Intertraffic of Endothelin 1 and Thrombospondin 1 between lungs and myocard via pulmonary circulation can alter cardiac loads, tissue integrity and atrial blood coagulability

Part I: Lungs and myocard as a self-regulated unit dependent on bidirectional portal-type endocrine loops

An important issue is whether mediators synthesized in the myocard can be selectively diverted between the pulmonary circuit and the systemic circuit. Here the proposed idea is that a controlled delivery to the left and to the right heart is done by the peculiar myocardial venous circulation that includes coronary sinus (CS) that drains venous blood to the right atrium, and Thebesian veins (TVs) that open in all four heart cavities^4,5, particularly numerous at the ventricle apex and at papillary muscles base⁶.

It was observed that the blood flow through TVs depends on the heart muscle stretching. In inactive heart muscle perfused through coronaries under pressure, more fluid can escape through TVs than through CS⁷, suggesting that fluid drainage via Thebesian veins in comparison to other veins might be more important in situations when heart chambers are stretched, due to the volume load.

If we look at the cardiopulmonary circulation in more detail (Figure 1), the pulmonary capillaries are in the serial position to the myocardial capillaries, meaning that mediators from lungs can directly influence myocardial cells after entering the coronary circulation. Myocardial veins to the right heart (mainly CS and also the right heart TVs) place myocardial capillaries in the serial position, in front of the pulmonary capillaries. Any mediator in the myocardial venous blood drained in the right heart will initially affect lungs before being diluted in the systemic circulation.

This unique setting can be described as a double portal system in which myocard and pulmonary capillaries are bidirectionally connected via short endocrine loops. Other, better-known examples of portal circulations in our body are unidirectional, since the tissue of the secondary capillaries (adenohypophysis or liver) has no way of endocrine action directed selectively on the primary organ (hypothalamus in the former and stomach and intestines in the latter). Instead of that mediators from secondary capillaries return to the heart and enter pulmonary circulation.

Figure 1. Schematic drawing of cardiopulmonary circulation.

The pulmonary capillaries are in the serial position to the myocard, so mediators from lungs can directly influence myocardial cells, after entering the coronary circulation. Myocardial venous blood that drain into the right heart (mainly via coronary sinus (CS) and also via the right heart Thebesian veins (TVs)) initially affects lungs before being diluted in the systemic circulation.

It should be noted that although this paper is focused on ET-1 and TSP1, due to their high synthesis rates in lungs and myocard, various other substances can act through these short, portal-type loops that connect cardiopulmonary organs.

Both lungs and myocard are rich in various receptors, so local perfusion clearance is expected for many mediators in the blood that passes through lungs and myocard.

As shown in Table 1, any surplus of myocardial mediators can leave the heart muscle through the left heart Thebesian veins and enter the systemic circulation, or leak to the right heart through CS and the right heart TVs. In the latter case, the right heart veins act as a shortcut from myocard to pulmonary circulation.

On the other hand, substances synthesized in lungs enter the left heart and aorta. Some of these can directly affect the myocard via coronary arteries, and their surplus can return to the lungs via CS and the right heart TVs.

An important consequence of the described setting is that for any disorder caused by direct cardiopulmonary endocrine loops it can be expected to remain undetectable by measuring the peripheral vein blood levels of involved mediators. This means that new diagnostic methods are probably required to recognize patients with problems caused by an alteration in cardiopulmonary control loops.

Part II: ET-1 as a real-time protector of the cardiopulmonary function

From the U133A data, in the probeset 218995 with Endothelin-1 (EDN1) data (http://biogps.org/#goto=genereport&id=1906), among 176 measurements of different tissue samples, only four values stand out. Two values are human cardiac myocytes (Clonetics Cat # CC-2582) with mRNA expression values of 502.7 and 118.1, and the other two are lung samples with values of 343.5 and 307.5. The mean EDN1 value for all reported tissue samples is only 13.28, clearly suggesting that cardiac myocytes and lungs synthesize much more ET-1 than all other tested tissues and cells.

A separate issue is the identification of target tissues for the circulating ET-1. Data of endothelin A receptor (gene EDNRA) (http://biogps.org/#goto=genereport&id=1909) were extracted from the probeset 216235. High EDNRA mRNA levels were reported in uterus, cardiac myocytes, heart, prostate, lungs, liver, appendix and skeletal muscle. In the second probeset 204463, uterus, prostate and lungs have the highest EDNRA values, while in the probeset 204464, fetal lungs and uterus standout as tissues with the highest EDNRA mRNA values.

A plausible interpretation is that lungs and cardiac myocytes produce so much ET-1 that the surplus of ET-1 molecules leaks into the circulation. Other tissues are able to synthesize ET-1 in modest quantities, probably acting as a paracrine mediator⁸. This interpretation is in concordance with papers that report cardiac secretion of ET-1 in animal models^9,10.

Table 1 is based on the expectation that the myocardial ET-1 synthesis increases due to stretching and increased work of the cardiac muscle, during heavy exercise as well as in pathologic conditions that dilate heart chambers. Exposure to humoral and paracrine mediators also influences the ET-1 synthesis. So, although atrial TVs can remain open during almost the whole heart cycle, with the exception of the short atrial systole (visible as the P-R interval on ECG), the ventricular TVs probably drain more blood during late diastole, when ventricles are stretched to maximal length and under low pressure. During ventricular systole TVs openings are reduced in size, the intraventricular pressure is higher than in the heart veins, particularly in the Left ventricle, so most of the myocardial venous blood probably leaves through the coronary sinus.

