1. Introduction
Origin in the Use of Digital Medication
Digitalis medication has been used for more than 200 years as a treatment initially for patients who had partial or total fluid retention.
CODICE BADIANO
YOLOXOCHILT (HEART FLOWER) (Figure 1)
The word Yollotl means “life force” and the sun for the indigenous according to the worldview of the mexicas works in the universe the same that the heart in the human, both they are responsible for maintaining life. The first book about a topic related to Cardiology was the “Book about the medicinal herbs of the Indians (Libellus of Medicine libus indorum herbis) made by Martín de la Cruz at the Santiago Tlatelolco School 1551, in which he not only described the effects of various medicinal plants but it was also illustrated by botanical drawings of the plants studied.
This work was written in Nahuatl language and translated into Latin by Juan
Badiano for what is known as “CODICE BADIANO”, it is emphasized that really the author was Martín de la Cruz. In this book describes charitable actions about the heart of Yolloxochitl (first description of a plant with digitalis action).
This work traveled through Peru, Madrid, Paris, Rome, the Library Windsor Royal in England and from there to the Vatican, where was preserved until than the original text was gifted by him Pope Juan Pablo II to Mexican state in 1990 and now the work rests in the of National Museum Anthropology, Mexico City [1] .
Digitalis medication (Figure 2), began to be used in Mexico in the 19th century, but it was not until the beginning of the 20th century (1920) that Dr. Ignacio Chávez in Mexico systematized its use and in his professional medical thesis, he wrote the results obtained, which in conclusion were that digitalis medication is useful in heart failure in small doses and it is not appropriate to give it when the heart did not need tonics [2] .
2. Scientific Research of Digitalis Medication
In 1961 Braunwald experimentally demonstrated the positive inotropic effect on isolated myofibrils. (Figure 3) [3] ; later, in 1964, Dean T. Mason demonstrated how digitalis, with its inotropic effect, significantly improves cardiac output and tissue perfusion, and at the same time blocks adrenergic action, producing arteriole and venous dilation, thereby reducing afterload and preload, which is followed by a marked clinical improvement in patients with HF quantitatively increasing blood flow, reducing peripheral resistance, as well as central venous pressure and heart rate [4] (Figure 4); effects that are opposite when digitalis is administered to subjects who do not have HF (with normal systolic function (SF) since increases them peripheral resistanc, cardiac output and blood flow whitout change (Figure 5), facts that show that the digitalis effect is only useful in patients with HF and are counterproductive when administered to patients with normal SF [2] [4] , facts that corroborate the clinical observations made 40 years earlier by Professor Chávez [2] . This digitalis effect is demonstrated by Vatner and Braunwald in 1974 (Figure 6), by administering intravenous Ouabain to dogs with HF, the dp/dt increased very significantly, an effect that was insignificant and of very short duration in dogs with normal cardiac function,
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Figure 2. Representation of digitalis plant in various parts of the world.
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Figure 3. The contractile force increased 89% in normal myofibrils with Ouabain in relation to the basal conditions.
with which it also show that digitalis drugs are useful in the failing heart, but not in the normally functioning heart [5] .
It is important to emphasize that digitalis is the only inotropic drug that reduces myocardial oxygen consumption (MVO2) in HF.
The balance between its determinants is favorably affected: increased contractility, decrease heart rate, wall stress (pre- and afterload) which reduces MVO2 and the bottom line is that the inotropic effect is accompanied by a decrease in MVO2 [6] [7] (Figure 7); I emphasize that digitalis is the only inotrope that has this effect.
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Figure 4. Peripheral effect and cardiac output of digitalis in patients with heart failure (3).
3. Digitalis Medication in Acute Heart Failure (Figure 8)
52-year-old patient with acute myocardial infarction and pulmonary edema due to acute heart failure. Figure 8(A) shows a patient with intense diusnea, audible crackles at a distance and “Salmony” expectoration. Figure 8(B) shows the ECG with tachycardia of 150 × min., Acute myocardial infarction in anteroapplical evolution with high lateral extension, digoxin, furocemide, spironolactone, IV
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Figure 5. Digitalis in peripheral effect in patients without HF.
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Figure 6. Effect of ouabain on dP/dT in normal and failing hearts in dogs with and whithout HF.
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Figure 7. Determinants of myocardial oxygen consumption (MVO2).
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Figure 8. Digitalis in acute heart failure (pulmonary edema) in acute myocardial infarction.
nitroglycerin and captopril are administered, Figure 8(C) shows reduction of cardiomegaly with clear lung fields with asymptomatic patient 24 hours. After starting the treatment, in Figure 8(D) the ECG shows a HR of 98 × min, and the image of the infarction in progress.
