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Extracardiac Abnormalities of Preload Reserve

Mechanisms Underlying Exercise Limitation in Heart Failure with Preserved Ejection Fraction, Autonomic Dysfunction, and Liver Disease
Originally published Heart Failure. 2021;14:e007308


    While many of the cardiac limitations to exercise performance are now well-characterized, extracardiac limitations to exercise performance have been less well recognized but are nevertheless important. We propose that abnormalities of cardiac preload reserve represents an under-recognized but common cause of exercise limitations. We further propose that mechanistic links exist between conditions as seemingly disparate as heart failure with preserved ejection fraction, nonalcoholic fatty liver disease, and pelvic venous compression/obstruction syndromes (eg, May-Thurner). We conclude that extracardiac abnormalities of preload reserve serve as a major pathophysiologic mechanism underlying these and other disease states.

    Cardiac output increases about 5-fold during exercise in healthy adults and about 8-fold in athletes.1 These adaptations during exercise are mediated predominantly by changes in the autonomic nervous system, principally by increases in sympathetic activity and withdrawal of parasympathetic tone, and include both cardiac and extracardiac mechanisms. Cardiac components leading to increased cardiac output include increases in both heart rate and stroke volume. A significant proportion of cardiac output increase during exercise is mediated by extracardiac mechanisms because of adjustments in the vascular system leading to increased venous return, thereby increasing cardiac output by exploiting the Frank-Starling relationship.2 The increase in cardiac output via augmented venous return is termed preload reserve and serves as the focus of the present review.

    The vascular system acts as both a conduit and a reservoir for intravascular blood volume. Compared with arteries, veins are thinner-walled and much more distensible, storing about 70% of intravascular blood volume (Figure 1).3 Thus, veins have a greater capacitance than the arterial system (Table). The majority of intravascular blood volume is located in the vascular rich organs of the splanchnic compartment, principally the liver, spleen, and gut.4–7 Approximately 20% to 30% of total blood volume is located in the splanchnic compartment. Data from both animals and humans indicate that blood shifts from the splanchnic to the central compartment can significantly alter cardiac and central vascular hemodynamics, leading to elevations in preload and cardiac output.4,5,7 Similar to arteries, veins have smooth muscles and are innervated by autonomic nerves, which allows the human body to regulate the capacitance of a particular vascular bed. However, the quantity of smooth muscle, the density of adrenergic innervations, and the type of adrenergic receptors (alpha 1 versus beta 2) of individual veins varies widely, partly reflecting their degree of participation in autonomically controlled responses.8–10 The splanchnic vascular compartment is uniquely and densely innervated with adrenergic nerve endings, significantly more than compared with central veins (eg, vena cava), peripheral veins (muscles of the extremities), or the skin.11

    Table. Overview of Key Terms

    Unstressed volumeThe volume adequate to fill blood vessels beyond which tension arises in elastic walls of vascular structures. About 70%–75% of total blood volume at rest.
    Stressed volumeThe volume that stretches vessel walls, about 25%–30% of total blood volume.
    CapacitanceThe total volume contained at a given pressure and includes both unstressed and stressed volume. Capacitance can be altered by contraction or relaxation of vascular smooth muscles.
    ComplianceA measure of distensibility. Compliance is the ratio of the change in volume (ΔV) resulting from a change in transmural distending pressure (ΔP) or ΔV/ΔP.
    Preload reserveThe major mechanism that allows stroke volume and cardiac output to adapt to acute changes in demand such as exercise.
    Figure 1.

    Figure 1. Blood volume distribution, pressure within each vascular compartment. Data derived from

    The capacity of the venous bed can change actively or passively and does not have to effect all compartments to the same degree or at the same time. Passive changes in venous capacitance can occur as a result of precapillary resistance changes (arterial vasoconstriction). Splanchnic arterial vasoconstriction decreases the inflow to the venous pool. Similar to venous constriction, arterial constriction is under control of the autonomic nervous system. A decrease in arterial perfusion of the splanchnic vascular compartment (eg, during exercise) results in an effective translocation of blood away from the splanchnic veins into the central circulation, thereby augmenting cardiac preload. Further, external compression by bending over12 (active) or by adipose tissue (passive) reduces vascular capacitance.13 The degree of external compression on splanchnic vasculature can be estimated with a measurement of intra-abdominal pressure via transduction of the bladder pressure. Obesity (especially visceral) is associated with increased intra-abdominal pressure (9–14 mmHg in obese versus 5–7 mmHg in nonobese).14 External vascular compression can lead to restrictive vascular physiology with reduction in splanchnic blood volume, thus leading to a redistribution of blood volume into the central (thoracic) circulation. Higher intra-abdominal pressure is correlated with a number of obesity-related comorbidities like systemic hypertension15,16 and weight loss surgery results in a reduction in intra-abdominal pressures (pre: 12.5±1.5 mm Hg; post: 7.4±0.7 mm Hg).17 External vascular compression can lead to restrictive vascular physiology with reduction in splanchnic blood volume, thus leading to redistribution of blood volume into the central circulation. On the contrary, gravitational forces (ie, upright posture) reduce intrathoracic blood volume by drawing it into the splanchnic compartment and lower extremities.

