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Intense Stress Leading to Raised Production and Accumulation of Lactate in Brain Ischemia – The Ultimate Cause of Acute Stroke: Mechanism, Risk Factors and Therapeutics

“In severe ischemia (and tissue hypoxia) oxygen delivery to brain cells is insufficient for normal energy production, and acid-base homeostasis is threatened by the accumulation of acid equivalents (metabolic acidosis)”.  Stig Rehncrona MD PhD - Lund, Sweden, 1985[1]

Abstract

The present paper introduces a new hypothesis postulating that acute stress, chronic stress overload and other risk factors with intense sympathetic nervous system activity may induce a raised lactate production and accumulation in brain ischemia. This represents, in our view, the ultimate cause for the triggering of acute stroke, resulting in the cerebral infarction. It explains how stress (sympathetic dominance) may lead to a raised lactate production.

The fundamental therapeutic for prevention and management of acute stroke, according to this proposed concept, are old drugs called cardiac glycosides (CGs). Studies using cardiac glycosides have demonstrated neuroprotective effects in experimental brain ischemia, on the protection against vasospasm in subarachnoid haemorrhage, sympatho-inhibitory effects and a potent inhibition of glycolysis (glucose consumption and lactate). The use of CGs has also shown a very low total mortality (including for stroke) in cardiac patients taking low doses of these drugs.

Cardiac glycosides like digoxin and Lanatoside C are drugs approved by the US Federal Drugs Administration (FDA), and by other similar organizations around the world, with some of these having also approval for the use of digitoxin and other CGs . Therefore, these drugs can be prescribed for prevention and in the management of acute stroke, with no major obstacles, by a well-informed physician.

The paper also discusses on the limitations and failures in the concept of thrombus as the cornerstone of acute ischemic stroke (AIS)

Introduction

Friede and Van Houten in 1961[2] related cellular injury in incubated brain tissue slices to the development of metabolic acidosis. Lindenberg postulated in 1963[3] that structural alterations in the hypoxic brain described as "morphotropic necrobiosis" are caused by intracellular acidosis. Rehncrona, in 1985[1] declared that severe tissue lactic acidosis limits the possibility for cell survival in brain ischemia. In his article, he reviewed data on the relationship between severe tissue acidosis and irreversible brain cell damage.

The measurement of interstitial pH and calculation of intracellular pH during cerebral ischemia indicate that increased acidosis accompanies increased tissue lactate [4, 5, 6] The accumulation of lactate in ischemic regions has been documented in studies during acute stroke.[7]

In 2008, a study involving 187 patients with ischemic stroke or transient ischemic attack has shown that lactate in cerebrospinal fluid (CSF) was a reliable marker for the metabolic crisis in acute ischemic stroke and a possible cause of secondary neuronal damage in cortical infarction resulting in unfavourable evolution in the sub-acute phase and poor long-term outcome.[7] Previous studies have already suggested that lactate dehydrogenase levels in the cerebrospinal fluid might be useful for recognizing those patients at high risk of developing severe stroke.[8]

A study from 2012 found that among patients with ischemic stroke, initial hyperlactatemia [a pathological state in which resting blood lactate concentration is abnormally high (>1.5 mmol/L)] represents an independent risk factor for poor outcome after controlling for stroke severity, risk factors, initial glucose level, and interval from onset of stroke symptoms to emergency department arrival.[9]

A recent study found that in subarachnoid haemorrhage (the most devastating form of hemorrhagic stroke), elevated serum lactate levels on admission may have a predictive role for mortality and represent a marker of disease severity.[10]

The Blood Clot as Cause of Acute Ischemic Stroke

Before presenting the basis for our hypothesis I would like to point out my disagreement about the current thinking that acute ischemic stroke occurs due to a sudden blood clot (thrombus) of an artery inside or leading to the brain, which may become completely blocked.