4. The First Scientific Study and Its of Digitalis Treatment Effect on Mortality
In 1997, the DIG study was carried out in 8000 patients, in digitalis treatment and the results revealed that the pharmacological treatment did not make any difference with placebo (Figure 9(A)) [8] , the reduction of mortality only ocurred when relapses (Figure 9(B)). After this study, the use of digitalis medication has declined to such an extent that clinical guidelines only use it when heart failure is complicated by atrial fibrillation, which is a very minor indication.
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Figure 9. Effect of digitalis on mortality in chronic heart failure.
We proposed to carefully review the DIG study regarding the effects of digitalis medication in heart failure and when looking at the DIG [8] study of 8000 (Figure 9(A)) HF patients, the question arises, why were 1000 patients who had minimally depressed EF > 45% (Figure 10) or no HF. When previous studies had already shown that digitalis had no effect, which obviously contaminates the mortality statistics when 1000 patients have no or minimal HF, since there is evidence which shows that the mortality of this disease is directly proportional to the reduction in the EF [9] [10] [11] [12] .
5. The DIG Sub-Study in Relation to Mortality
When the evidence of the effects of digitalis medication is analyzed, the great value of the recently published article by Gheorghiade et al. [13] can be understood in which he rescues the true value of digitalis medication when he ranks the most severe patients in the DIG [8] study: in NYHA functional class III - IV, with EF < 25% and WHR > 55% and demonstrates that the mortality of this group of patients with the highest risk at 37.9 months (Figure 10), even, Gheorghiade and Braunwald [14] suggest that digitalis should be used in patients with acute severe heart failure, fact that we have corroborated in clinical practice (Figure 11).
6. Others Studies on Prevention of Digitalis in Relapses in Heart Failure
The studies PROVED and RADIANCE TRIAL (Figure 12) showed that in patients who were hospitalized for symptomatic HF who were discharged asymptomatic, a group with only diuretic and placebo, 44% returned to the hospital at 3 months, with symptomatic HF; another group was discharged with ACEI, diuretic and placebo and at 3 months, 30% returned with relapsed in HF; other
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Figure 10. 1000 patients with normal or slightly decreased EF (DIG).
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Figure 11. DIG sub-study. Mortality in the most severe patients.
group were discharged with digoxin, diuretics and placebo, the relapse was 20% and finally, when they were discharged with the triple regimen, only 5% of the patients relapsed, which shows that the combined therapy is superior to t isolated treatment.
7. Other Beneficial Pharmacological Effects of Digitalis in HF
Digitalis has a modulating effect on the neuroendocrine system, by blocking the catecholamines and renin secretion in patients with symptomatic HF [15] [16] (Figure 13).
By other hand its vagal effect, restores the function of the baroreceptors (Figure 14) with heart rate variability is recovered in these patients [16] [17] which, as we know, reduces the possibility of sudden death, finally, digitalis, due to its vagal effect by reducing heart rate, restores the Bowditch effect (Figure 15), which is lost with sinus tachycardia sustained by adrenergic activation [18] [19] .
The results of Gheorghiade study is similar to COPERNICUS Study (Figure 16)
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Figure 13. Digitalis effect of neuroendocrine system.
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Figure 14. Digitalis effect on heart rate variability.
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Figure 15. (A) Bowditch effect: force/frequency relationship. Increased heart rate increases contractility. (B) Sustained tachycardia, on the other hand, reduces contractility. (C) Digitalis administration in chronic heart failure due to its vagal effect reduces tachycardia and increases contractility.
[20] in relation of mortality achieved by Carvedilol in patients with HF in functional class IV.
Medications currently accepted for the treatment of HF: digitalis, diuretics, spironolactone, ACE inhibitors, beta-blockers, sacubitril-valsantan and gliflozina, have shown their maximum usefulness in combination by adding their pharmacological benefits; each one in isolation has a significantly lower beneficial
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Figure 16. Carvedilol in heart failure in functional class IV (Copernicus study).
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Table 1. Digitalis in heart failure.
effect, but the combination between them, which must be individualized to the condition of each patient, improves functional class and reduces mortality, which is the most important objective in patients with HF.
8. Conclusion
The clinician and especially the cardiologist, thoroughly understands the digitalis effect in patients with and without heart failure, and all the pharmacological characteristics on inotropism, the neuroendocrine system, the autonomic nervous system, heart rate, baroreceptors, the Bowditch effect, functional class, beneficial effect on mortality reduction, the clinician will be able to make a correct use of the digitalis medication of its benefits, toxic effects, its contraindications of patients with heart failure, in other words, the cardiologist must have a fine clinical skills for treatment to this patients (Table 1).