Philip David Houck, Texas A&M College of Medicine, Cardiology Division, 1H, Scott & White Healthcare, 2401 South. 31st Street, Temple, Texas 76508
* Corresponding author: E mail: email@example.com
Lymphatic function and inflammation are two related concepts that have been neglected in heart failure. All of the symptoms of heart failure, hence, compensatory mechanisms can be related to overwhelmed or dysfunctional lymphatic function. Lymphatics are responsible for tissue homeostasis controlling approximately 12 litres of fluid. These thin-walled valved pumping systems are also intimately involved in immunity, control of inflammation and lipid and nutritional transport. Repair of damaged tissues by cellular transport explain its many functions. The aim is to review the role of lymphatic function and inflammation in congestive heart failure exacerbations.
Inflammation is the cause of decompensated heart failure, and lymphatics and their reaction to environment are the primary mediators. This concept is consistent with a new model of disease-regeneration balanced by degeneration with inflammation (lymphatic function) serving as the fulcrum.
Evaluation of the hypothesis
The pharmacology of lymphatic function in the context of heart failure is lacking. A new term ‘lymphangiontrope’ is introduced and is defined as an intervention that improves the function of lymphatics by increasing amplitude and frequency of lymphangion contraction. The known pharmacological effects on lymphatic function is presented here, and new performance parameters and interventions directed toward improvement of lymphatic function, inflammation, and regeneration are proposed, allowing patients to compensate for cardiac dysfunction.
The lymphatic system represents a peripheral therapeutic target for improving heart failure symptoms.
The lymphatic system is difficult to study; hence, there is little information on how this system may influence heart failure patients[1,2]. In 1969, cannulation and unloading of lymph from the thoracic duct remitted the symptoms of congestive heart failure and improved cardiac output in 12 patients with intractable congestive heart failure.
Exacerbations of heart failure have previously been attributed to salt and water excess, or other stressors such as anaemia, tachycardia, and recurrent ischemia. These exacerbations are manifested by pulmonary oedema and peripheral oedema. Therapies to remove salt and water excess have improved acute symptoms but have not lead to better outcomes. In fact, in some cases such therapies have contributed to worse outcome such as cardio-renal syndrome. The mainstay in the treatment of congestive heart failure has been diurectic therapy. However, the chronic use of furosemide has increased mortality in congestive heart failure[4,5]. Other methods of pre-load reduction such as ultrafiltration have also shown no benefit. These findings suggest that the strategy to reduce pre-load is flawed even though it has been a common and excepted practice.
The lymphatic system as a target of therapeutics has been ignored in the heart failure community. The stimulation of this system to remove systemic and pulmonary oedema is appealing as an alternative approach to pre-load reduction. The additional benefit of controlling the inflammatory process is attractive to the entire community of medicine that cares for chronic inflammatory related diseases such as diabetes, coronary artery disease, arthritis and autoimmune disease.
The purpose of this paper is to review lymphatic function in the context of heart failure and to again consider lymphatic function as a therapeutic target.
Inflammation is the cause of decompensated heart failure and lymphatics and their reaction to environment are the primary mediators. This concept is consistent with a new model of disease- regeneration balanced by degeneration with inflammation (lymphatic function) serving as the fulcrum.
As the paradigm of chronic disease shifts toward a common aetiology of inflammation, the lymphatic systems’ role becomes more prominent. Inflammation may be the primary reason for decompensation in heart failure in a previously compensated patient. Cardiac dysfunction and heart failure are not synonymous. Patients can have many different central measures of ejection fraction and different measures of BNP, an indicator of myocardial wall stress, with little or no symptoms. These measures may be better indicators of cardiac reserve and predictive of future heart failure exacerbations than current symptoms.
Inflammation has not been considered as a significant cause for heart failure exacerbation. Increased inflammatory state with production of cytokines has often been considered a product of heart failure due to low cardiac output and loss of integrity in mucosal surfaces that allow more antigens to enter lymphatic drainage. Heart failure is an inflammatory state manifested by increased thrombophilia, cachexia and white count elevations.
Inactivity, diabetes type II, age and smoking are all pro-inflammatory. These pro-inflammatory conditions are associated with increased risk for heart failure. Diet is associated not only with increased salt and fluid intake, but also simple carbohydrate excess that can increase bacterial activity. The immune system has to respond to this increased activity with an inflammatory response. The lymphatic system is responsible for this inflammatory response, as it is the portal from the environment to the core of the individual. It is also responsible for the symptoms of inflammation: Dolor (pain), Calor (heat), Rubor (redness), Tumor (swelling) and Functio laesa (loss of function).