In our point of view, the blood clot doesn’t have a fundamental role in the triggering of AIS. That also applies to the relationship between the thrombus and acute myocardial infarction.[11] The collateral circulation may protect the brain against ischemic injury and can potentially bypass the effect of a blocked artery, thereby influencing ischemic lesion and growth. [12]

Some data on limitations and failures in the concept of thrombus as the cornerstone of AIS

1. Cerebral Thrombi

An analysis of thrombi in acute ischemic stroke, published in 2017,[13] raise some questions like complexities, varieties, etc.... The authors say these points make difficult the improvement for the acute ischemic stroke therapy.

a)           ‘The age of the thrombus may provide additional useful information on, for example, etiology. Current age descriptors of thrombi in the literature include old, mature, young, fresh (less than five days old), lytic (1–5 days old) and organized (greater than five days old)’.

b)          ‘Since the thrombus itself is the primary target of current acute stroke treatments, its composition will most likely determine the most effective treatment modality. Thrombus composition is a key factor in determining susceptibility to mechanical and pharmacological thrombus disruption and thus the degree of successful recanalization. Yet such information is currently unknown prior to treatment and thus all thrombi are approached in the same manner. Several studies have investigated the histopathological composition of cerebral thrombi from stroke patients and revealed a wide variety. Correlations between thrombus components (red block clots, fibrin, platelets, white blood cells) and parameters such as stroke aetiology, imaging parameters and treatment outcome have been reported but remain inconsistent, potentially due to the small sample sizes. One challenge is that the most treatment-resistant thrombi, which lead to failure of the procedure, are not available for analysis’.

c)           Current imaging techniques can provide some information about the thrombus, but there remains much to learn about what relationships exist between thrombus composition, various occlusion characteristics and treatment outcomes.

2. Trombolysis

Clot properties have a number of potential implications for clinical treatment. Modest rates of early recanalization with IV rtPA [Recombinant Tissue Plasminogen Activator] therapy are associated with specific thrombus properties (short thrombus length, RBC-rich composition, and perviousness/residual forward flow). If a combination of these or more sophisticated features could predict successful intravenous thrombolysis prior to treatment, then transport and procedural costs of endovascular therapy could be saved. However, only those thrombi that did not dissolve spontaneously or after rtPA administration and that can be successfully retrieved via thrombectomy are available for study, which impedes the assessment of rtPA susceptible and thrombectomy-resistant thrombi.[13]

Despite of the spreading use of rtPA in different countries and continents, there are still a number of burdens and failures in the optimal accomplishment of thrombolytic treatment.[14] The low number of victims with AIS typically eligible for rtPA treatment occurs in part because of the varying etiologies of stroke and the very brief window of time for reperfusion therapy.

A study from Cochrane Database, published in 2014[15] states in its conclusion:

“Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.

Deaths from all causes during follow-up:  Data were available for all 27 trials (10,187 participants). There was a modest but significant increase in deaths within scheduled follow-up, from 18.0% in controls to 19.4% in the participants allocated to thrombolysis. In absolute terms, this represented an extra 15 deaths at the end of follow-up per 1000 participants treated with thrombolysis.” That means an increased absolute risk in mortality of 1.5%, in the group treated with thrombolysis [15]

Intravenous administration of rtPA (alteplase) is the only U.S. Food and Drug Administration (FDA) - approved medical therapy for treatment of patients with acute ischemic stroke.

3. Mechanical Thrombectomy Devices to Remove the Thrombus

The history of endovascular therapy for acute ischemic stroke has been controversial. In 2013, three trials of first generation mechanical thrombectomy devices for acute ischemic stroke were published showing no benefit of endovascular therapy on functional or clinical outcomes. These trials caused a noticeable increase in clinical scepticism regarding the utility of endovascular therapy for acute ischemic stroke.

The scepticism was enhanced by subsequent meta-analyses emphasizing the lack of efficacy of endovascular treatment in acute ischemic stroke patients.

