alternative view of congestive heart failure exacerbations: role of … · 2014-03-02 ·...

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For citation purposes: Houck PD. Alternative view of congestive heart failure exacerbations: Role of lymphatic function and inflammation. OA Medical Hypothesis 2013 May 01;1(1):6.

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Alternative view of congestive heart failure exacerbations: Role of lymphatic function and inflammation

PD Houck*

Med

icin

e

AbstractIntroductionLymphatic function and inflamma-tion 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 approxi-mately 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 dam-aged tissues by cellular transport ex-plain its many functions. The aim is to review the role of lymphatic func-tion and inflammation in congestive heart failure exacerbations.HypothesisInflammation is the cause of decom-pensated heart failure, and lymphatics and their reaction to environment are the primary mediators. This concept is consistent with a new model of dis-ease-regeneration balanced by degen-eration with inflammation (lymphatic function) serving as the fulcrum. Evaluation of the hypothesisThe pharmacology of lymphatic function in the context of heart fail-ure is lacking. A new term ‘lym-phangiontrope’ is introduced and is defined as an intervention that im-proves 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 com-pensate for cardiac dysfunction.ConclusionThe lymphatic system represents a peripheral therapeutic target for improving heart failure symptoms.

IntroductionThe lymphatic system is difficult to study; hence, there is little informa-tion on how this system may influ-ence heart failure patients1,2. 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 failure3.

Exacerbations of heart failure have previously been attributed to salt and water excess, or other stressors such as anaemia, tachycardia, and recur-rent ischemia. These exacerbations are manifested by pulmonary oede-ma and peripheral oedema. Thera-pies 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 conges-tive heart failure has been diurectic therapy. However, the chronic use of furosemide has increased mortality in congestive heart failure4,5. Other methods of pre-load reduction such as ultrafiltration have also shown

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 inflamma-tory process is attractive to the entire community of medicine that cares for chronic inflammatory related diseas-es 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.

HypothesisInflammation is the cause of decom-pensated heart failure and lymphatics and their reaction to environment are the primary mediators. This concept is consistent with a new model of dis-ease- regeneration balanced by degen-eration with inflammation (lymphatic function) serving as the fulcrum.

As the paradigm of chronic disease shifts toward a common aetiology of inflammation, the lymphatic sys-tems’ 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,

* Corresponding author Email: [email protected]

Philip David Houck, Texas A&M College of Medicine, Cardiology Division, 1H, Scott & White Healthcare, 2401 South. 31st Street, Temple, Texas 76508

no benefit6. These findings suggest that the strategy to reduce pre-load is flawed even though it has been a common and excepted practice.

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with little or no symptoms. These measures may be better indicators of cardiac reserve and predictive of fu-ture heart failure exacerbations than current symptoms7.

Inflammation has not been consid-ered as a significant cause for heart failure exacerbation. Increased in-flammatory 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 drain-age. Heart failure is an inflammatory state manifested by increased throm-bophilia, 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 re-sponsible for the symptoms of inflam-mation: 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 causa-tive agent in the exacerbation of con-gestive heart failure in a previously compensated patient. Pulmonary oedema, peripheral oedema and car-dio-renal syndrome are all manifes-tations 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 exer-cise, are all anti-inflammatory8–11.

The intention of this review is to understand lymphatic function. Anatomy and function will be re-viewed 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. Lym-phatics 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 re-pair. The term “lymphangiontrope” is introduced. Lymphangiontrope is defined as an intervention that im-proves the function of lymphatics by increasing amplitude and frequency of lymphangion contraction.

Evaluation of the hypothesisThe author has referenced some of its own studies in this review. The protocols of the studies have b-een approved by the relevant ethics committees related to the institu-tion in which they were performed.