The lymphatic system is involved with immunity, inflammation, repair and interstitial homeostasis, making dysfunction of this system a causative agent in the exacerbation of congestive heart failure in a previously compensated patient. Pulmonary oedema, peripheral oedema and cardio-renal syndrome are all manifestations of the failure of the lymphatic system to compensate for the volume loaded state of heart failure. It is of no surprise that the medications that we use to treat heart failure such as beta blockers, ACEI, Spironolactone, aspirin, warfarin, Statins and exercise, are all anti-inflammatory[8,9,10,11].
The intention of this review is to understand lymphatic function. Anatomy and function will be reviewed with emphasis on factors that modify lymphatic function. These functions provide for interstitial equilibrium, transport of nutrients, protection from infection and serve as channels for reparative cells. Lymphatics are intimately involved in the repair process through transport of regenerative cells and removal of cellular debris. Dysfunction of this system can lead to inadequate repair. The term “lymphangiontrope” is introduced. Lymphangiontrope is defined as an intervention that improves the function of lymphatics by increasing amplitude and frequency of lymphangion contraction.
The author has referenced some of its own studies in this hypothesis. The protocols of the studies have been approved by the relevant ethics committees related to the institution in which they were performed.
Anatomy and Function
The lymphatic system is a complex architecture of vessels composed of a lymphatic capillary network enmeshed within the interstitium that is connected to the downstream network of fusiform, valved lymphangions which make up the lymphatic collectors and transport vessels. Fluid, macromolecules and cells in the interstitial space passively enter the lymph collecting system through breaks in basement membrane and become lymph. Lymph is propelled down the lymphatic network by intrinsic muscular contractions of the lymphangions as well as compression of the lymphatics by external forces. The lymphangion has a unique fusiform configuration and innervation, both striated and smooth muscular elements and valves of two to five leaflets (Figure 1)[12,13,14].
Lymphangion contracted and dilated, demonstrating amplitude of contraction.
There is a peristaltic intrinsic contractile pattern, producing phasic flow with brief periods of flow reversal which close the valves. Net central flow is the sum of centripetal flow toward the thoracic duct. The centripetal flow is mediated by the valves, resonate frictional forces and inertia of the fluid column that favours forward flow due to resistive forces of back flow. Flow is both intrinsic from the pumping action of the lymphangion and extrinsic from the mechanical influence of the tissues. These mechanical forces include driving forces of lymph production, arterial contractions, peristalsis of the gastro-intestinal tract, muscular contractions, cardiac pulsations, diaphragmatic and dynamic pressure changes in the chest, gravity, and finally, central venous pressure where the lymph is eventually deposited. The extrinsic forces are important factors in gut wall lymphatics that periodically receive large boluses of nutrition through feeding and thus experience large increases in lymph formations. Extrinsic flow in gut wall lymphatics is also driven by gastro-intestinal peristalsis and enhanced by relaxation of gut lymphatics. This relaxation appears to be an energy saving step with the driving forces of tissue oedema being the predominant force. How important a factor of this extrinsic flow is in other solid organs is not clearly known, although it appears to be very important in cardiac lymph flow. In gastro-intestinal lymphatics outside of the gut-wall, lymphangions exhibit their own systolic and diastolic contractile properties via the intrinsic lymph pump. The pressure production of the intrinsic lymph pump of the mesentery is in the range of 5–10 cm H2O but can be higher depending on external pressure and position. The average flow generated is 13.95 micro litres per hour with a movement of lymphocytes and other cells ranging between 206 and 2030 cells per minute. The dynamics of the flow can be characterised by frequency and amplitude of contraction. The flow rate appears to be self-adjusting according to demand, modulated by stretch and shear forces of the lymphangion. The lymphatic system manages approximately 12 litres of extracellular fluid, about 4 litres of which is transported through the thoracic duct each day in normal humans.
Age shows a reduction in amplitude and frequency of the intrinsic lymph pump. Nitric oxide inhibits contractile force and frequency and its release decreases the tone of the lymphatic vessels enhancing refilling of the intrinsic pump and allowing more extrinsic flow, possibly as an energy saving step. From the standpoint of lymphatic function in congestive heart failure, the amplitude and frequency of lymphangion contraction is assumed to be the predominant driving force and, therefore, dilatation for extrinsic flow is not desirable. This assumption is valid since the pre-load of the lymphangion is high and the after-load, central venous pressure is elevated. Medications that increase lymphatic amplitude and frequency can be considered to have positive lymphangiontrope.