A meta-analysis of five prospective randomized controlled trials comparing endovascular therapy using predominantly second-generation mechanical thrombectomy devices as an adjunct to medical management versus medical management alone in acute ischemic stroke was published in 2016. In one hand it has demonstrated superior functional outcomes in subjects receiving endovascular therapy. On the other hand, however, it found no significant differences in symptomatic intracerebral haemorrhage or 90-day all-cause mortality between endovascular therapy and medical management of stroke patients.[16]

4. Anticoagulants

A review from the Cochrane Database found that immediate anticoagulant therapy in patients with acute ischaemic stroke is not associated with net short- or long-term benefit. The authors say that their review data do not support the routine use of any type of anticoagulant in acute ischaemic stroke. People treated with anticoagulants had less chance of developing deep vein thrombosis and pulmonary embolism following their stroke, but these sorts of blood clots are not very common and may be prevented in other ways.[17]

Our Current Hypothesis

In 2006 we have postulated [18] that most risk factors for atherosclerosis have as a common denominator the dysregulation of the autonomic nervous system, related with sympathetic dominance, through sympathetic over-activity or withdrawal of the parasympathetic system.

In the present article, we introduce the hypothesis that acute stress, chronic stress overload and other risk factors with intense sympathetic nervous system activity may lead to a raised lactate production and accumulation in the brain what may eventually trigger the acute stroke, resulting in the cerebral infarction,

Thus, reducing the incidence of risk factors for atherosclerosis (related to autonomic dysfunction)[18], by avoiding elevated levels of lactate in ischemic regions may, greatly lower acute stroke occurrence.

Autonomic dysfunction has been associated with worse functional outcome and increased mortality for ischemic stroke. However, a recent and extensive review says that autonomic dysfunction is not yet considered a specific therapeutic target, mainly because researchers do not fully understand its mechanisms and role. Such review deals with methods to measure autonomic dysfunction, clinical manifestations that have been associated with autonomic dysfunction and poor outcome in AIS, the role of brain infarct location, as well as therapeutic implications.[19]

The Increase of Heart Rate over Time May Predict Cardiovascular Events, Including Stroke

A paper published a few months ago in JAMA Cardiology, presented a retrospective analysis of ARIC (Atherosclerosis Risk in Communities Study), assessing data from 15,680 patients in over 28 years of follow-up. It has shown that for each 5 beats per minute (bpm) increase of heart rate overtime, with a median of 3 years between measurements, was associated with 12% for all-cause mortality, 13% for incident heart failure, 9% for myocardial infarction, and 6% for stroke.[20]

Earlier, a meta-analysis published in 2015 involving a total of 46 studies with more than a million patients found that high resting heart rate is independently associated with increased risk of all-cause and cardiovascular mortality in the general population. Its results suggested the risk is increased by 9% and 8% for every 10 bpm increment of resting heart rate. Higher resting heart rate is a marker of an imbalance between the vagal and the sympathetic tone, and dysfunctional autonomic nervous system, playing a central role in the pathogenesis of numerous adverse health conditions.[21]

Some risk factors for acute stroke, based on our present concept:

(Autonomic dysfunction leading to significant elevation in plasma lactate levels)

• Stress, depression, anger, hostility, panic disorder [22-25]
• Age [26-29]
• High carbohydrate diets [30-33]
• Rheumatoid arthritis [34-37]
• Migraine [38-41]
• Hypertension [42-47]
• Diabetes [48-52]
• Infection through bacteraemia [53-55]
• Smoking [56-59]
• Atrial fibrillation [60-62]
• Heart Failure [63-65]

Stress (Sympathetic Dominance) and the Development of Lactate / Lactic Acid

The sympathetic dominance leads to a raised catecholamine (adrenaline/epinephrine and noradrenaline) release, accelerating glycolysis metabolism, therefore increasing lactic acid and lactate concentration in blood and tissues.

The first to observe the influence of adrenaline on lactic acid production was Carl F Cori in 1925.[66] He, together with his wife Gerty Cori, received a Nobel Prize in 1947 for their discovery of how glycogen - a derivative of glucose - is broken down and resynthesized in the body.[67]

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.[68] An article published in 1982[69] supported the following points for a direct participation of catecholamines in the development and/or maintenance of lactic acidosis:

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 phaeochromocytoma;
4. The vasoconstrictor effects of catecholamines leading to tissue anoxia and lactic acid production.

However, according to new findings, hyperlactatemia is not a consequence of anaerobic glycolysis, tissue hypo-perfusion, or cellular hypoxia, as believed in the past. Such hyperlactatemia is probably indicative of a stress response, with increased metabolic rate and sympathetic nervous system activity.[70]

Nevertheless, an important point to take in consideration is that the heart is an organ of high metabolic activity -  being susceptible to drops in pH during ischemia and hypoxia. [71]  According to Rehncrona[1] the evidence for a deleterious effect of increased lactic acid accumulation during ischemia in vivo was first presented by Myers and associates, who found that glucose pre-treatment of animals worsened the outcome of reversible ischemic-hypoxic insults.[72] Recent studies confirmed that increased lactate in the brain may be a signal of cerebral harm in other medical conditions. For example, it was shown that patients with panic disorder consistently build up excess lactate. The authors of this study have suggested that one of the triggers for “spontaneous” panic attacks in patients with panic disorder might be lactic acid accumulating in acid-sensitive fear circuits.[73]  Also, a study published in 2017, suggested that lower pH associated with increased lactate levels is not a mere artefact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.[74]

An older study by Shimoda et al. published in 1989, have reported that the increase of cerebrospinal fluid lactate concentration reflected not only glycolysis of shed blood cells but also brain tissue hypoxia caused by primary subarachnoid haemorrhage. It was demonstrated that the delayed increase of CSF lactate occurred concurrently with the onset of cerebral vasospasm. These authors attributed this result to brain hypoxia due to the vasospasm.[75]

On the other side studies have shown that acute exposure to hypoxia may cause chemo-reflex activation of the sympathetic nervous system, including in cerebral vasculature.[76, 77]

The relationship between sympathetic dominance and increased lactic acid/lactate concentration was recently discussed by us as having a causal role for atherosclerosis,[18, 78] acute myocardial infarction[79] and cancer. [80]

Notes

1. Hyperlactatemia is defined as a mild to moderate persistent increase in blood lactate concentration (2-4 mmol/L) without metabolic acidosis, whereas lactic acidosis is characterized by persistently increased blood lactate levels (usually >4-5 mmol/L) in association with metabolic acidosis;
2. Lactic acidosis results from increased production of lactate, the final product in the pathway of glucose metabolism. Lactate and lactic acid are not synonymous. Lactic acid is a strong acid which, at physiological pH, is almost completely ionized to lactate

Cardiac Glycosides, the Fundamental Drugs for Prevention of Stroke

“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: 1) 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 [81]

The Reason of our Interest in Relation to Stroke (Cerebrovascular Accident)

The following extract of our article published at the News Bulletin of Infarct Combat Project from July, 2006 [82] is self-explanatory:

Cardiac Glycosides in Prevention of Stroke

Brazilian study confirms the findings of Duke University Medical Center researchers that cardiac glycosides provide neuroprotection in stroke occurrence. It was a study of 28 years that showed a low mortality for stroke in 1150 cardiac patients taking these drugs.

ICP, July 10, 2006: Using a novel screening technology, Duke University Medical Center researchers have shown that drugs called cardiac glycosides can protect brain cells from death after stroke in laboratory models, and that the drugs are effective even if delivered six hours or more after the onset of stroke conditions. [83]

"This discovery is exciting because it may lead to interventions to prevent or lessen the amount of brain damage suffered after stroke," said Donald C. Lo, PhD, Director of the Center for Drug Discovery and associate professor of neurobiology at Duke, and primary investigator on the study.