When considering the mRNA distributions for ET-1 and its receptor A together, here the proposed interpretation is that an elaborate regulatory system mediated by ET-1 selectively tunes resistance in the pulmonary and in the systemic circulation to meet ever-changing demands during rest and exercise (Table 1):

These simple changes in resistance of pulmonary and systemic arteries help the myocard to adapt to many different settings of physical work, particularly to quickly alleviate extremely low afterload and thus reduce the increased venous return (the right heart preload) during intense muscular work.

Part III: Local TSP1 synthesis in tissues under continuous mechanical stress

It is known that blood levels of thrombospondin 1 can be altered in patients with ischemic disease^11,12, malignancy, particularly in pancreatic cancer patients¹³ or metabolic problems¹⁴. Based on many TSP1 roles, some synthesis is expected to be almost ubiquitous, but only few cells/tissues require so much thrombospondin 1 that the local surplus normally leaks into circulation.

There are two important aspects of the reported TSP1 mRNA values (http://biogps.org/#goto=genereport&id=7057). The first is that almost all tested cells/tissues contained this mRNA, and the second is that few cells/organs have shown high levels. Among the main sources of TSP1 synthesis are Cardiac Myocytes, Bronchial Epithelial Cells, Smooth Muscle Cells and Uterus. All these cells/tissues are unique by their special ability to actively or passively adapt to changes in the cellular shape and surface area. Cardiac myocytes and smooth muscle cells form tissue layers that contract by reducing their area in a manner of bidimensional shrinkage:

In all these three examples, changes in the cell shape are repetitive. This means that the tissue structure integrity strongly depends on interconnections between cells. This is a point where plentiful TSP1 availability becomes important, since TSP1 is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions, binds to fibrinogen, fibronectin, laminin, type V collagen and integrins¹⁵. This means that beside other factors (glucose, insulin^14,16), the local synthesis of TSP1 is probably related to the average mechanical stress, in tubular structures governed by the Law of Laplace.

Part IV: Health disorders possibly related to the alteration of ET-1 and TSP1 cardiopulmonary loops

Based on the mentioned link of ET-1 and TSP1 to pulmonary fibrosis, it can be assumed that other health issues can be linked to the imbalance in pulmonary or myocardial synthesis of these two mediators.

Disorders possibly related to the ET-1 over-exposure of myocard and lung tissue

Table 2. shows possible damage of supraphysiologic myocardial and pulmonary ET-1 secretion. Two auto-endocrine loops that start and end in the same tissue are proposed. The first possibility is that the presence of endothelin A receptors on cardiac myocytes can explain the ET-1 mediated heart hypertrophy. Beside pulmonary ET-1, the left heart Thebesian veins can increase deliverance of ET-1 to the coronary circulation and lead to heart hypertrophy¹⁷ and to the diastolic dysfunction¹⁸.

The second autocrine loop is possible in patients with a significant left-to-right cardiac shunt. Surplus of pulmonary ET-1, due to increased pulmonary perfusion can leak through the shunt opening from the left heart to the right side. Once on the right side, the excess ET-1 leaves the right ventricle and through pulmonary arteries reach lungs. This recycling of pulmonary ET-1 via left-to-right shunt can lead to pulmonary hypertension and fibrosis. Both conditions are components of the Eisenmenger's syndrome, often treated by bosentan, a blocker of endothelin receptors¹⁹.

Possible risk of thrombus formation due to local accumulation of TSP1 in the left atrium

Some patients with long-lasting atrial fibrillation never suffer from peripheral embolism, despite not being on anticoagulant therapy, while others experience peripheral artery embolisms despite regular therapy²⁰. Only rare patients develop thrombi in the right atrium, although both atria are fibrillating, with similar magnitude reductions in ejection velocities²⁰. These observations point to the unsolved question why is the left atrium so much more prone to the thrombus formation during fibrillation.

It is here assumed that the local rate of TSP1 synthesis probably depends on the local myocardial and pulmonary pathology, some patients produce a surplus of myocardial TSP1 due to cardiac dilatation, myocytes stretching or metabolic conditions, while diverse pulmonary problems can augment leaking of pulmonary TSP1 into circulation.

As shown in Table 3, the right atrium receives the systemic venous blood, normally poor in TSP1. On the other hand, the coronary venous blood via CS and TVs, normally contain some myocardial TSP1, but endocrine factors or local condition within the heart muscle can increase the TSP1 content. The situation is similar in the right ventricle.

The left atrium is exposed to two separate thrombospondin 1 sources, from lungs via pulmonary veins and from myocard via left atrial Thebesian veins. It can be presumed that in many pulmonary or cardiac patients, these two organs often secrete a surplus of TSP1, thus making TSP1 blood levels increased in the left heart, particularly in the left atrium. In short, this means that the left atrium and ventricle are only chambers that receive both pulmonary and myocardial TSP1.

A thin and TSP1-rich juxtamural layer of blood surrounding Thebesian veins can temporary form during the end-diastolic atrial and ventricular phases. In a normal heart this should not increase the risk of thrombus formation, since all secreted TSP1 will be quickly diluted by the inevitable systole that mixes all blood during ejection.

Here the proposed sequence of events starts with the onset of atrial fibrillation:

Part V. How to prove the proposed interpretation of mRNA data

Since levels of ET-1 and TSP1 in the peripheral vein is not expected to be adequately related to the pulmonary and coronary levels of these two mediators, here proposed interpretations can be tested by taking blood samples from other vascular segments.

One possibility is to measure ET-1 values in samples of blood taken during systole and diastole from the right atrium (near the coronary sinus) and from aorta (below the aortal valve):

On the other hand, it might be important to measure the TSP1 level in simultaneously taken samples of blood from a systemic artery and from a central vein: