watanabe, 1985[46]

Cardiac Glycoside Drugs that Inhibit The Sympathetic or Enhance Parasympathetic Effects:

• Cedilanid*[47]
• Digoxin [48,49]
• Digitoxin [50]
• Ouabain [51]

* Cedilanid is the trade name. The active ingredient is Lanatoside C

Cardiac Glycosides and Reduction of Lactate Production

A paper from 2013 has demonstrated that inhibiting the overproduction of catecholamine by digoxin, digitoxin and ouabain may induce a potent inhibition of glycolysis (glucose consumption and lactate).[52] It confirm the results of old studies on this matter.[53]

Blood Pressure (BP), Atrial Fibrillation (AF), ANS and Digoxin

A recent study[54] found an association between increased BP levels and the risk of atrial fibrillation is likely causal and applies for different BP indices independently from other risk factors. Also, that optimal BP control might represent an important therapeutic target for AF prevention in the general population.

The autonomic nervous system plays an important role in the regulation of blood pressure. Their role in the short-term regulation of blood pressure, especially in responses to transient changes in arterial pressure, via baroreflex mechanisms, is well known.[55]

In a significant portion of patients with atrial fibrillation, the autonomic nervous system activity is likely a composite of reflex excitation due to atrial fibrillation itself and contribution of concomitant risk factors such as hypertension, obesity and sleep-disordered breathing.[56]

According to the European Society of Cardiology guidelines,[57] which is endorsed by the European Stroke Organization, lower doses of digoxin (< 0.25 mg once daily) corresponding to serum digoxin levels of 0.5 – 0.9 ng/mL, may be associated with better prognosis for the management of atrial fibrillation.

Covid-19

Finally, it is important to mention the clinical perspective from a recent study showing that patients with cardiometabolic conditions, in particular obesity, hypertension, diabetes mellitus, and heart failure, have a high risk of poor outcomes from coronavirus disease 2019 infection. Among >900 000 US coronavirus disease 2019 hospitalizations through November 18, 2020, nearly two thirds (63.5%) were estimated to be attributable to these cardiometabolic conditions, that is, preventable if these conditions had not been present. The top risks were obesity (30.2%), hypertension (26.2%), and diabetes mellitus (20.5%).[58]

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