Currently, only one drug has been approved by the Food and Drug Administration to treat stroke -- and it faces serious limitations, Lo said. Called recombinant tissue plasminogen activator, the drug must be given within a three-hour window after the onset of stroke. Also, because the drug is delivered intravenously and acts by breaking blood clots, it is ineffective against "hemorrhagic" strokes that happen when an artery bursts.

Lo speculates that cardiac glycosides may exert their beneficial effect during stroke in an analogous manner that in heart disease, by restoring calcium to healthy levels in brain cells and thereby preventing cell death. Calcium plays a key role in regulating normal cell function, and any changes in its cellular concentration -- such as those caused by stroke -- can be toxic. [84]

Another recent study with statin drugs concluded that its use is associated with a reduced risk of stroke but not severity or mortality. [85]

Related to the Duke University Medical Center research, a case study from Brazil confirm the very low mortality for stroke in 1150 patients with stable heart disease taking cardiac glycosides, during 28 years. The study was authored by Quintiliano H. de Mesquita and Claudio A. S. Baptista and published in Ars Cvrandi, a Brazilian medical journal in 2002. [86]

The stroke (ischemic + hemorrhagic) mortality in 28 years for the cardiac patients taking cardiac glycosides was:

• 994 patients w/out prior infarction - Stroke mortality: 13 cases (1.3%) = 0.04% per year.
• 156 patients with prior infarction - Stroke mortality: 7 cases (4.4%) = 0.15% per year.

For a better comparison in stroke mortality, with those taking cardiac glycosides, we can take the data from the HPS study, which had a follow-up of 5 years, involving 20.536 patients aged 40-80 years with coronary heart disease, other vascular diseases or diabetes. The HPS found a total stroke mortality of 0.9% (0.18% per year) in patients taking statins and 1.2% (0.24% per year) in patients taking placebo.[87]

The permanent use of cardiac glycosides (Digitoxin, Digoxin, Acetildigoxin, Lanatoside-C, Betametildigoxin, or Proscillaridin-A) in low, daily therapeutic (non-toxic), doses from the Brazilian study was based on the Myogenic Theory of Myocardial Infarction and had as its objective the prevention of acute coronary syndromes.[79] The global mortality for the patients without previous myocardial infarction was 14.2% (0.5% per year), while the global mortality for the patients with previous myocardial infarction was 41.0% (1.4% per year).”

Before presenting an update on the previous information published in 2006 at the News Bulletin from ICP, it is important to inform the daily maintenance doses, for the cardiac glycosides used by Quintiliano de Mesquita and Claudio Baptista in their study.[86] It follows:

Daily Maintenance Doses [88]

• Proscillaridin A:          0,75 – 1.50 mg
• Acetyldigoxin:                0,50  mg
• Lanatoside C:                0,50 mg
• Digitoxin:                        0,1 mg
• Digoxin:                      0,125 – 0,25 mg
• Betamethyldigoxin:     0,10 – 0,20 mg

Note:

Digoxin, since its insertion, still is the cardiac glycoside most used in Brazil. Therefore, it represented a large proportion of the prescriptions from these authors to their patients.

Neuroprotective Effects of Digoxin and other CGs in Brain Ischemia

A study from 2009 [89] investigated the possible neuroprotective effect of digoxin-induced pharmacological preconditioning and its probable mechanism in ischemia and reperfusion in cerebral injury in male Swiss albino mice.  Digoxin treatment produced a significant decrease in cerebral infarct size and reversal of ischemia and reperfusion-induced impairment of memory and motor incoordination. These findings indicated to the authors that digoxin preconditioning exerts a marked neuroprotective effect on the ischemic brain.

A study published in 2010 [90] has discussed findings showing the effects of cardiac glycosides drugs (digoxin, ouabain and marinobufagenin), when given at low dosages, on the increase (stimulation) of the sodium-potassium ATPase activity. Then, they examined whether digoxin, ouabain and marinobufagenin increased the Na+/K+ATPase  in hippocampal slice cultures and whether this increased Na+/K+ATPase protected against experimental ischemia. They made tests in vitro in hippocampal slice cultures as well in the hippocampus in vivo. The increased Na+/K+ATPase activity protected slice culture neurons from hypoxia-hypoglycaemia. These data suggested to the authors that the protective effect of these drugs was due to increased Na+/K+ATPase activity. Also, this demonstrated that the neuroprotective effect of these drugs could protect against in vitro experimental ischemia, representing a potential treatment strategy for their use in the management of stroke.

A study from 2016[91] had the aim to investigate the possible neuroprotective effect of digoxin-induced pharmacological preconditioning after hypoxia-ischemia and underlying mechanisms. Neonatal rats were assigned randomly to control, hypoxic-ischemic brain damage (HIBD), or HIBD+digoxin groups. Pharmacological preconditioning was induced by administration of digoxin 72 h before inducing HIBD by carotid occlusion+hypoxia. Behavioural assays and neuropathological and apoptotic assessments were performed to examine the effects; the expression of Na+/K+ATPase was also assessed. Rats in the HIBD group showed deficiencies on the T-maze, radial water maze, and postural reflex tests, whereas the HIBD+digoxin group showed significant improvements on all behavioural tests. The rats treated with digoxin showed recovery of pathological conditions, increased number of neural cells and proliferative cells, and decreased number of apoptotic cells. Meanwhile, an increased expression level of  Na+/K+ATPase was observed after digoxin preconditioning treatment. The preconditioning treatment of digoxin contributed toward an improved functional recovery and exerted a marked neuroprotective effect including promotion of cell proliferation and reduction of apoptosis after HIBD, and the neuroprotective action was likely associated with increased expression of Na+/K+ATPase.

Incidentally, cardiac glycosides like digoxin and Lanatoside C are drugs approved by the U.S. Federal Drugs Administration (FDA), and by other similar organizations around the world, with some having also approval for the use of digitoxin and other CGs. Therefore, these drugs can be prescribed for prevention and in the management of acute ischemic stroke, with no major obstacles, by a well-informed physician.

Digoxin Use in Some Risk Factors for Stroke

Heart Failure

Digitalis was used for more than 200 years in the treatment of heart failure.  Digoxin and digitoxin are some of the cardiac glycosides derived from digitalis (foxglove plant)..

The daily oral maintenance dosages of digoxin recommended for heart failure, until recently, were 0,125 mg, 0,250 mg and 0,375. These dosages had the objective of achieving a therapeutic serum digoxin concentration (SDC) in the range of 0.5 to 2.0 ng/ml.

The DIG (Digitalis Investigated Group) trial, published in 1997[92] indicated that digoxin had no effect on overall mortality in heart failure compared to patients taking placebo, but reduced the rate of hospitalization both overall and for worsening heart failure.

The results from the DIG trial were interpreted with disappointment being the use of digitalis subsequently declined. Although digoxin received approval from the FDA in 1997, the major guideline-issuing professional societies currently offer a secondary recommendation for digoxin in patients with HF with reduced ejection fraction (EF) in normal sinus rhythm experiencing persistent symptoms despite optimal medical therapy.[93]

Digoxin: Lowering the Dosage for Better Outcomes in Heart Failure

“However, there is available clear clinical experimental proof of the beneficial action of very small doses (of digitalis), and, as I have said repeatedly, this puts us under the obligation of not omitting this safe clinical experiment in suitable cases”, Wenckebach K. F., 1930 [94]

Rathore et al, in a study published in 2003[95], on a post hoc analysis of data from the DIG Trial,[92] dividing the man treated into three groups according to their serum digoxin concentration after one month of treatment: 0.5-0.8 ng/ml, 0.9-1.1 ng/ml and > 1.2 ng/ml, found that mortality in men in the lowest level group was 6.3% lower than that of men in the placebo group. In contrast, mortality in men in the intermediate and highest level groups was 2.6% and 11.8% higher respectively than that of the placebo group.