Besides transport of lymph to the central circulation, this fine network is integral to immunity and the inflammatory system. It collects antigens and displays them to the lymph follicles for processing. These channels are a direct link to the environment. Changes in the environment affect homeostasis of electrolytes, fluid balance, nutrition and inflammation. It has been documented that inflammatory proteins of gut origin are carried by this system. The inflammatory cytokines have been implicated in multi-system organ failure seen in shock[19,20]. These inflammatory proteins and cellular elements should be considered as a possible aetiology of the inflammatory state of congestive heart failure.
Table 1 is a compilation of data from a number of articles using different animal models and should be viewed critically[21,22,23,24,25,26,27,28]. To make a fair comparison in the setting of heart failure the pre-load and after-load of the lymphangion should be held constant (high consistent with the prevailing conditions of heart failure) and the amplitude and frequency should be measured, which is the active energy requiring state to move the excess fluid back into the central circulation so it can be removed by the kidney.
Lymphaniontrope under various stimuli
The tissue oedema formation is a complex system that involves the permeability of capillaries, interstitium, lymph, venules, arteriolar and venous pressure, and protein concentrations. Increases in permeability relate to large macromolecules and does not necessarily imply a preferred movement of interstitial fluid. Many pharmacologic substances can alter this permeability and can also alter the amplitude and frequency of the lymphangion. In addition, inflammatory cytokines can also alter permeability and influence the pumping ability of the lymphangion. This is evident in sites of injury with initial swelling and oedema followed by removal of the swelling. The same structures that cause the swelling must alter their function to remove the swelling. The results of the table do not represent consistency in respect to biphasic response. In addition, increased tonic response generally correlates with increased amplitude and frequency of the pre-nodal lymphangion and tone predominates in post-nodal lymphatics. Many of the experiments are accompanied by both inhibitory and stimulating effects of other drugs to suggest the presence of receptors. These studies demonstrate that the lymphangion has multiple receptors including nervous, immunologic, vasoactive, peptide and other receptors.
These thin-walled vessels are involved in multiple pathways with multiple communication possibilities. There are inconsistencies in the data in the sense that different animal preparation is used and function defined by frequency, amplitude and tone has to be viewed in the setting of all of the other stimulants of the interstitium. An attempt is made to summarise this data by amplitude, frequency of contraction of the lymphangion, and tone, which could be considered as systolic function, chronotropy, and diastolic function of these small pumps. There are important gaps in this knowledge, illustrated as blanks in Table 1.
Lymphatics in specific organs
The symptoms and physical findings of overwhelmed lymphatic function in various organs are summarised in Table 2[29,30,31,32,33,34,35,36,37]. Inadequate compensation of the lymphatics of the lungs (rales), extremities (oedema), and even the kidneys (proteinuria and rising creatinine) are evident by physical examination and laboratory analysis.
Lymphatics in Specific Organs
The heart is the most difficult organ to visualise lymphatic function in. The drainage of the cardiac lymph has been limited to some India ink or hydrogen peroxide administrations in animal models. Three plexus are proposed: the sub-endocardial, myocardial, and sub-epicardial. The distributions and flow have not been adequately described. The sub-epicardial lymphatics appear to terminate in lymphatic trunks that travel with blood vessels. The right heart drains through the right efferent trunk. The left heart has more variable drainage but also utilises the left thoracic duct. Lymphatic plexuses are incorporated into cardiac valvular structures on the low pressure side of the valve, papillary muscles and chordae. This anatomy may explain the predilection of vegetations to these same locations. Lymphatics have also been demonstrated to run with the conducting fascicle and have been implicated in heart blockage associated with myocardial infarction and arrhythmia due to oedema of the conduction fibres resulting in non-uniformity of depolarisation[38,39,40,41,42].
Obstruction of cardiac lymphatics has implications in cardiac surgery, transplantation and myocardial infarction. The consequences are myocardial oedema, pericardial effusion, and electrical disturbances with resultant myocardial dysfunction, tamponade and arrhythmia. Valvular lymphatic obstruction could explain lipid deposition in the valve, and acceleration of valvular degeneration in aortic stenosis and senile calcific mitral stenosis.
Inflammatory and Reparative Functions of Lymphatics
Transport of stem cells into the interstitial space is accomplished through arteries, veins and lymphatics. Coagulation of the lymphatic drainage to infarcted tissue by tissue debris and thrombus prevents reparative cells from reaching the site of injury. Lymphatics control oedema, inflammation, and transport of stem cells and ultimately the regeneration of damaged tissues.
The immune system protects us from invaders. In this process an infection can be cured or kill us by over-reacting to a threat. It is a complex process involving multiple pathways with multiple checks and balances. It utilises cellular and humoral components. Immunity and protection from the environment is an important function of the lymphatic system secondary to the close proximity of the intestinal flora and airways. The lymphatic system is the channel from the environment to the core of organisms. Nutrients, bacterial, viral and toxic threats travel through this system. In addition to the “self organism” being affected by the environment, the multi-organism conglomerate “bacterial microcosm” is also stressed or bolstered by the foods that we eat. The homeostasis between the microcosm and the self is disrupted requiring adjustments of the immune system to rebalance. Dietary indiscretions via the lymphatics put additional pre-load stress and inflammatory stress on the heart. Heart failure can also alter gut lymphatics. In right heart failure, the lymphatics have a difficult time transporting nutrients toward a high pre-loaded right atrium. The bowel becomes oedematous with patients complaining of abdominal pain and swelling from ascites. The dysfunctional lymphatic system contributes to an increased systemic inflammatory state. The inflammation further impairs lymphatic function starting a cascade of events that leads to further dysfunction by increasing more cytokines produced in the gut pushing heart failure from a chronic compensated state to an inflamed heart failure exacerbation.
The lungs are similarly exposed to the environment explaining why smokers, pulmonary exacerbations due to bronchitis, with pneumonia often have an additional component of heart failure.
Speculation invoking transient lymphatic obstruction could lead to an explanation of TakoTsubo cardiomyopathy and transient apical ballooning. If the myocardial plexus has varied distributions similar to apical, mid ventricle, and whole ventricle distributions, the unusual patterns of this transient dysfunction could have an anatomical explanation. When lymphatic function is restored, the oedema resolves and function returns to normal. The above speculation deserves a greater understanding of lymphatic function since new pathophysiological explanations can lead to new therapies.
The inflammatory pathways are more complicated than the coagulation pathways and have proven to be far more difficult to target with therapeutics. The inflammatory pathways are also instrumental in repair and regeneration. Senescent cells are labelled by natural autoantibodies and reprocessed by macrophages. Disruption of one inflammatory pathway may have deleterious effects as other pathways compensate for the disruption and is the aetiology of chronic disease. Lymphatics are intimately involved with chronic inflammation. The drainage of these small vessels is into lymph nodes where antigen identification and response occurs. Processing antigen can occasionally be performed poorly introducing noise or errors into the inflammatory system. Figure 2 is a summary of a new model of health and disease that balances regeneration/ degeneration with inflammation as the fulcrum. Lymphatic function could replace the inflammatory fulcrum being both beneficial and detrimental with the additional responsibility of transport of reparative cells.
New Model of Health. Adapted with permission from Houck PD, de Oliveira JMF. Applying laws of biology to diabetes with emphasis on metabolic syndrome. Med Hypotheses (2013).
Table 3 classifies various interventions in terms of lymphangiotrope, regeneration/degeneration, and inflammation[46,47,48,49,50,51,52,53,54]. Heart failure interventions have not been considered in this format favouring hemodynamic measures of pre-load, afterload, contractility and compliance. These measures are ideal for describing the cardiac (central) cause of heart failure. They fail to explain (peripheral) causes for exacerbations when there is no measurable change in central cardiac function. Heart failure therapies should be studied for remodelling potential. Therapies that favour increase in stem cells should be favoured over those that decrease stem cells. is in the table indicate that the proposed intervention has not been proven. The table is based on known influences and also on speculation that can serve as a platform for debate and discovery. Every new therapy for heart failure should be considered in terms of these peripheral performance parameters including inflammation, regeneration, degeneration, and “lymphangiontrope”.
New performance parameters and interventions
The lymphatic system is an unexplored fine vascular network involved in interstitial homeostasis and inflammation. This network helps to relieve symptoms of heart failure mainly oedema and dyspnoea. The system is directly linked to inflammation, which is responsible for protection from the environment and for repair. “Lymphangiontrope” is a new term that characterises lymphatic pumping function. Medication that improves lymphangiontrope will help relieve symptoms of heart failure. Current therapies should be re-evaluated to understand the influence of interventions on lymphangiontrope. This concept is especially important considering that current therapy of pre-load reduction is associated with increased mortality. New therapies that influence lymphatics will likely be chemical drugs, mechanical stimulants, electrical stimulants, biologicals, and cellular treatments. These therapies will also influence inflammation and regeneration and remodelling of the heart.