Anatomy and FunctionThe lymphatic system is a complex architecture of vessels composed of a lymphatic capillary network en-meshed within the interstitium that is connected to the downstream net-work of fusiform, valved lymphang-ions 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 in-trinsic muscular contractions of the lymphangions as well as compression of the lymphatics by external forces. The lymphangion has a unique fusi-form configuration and innervation, both striated and smooth muscular elements and valves of two to five leaflets (Figure 1)12–14.

There is a peristaltic intrinsic con-tractile pattern, producing phasic

flow with brief periods of flow re-versal which close the valves. Net central flow is the sum of centrip-etal 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 resis-tive forces of back flow. Flow is both intrinsic from the pumping action of the lymphangion and extrinsic from the mechanical influence of the tissues15. These mechanical forces in-clude driving forces of lymph produc-tion, arterial contractions, peristalsis of the gastro-intestinal tract, muscu-lar contractions, cardiac pulsations, diaphragmatic and dynamic pressure changes in the chest, gravity, and fi-nally, 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

Figure 1: Lymphangion contracted and dilated, demonstrating amplitude of contraction.

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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 predomi-nant force. How important a factor of this extrinsic flow is in other solid or-gans is not clearly known, although it appears to be very important in car-diac lymph flow. In gastro-intestinal lymphatics outside of the gut-wall, lymphangions exhibit their own sys-tolic and diastolic contractile prop-erties via the intrinsic lymph pump. The pressure production of the in-trinsic lymph pump of the mesentery is in the range of 5–10 cm H2O but can be higher depending on exter-nal pressure and position. The aver-age flow generated is 13.95 micro litres per hour with a movement of lymphocytes and other cells ranging between 206 and 2030 cells per min-ute. The dynamics of the flow can be characterised by frequency and am-plitude of contraction14. The flow rate appears to be self-adjusting accord-ing to demand, modulated by stretch and shear forces of the lymphang-ion. The lymphatic system manages approximately 12 litres of extracel-lular fluid, about 4 litres of which is transported through the thoracic duct each day in normal humans.

Age shows a reduction in ampli-tude and frequency of the intrinsic lymph pump16. Nitric oxide inhibits contractile force and frequency and its release decreases the tone of the lymphatic vessels enhancing refill-ing of the intrinsic pump and allow-ing more extrinsic flow, possibly as an energy saving step17. From the standpoint of lymphatic function in congestive heart failure, the ampli-tude and frequency of lymphangion contraction is assumed to be the pre-dominant driving force and, there-fore, dilatation for extrinsic flow is not desirable. This assumption is

valid since the pre-load of the lym-phangion is high and the after-load, central venous pressure is elevated. Medications that increase lym-phatic amplitude and frequency can be considered to have positive lymphangiontrope.

Besides transport of lymph to the central circulation, this fine net-work 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 envi-ronment affect homeostasis of elec-trolytes, fluid balance, nutrition and inflammation. It has been document-ed that inflammatory proteins of gut origin are carried by this system18. The inflammatory cytokines have been implicated in multi-system or-gan failure seen in shock19,20. These inflammatory proteins and cellular elements should be considered as a possible aetiology of the inflamma-tory state of congestive heart failure.

Empirical dataTable 1 is a compilation of data from a number of articles using different animal models and should be viewed critically21–28. To make a fair compari-son in the setting of heart failure the pre-load and after-load of the lym-phangion 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.

The tissue oedema formation is a complex system that involves the permeability of capillaries, interstit-ium, lymph, venules, arteriolar and venous pressure, and protein con-centrations. Increases in permeabil-ity relate to large macromolecules and does not necessarily imply a pre-ferred movement of interstitial fluid. Many pharmacologic substances can alter this permeability and can also

alter the amplitude and frequency of the lymphangion. In addition, in-flammatory cytokines can also al-ter permeability and influence the pumping ability of the lymphang-ion. 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 consist-ency in respect to biphasic response. In addition, increased tonic response generally correlates with increased amplitude and frequency of the pre-nodal lymphangion and tone pre-dominates in post-nodal lymphatics. Many of the experiments are ac-companied 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, vas-oactive, peptide and other receptors.

These thin-walled vessels are in-volved in multiple pathways with multiple communication possibili-ties. There are inconsistencies in the data in the sense that different ani-mal 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 lym-phangion, and tone, which could be considered as systolic function, chronotropy, and diastolic function of these small pumps. There are im-portant gaps in this knowledge, illus-trated as blanks in Table 1.

Consequences of hypothesis Lymphatics in specific organsThe symptoms and physical findings of overwhelmed lymphatic function in various organs are summarised in Table 229–37. Inadequate compensa-tion of the lymphatics of the lungs (rales), extremities (oedema), and even the kidneys (proteinuria and

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rising creatinine) are evident by physical examination and laboratory analysis.

Cardiac LymphaticsThe 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 de-scribed. The sub-epicardial lymphat-ics 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 uti-lises the left thoracic duct. Lymphatic plexuses are incorporated into cardiac valvular structures on the low pres-sure side of the valve, papillary mus-cles 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 as-sociated with myocardial infarction and arrhythmia due to oedema of the conduction fibres resulting in non-uni-formity of depolarisation38–42.

Obstruction of cardiac lymphatics has implications in cardiac surgery, transplantation and myocardial in-farction43. The consequences are myocardial oedema, pericardial effu-sion, and electrical disturbances with resultant myocardial dysfunction, tamponade and arrhythmia. Valvular lymphatic obstruction could explain lipid deposition in the valve, and ac-celeration of valvular degeneration in aortic stenosis and senile calcific mitral stenosis.

DiscussionInflammatory and Reparative Functions of LymphaticsTransport of stem cells into the inter-stitial space is accomplished through arteries, veins and lymphatics.

Table 1 Lymphaniontrope under various stimuli

Medication/Intervention

Amplitude Frequency Tone Model

Prostanoids

PGF2a Bovine, Ovine

PGH2/TXA2 Canine, Porcine

PGE1 and PGE2 Rat, Guinea Pig

PGI2 Pig mesentery

Histamine H1H2

Bovine

Nitric OxideBovine, Mouse, and Rat (mesentery and thoracic duct)

LDL

Aging Rat mesentery

Neuropeptide substance PGastrin releasing peptide

Rat (mesentery, thoracic duct, cervical

Aspirin Bovine Messentery

Electrical stimulation

Bovine Messentery

PentobarbitoneHalothane

Bovine Messentery

Ether Bovine Messentery

Endothelin Bovine Messentery

BNP ANP

Unpublished data in rat mesentery

FurosemideSpironolactoneACEI / ARBBeta Blockers

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 TryptamineSerotonin

Isolated canine thoracic duct

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Table 2 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 perfu-sion 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 car-diac dysfunction. The explanation is a variable response in lymphatic function, activity level of the patient, and in-flammatory 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 – 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.

Coagulation of the lymphatic drain-age to infarcted tissue by tissue debris and thrombus prevents repar-ative 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 hu-moral components. Immunity and protection from the environment is an important function of the lym-phatic 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, bac-terial, 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.44 The homeostasis between the microcosm and the self is disrupted requiring adjustments of the immune system to rebalance. Die-tary indiscretions via the lymphatics put additional pre-load stress and in-flammatory stress on the heart. Heart failure can also alter gut lymphatics. In right heart failure, the lymphat-ics have a difficult time transporting nutrients toward a high pre-loaded right atrium. The bowel becomes oe-dematous 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 lym-phatic function starting a cascade of events that leads to further dysfunc-tion by increasing more cytokines produced in the gut pushing heart failure from a chronic compensated state to an inflamed heart failure ex-acerbation.

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 cardio-myopathy and transient apical bal-looning. If the myocardial plexus has varied distributions similar to apical,

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studied for remodelling potential. Therapies that favour increase in stem cells should be favoured over those that decrease stem cells. Ital-ics 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 pa-rameters including inflammation, regeneration, degeneration, and “lymphangiontrope”.

ConclusionThe lymphatic system is an unex-plored fine vascular network in-volved in interstitial homeostasis and inflammation. This network helps to relieve symptoms of heart failure mainly oedema and dyspnoea. The system is directly linked to in-flammation, which is responsible for protection from the environment and for repair. “Lymphangiontrope” is a new term that characterises lym-phatic pumping function. Medication that improves lymphangiontrope will help relieve symptoms of heart failure. Current therapies should be re-evaluated to understand the influ-ence of interventions on lymphang-iontrope. This concept is especially important considering that current therapy of pre-load reduction is as-sociated with increased mortality. New therapies that influence lym-phatics will likely be chemical drugs, mechanical stimulants, electrical stimulants, biologicals, and cellular treatments. These therapies will also influence inflammation and regen-eration and remodelling of the heart.

AcknowledgementThe author would like to thank Da-vid C. Zawieja, Ph.D, Professor and Vice Chairman Systems Biology and Translational Medicine, Director, Di-vision of Lymphatic Biology Texas A&M Health Science Centre for his

occurs. Processing antigen can oc-casionally 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. Lym-phatic function could replace the inflammatory fulcrum being both beneficial and detrimental with the additional responsibility of trans-port of reparative cells.

Future PerspectivesTable 3 classifies various interven-tions in terms of lymphangiotrope, regeneration/degeneration, and in-flammation46–54. Heart failure inter-ventions have not been considered in this format favouring hemody-namic measures of pre-load, after-load, contractility and compliance. These measures are ideal for de-scribing the cardiac (central) cause of heart failure. They fail to explain (peripheral) causes for exacerba-tions when there is no measurable change in central cardiac function. Heart failure therapies should be

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 spec-ulation deserves a greater under-standing of lymphatic function since new pathophysiological explanations can lead to new therapies.

The inflammatory pathways are more complicated than the coagu-lation pathways and have proven to be far more difficult to target with therapeutics. The inflammatory pathways are also instrumental in repair and regeneration. Senes-cent cells are labelled by natural autoantibodies and reprocessed by macrophages. Disruption of one inflammatory pathway may have deleterious effects as other path-ways compensate for the disrup-tion and is the aetiology of chronic disease45. Lymphatics are intimate-ly involved with chronic inflamma-tion. The drainage of these small vessels is into lymph nodes where antigen identification and response

Figure 2: New Model of Health.Adapted with permission from Houck PD, de Oliveira JMF. Applying laws of biol-ogy to diabetes with emphasis on metabolic syndrome. Med Hypotheses (2013).

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guidance and ground- breaking work in the study of lymphatic function.

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Table 3 New performance parameters and interventions

Performance parameter Intervention increases Intervention decreases

Lymphangiontrope NesiritideSpironolactoneLymphedema pumpsMechanical stimulationExerciseSympathomimeticsPhosphodiesterase Inhibitors

Calcium Channel block-ersGlitizonesHigh dose loop diureticsEndotoxin and cytokinesNitric Oxide

Regenerative(Proliferative)

Degenerative(Apoptotic)

Regenerative Lipophilic beta blockersACEIExerciseEECPStatinsInsulin Growth hormoneClenbuterolNesiritide

Degenerative AGEInactivityInflammatory statesEndogenous and ExogenousTaxolimusDenervationSympathomimeticsPhosphodiesterase Inhibitors

Inflammation Smoking Weight gainInflammatory conditions (RA Lupus etc.)OestrogenDiabetes IIMetabolic syndromeInfectionsImmobilitySurgeryNSAID’s

ExerciseStatinsAspirinPlavix 150 better than 75Beta BlockersACEIWarfarinHeparinWeight lossTestosteroneAlcohol low dosePlasmapheresisBiological anti-inflammatories

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