Adams et al, in a study published in 2005,[96] presenting another retrospective analysis of data from the DIG trial,[88] have indicated a beneficial effect of digoxin on morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentrations > or =1.2 ng/ml seemed harmful.

The result of the studies from Rathore et al[95] and Adams et al[96] led to changes on the Heart Failure Guidelines issued by the Heart Failure Society of America in 2010.[97] Following are some extracts of the Session 7 of these guidelines related to the use of Digoxin recommendations from the chapter ‘Heart Failure in Patients with Reduced Ejection Fraction’:

1. Recent data suggest that the target dose (and serum concentration) of digoxin therapy should be lower than traditionally assumed. Although higher doses may be necessary for maximal hemodynamic effects, beneficial neurohormonal and functional effects appear to be achieved at relatively low serum digoxin concentrations (SDC) typically associated with daily doses of 0.125 to 0.25 mg. A retrospective analysis of the relationship of SDC to outcomes in the DIG trial demonstrated a strong direct relationship between the risk of death and SDC, with concentrations ≥ 1.2 ng/mL being associated with harm, whereas concentrations ≤ 1.0 ng/mL were associated with favourable outcomes;
2. The efficacy of digoxin in HF with reduced LVEF [left ventricular ejection fraction] has traditionally been attributed to its relatively weak positive inotropic action arising from inhibition of sodium potassium ATPase and the resulting increase in cardiac myocyte intracellular calcium. However, digitalis has additional actions that may contribute significantly to its beneficial effects in patients with HF. Digoxin has important neuro-hormonal modulating effects that cannot be ascribed to its inotropic action, and it ameliorates autonomic dysfunction as shown by studies of heart rate variability, which indicate increased parasympathetic and baroreceptor sensitivity during therapy.

Atrial Fibrillation

“Digitalis itself, which in large doses may be the cause of regular extra-systoles, may in very small doses abolish this phenomenon and be very helpful in combating auricular (atrial) fibrillation.”, Wenckebach K. F., 1930 [94]

Digitalis is indicated for patients with atrial fibrillation, with or without heart failure, since the beginning of the last century.

Observational studies have associated digoxin use with excess mortality in atrial fibrillation patients, but this association is likely due to selection and prescription biases rather than harm caused by digoxin, particularly as digoxin is commonly prescribed to sicker patients. [98]

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, according to the European Society of Cardiology guidelines which is endorsed by the European Stroke Organization. [98]

Digoxin and Vasospasm in Subarachnoid Haemorrhage

Vasospasm is a significant reason for poor clinical outcome in subarachnoid haemorrhage (SAH). A study from 2009[99] investigated the effect of digoxin on an experimental vasospasm after SAH in rats.

It has shown that increased wall thickness and reduced vessel luminal area were conspicuously significant in the SAH groups which did not receive digoxin. In SAH groups after digoxin administration, the vessel wall thickness decreased, and no significant change was found in vessel wall thickness when compared with the normal and saline groups. The vessel luminal area was not reduced in SAH after digoxin administration.

According to the authors their results suggest that digoxin administration in experimental SAH may have a beneficial effect on the protection against vasospasm. Also saying that “if further investigations support our results, the present study may offer a new insight into the treatment of SAH.”[99]

Cardiac Glycosides and Sympatho-Inhibitory Effects

Evidences that the following cardiac glycosides have a sympatho-inhibitory response:

• Cedilanid* [100]
• Digoxin [101-102]
• Digitoxin [103]
• Ouabain [104]

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

Cardiac Glycosides in Reduction of Lactate Production

A recent paper has demonstrated that inhibiting the overproduction of catecholamine by digoxin, digitoxin and ouabain may induce a potent inhibition of glycolysis (glucose consumption and lactate). [105] It confirms the results of old studies on this matter. [106]

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