The author would like to thank David C. Zawieja, Ph.D, Professor and Vice Chairman Systems Biology and Translational Medicine, Director, Division of Lymphatic Biology Texas A&M Health Science Centre for his guidance and ground- breaking work in the study of lymphatic function.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Lymphaniontrope under various stimuli
|PGE1 and PGE2||↑→||↓||Rat, Guinea Pig|
|Histamine H1 H2||↑||Bovine|
|Nitric Oxide||↓||↓||↓||Bovine, Mouse, and Rat (mesentery and thoracic duct)|
|Neuropeptide substance P Gastrin releasing peptide||↑||↑||Rat (mesentery, thoracic duct, cervical|
|Electrical stimulation||↑||↑||Bovine Messentery|
|Pentobarbitone Halothane||↓||↓||Bovine Messentery|
|BNP ANP||↑↑↑↑||↑↑↑↑||Unpublished data in rat mesentery|
|ACEI / ARB|
|Acetylcholine||↓↓↓||↓↓↓||Isolated canine thoracic duct|
|Isoproterenol||↓↓||↓↓||Isolated canine thoracic duct|
|Adenosine||↓||↓||Isolated canine thoracic duct|
|ATP||↓||↓||Isolated canine thoracic duct|
|Epinephrine||↑↑↑||↑↑↑||Isolated canine thoracic duct|
|Norepinephrine||↑↑||↑↑||Isolated canine thoracic duct|
|5 Hydroxy Tryptamine Serotonin||↑||↑||Isolated canine thoracic duct|
Lymphatics in Specific Organs
|Organ||Symptoms/Findings of lymphatic dysfunction|
|Lung||Dyspnoea is a major symptom in heart failure secondary to the increased work of respiration from excess weight of lung water. On the chest X-Ray, the lymphatics can be seen as Kerly B lines. One of the adaptations in chronic heart failure is to enhance the function of the lymphatics so that the increased interstitial fluid is removed more efficiently.|
|Kidney||Water and salt homeostasis, blood vessel constriction, and erythrocyte regulation are all critical to the management of congestive heart failure. Perfusion of the kidney depends on cardiac output and perfusion pressure. The perfusion pressure across the kidney depends on systemic pressure and central venous pressure. Additional forces such as abdominal pressure from trauma, tumour or ascites can further reduce kidney function. Starling forces will cause oedema of the kidney and indeed is a strong contributor to the development of cardio-renal syndrome. An oedematous kidney may even affect regulation of erythrocytes explaining the anaemia of congestive heart failure. Impaired lymphatic drainage causes proteinuria.|
|GI||Ascites, abdominal pain of right heart failure is secondary to bowel oedema and failure of lymphatics to transport extravascular fluid back to the vascular space. The gastro-intestinal lymphatic drainage, in addition to tissue fluid homeostasis, has a role in carrying nutrition to the vascular system for dispersion to all the cells of the body. The overall inflammatory status of the individual is controlled through gut lymphatics.|
|Legs||Peripheral oedema is the easiest heart failure manifestation to recognise, usually occurring before respiratory complaints. It is elusive since peripheral oedema can occur without heart failure in setting venous insufficiency, primary lymphatic dysfunction, infection and trauma. Not all patients have peripheral oedema with similar cardiac dysfunction. The explanation is a variable response in lymphatic function, activity level of the patient, and inflammatory state. Aldosterone inhibitors are far better at mobilizing fluid in oedematous states such as cirrhosis, right heart failure and this medication is expected to have a positive influence on lymphatic function ߝ positive lymphangiontrope.|
|Brain||The brain is very sensitive to oedema secondary to trauma, infarction and under perfusion. Mental confusion is common in heart failure, in part due to poor perfusion and the oedema that may form due to decreased lymphatic function. This tends to happen in older patients who already have age-related dysfunction of their lymphatics. The existence of brain lymphatics is in question.|
New performance parameters and interventions
|Performance Parameter||Intervention Increases||Intervention Decreases|
|Lymphangiontrope||Nesiritide Spironolactone Lymphedema pumps Mechanical stimulation Exercise Sympathomimetics Phosphodiesterase Inhibitors||Calcium Channel blockers Glitizones High dose loop diuretics Endotoxin and cytokines Nitric Oxide|
|Regenerative (Proliferative) Degenerative (Apoptotic)||Regenerative Lipophilic beta blockers ACEI Exercise EECP Statins Insulin Growth hormone Clenbuterol Nesiritide||Degenerative AGE Inactivity Inflammatory states Endogenous and Exogenous Taxolimus Denervation Sympathomimetics Phosphodiesterase Inhibitors|
|Inflammation||Smoking Weight gain Inflammatory conditions (RA Lupus etc.) Oestrogen Diabetes II Metabolic syndrome Infections Immobility Surgery NSAID’s||Exercise Statins Aspirin Plavix 150 better than 75 Beta Blockers ACEI Warfarin Heparin Weight loss Testosterone Alcohol low dose Plasmapheresis Biological anti-inflammatories|