    Active changes of venous capacity occur because of vessel contraction and relaxation leading to active expulsion of blood from the respective venous bed into the central circulation or pooling of blood respectively. Venous tone is determined by neurohormonal mechanisms, specifically the sympathetic nervous system, as well as circulating substances such as angiotensin II.18,19

    Exercise—Role of Preload Reserve

    During physical activity in healthy adults, augmentation of cardiac output depends heavily on recruitment of blood volume toward the heart from the legs and the abdominal compartment. Even small changes in venous pressure are associated with significant changes in preload return because of the marked capacitance of the venous tree.21,22 This is in accordance with the Frank-Starling relationship of cardiac preload and cardiac output and applies to the range of low-normal filling pressures. In this range, the pressure/cardiac output relationship on the Frank-Starling curve operates on a steep relationship. Absent a parallel increase in venous return, increased heart rate and contractility alone results in minimal to no augmentation in cardiac output.21,23 In response to exercise, there is both active and passive recruitment of stressed blood volume, leading to increased cardiac output occurring within seconds to minutes of exercise onset. Along with arterial vasodilation in skeletal muscles, increased venous vascular tone occurs in the extremities and abdomen. Venous constriction is induced via arterial (and cardiopulmonary) baroreflex and chemoreflex-mediated sympatho-activation.24 Further, a reduction in precapillary blood flow to the splanchnic compartment minimizes abdominal blood pooling given the parallel efflux of splanchnic blood volume. Recruitment of the splanchnic blood reservoir is much more sensitive to autonomic reflex control than are veins of the extremities due to higher adrenergic innervation/receptor density.8–11 An additional mechanism of sympatho-activation and parasympathetic withdrawal is the so-called exercise-pressor reflex triggered by mechanoreceptors in exercising skeletal muscle. Central blood volume recruitment is aided by venous compression by exercising muscles and increased intra-abdominal pressure as a result of forceful respiration and action of abdomino-thoracic pump forces.25

    Investigations of blood volume shifts in humans during exercise are limited. Using an indicator dilution technique in 5 healthy adults, circulating splanchnic blood volume was estimated to be 1160 mL and reduced to 760 mL (34%) with light supine exercise.6 A study using the radiodilution technique measured relative changes in regional blood volume from different compartments and the timing of blood shifts relative to each other. An initial shift of blood volume from the legs (23% blood volume reduction) was followed by a shift of blood from the splanchnic compartment into the chest (19%).26 Augmentation of stressed blood volume with exercise results in an average 38% increase in thoracic blood volume. Total blood volume in the lower extremities is about one-third of splanchnic blood volume.27 Thus, despite the overall smaller percent reduction in splanchnic blood volume, the amount of translocated blood volume is larger when considered in absolute terms. There appears also to be a phase-dependent contribution of preload reserve to cardiac output increases during exercise. Increased preload is a major determinate of early exercise increases of stroke volume as indicated by early increases in left ventricular end-diastolic volume.2 At a later stages of exercise, left ventricular end diastolic volume decreases again as a result of decreased diastolic filling time and possibly decreased contribution of preload reserve.

    In summary, during exercise, the combination of reflex-mediated active blood volume recruitment and the pumping action of skeletal muscles and abdomino-thoracic pump augment venous return and allow for several important adaptations to occur: (1) increased central volume and filling pressures; (2) maintain or augment pulmonary perfusion; and (3) provide additional blood for the dilated arterial beds in active muscles. Adequate arterial perfusion of exercising muscle requires recruitment of venous capacitance volume and cardiac preload-dependent increases in stroke volume. This additional preload recruited during conditions requiring increased cardiac output is referred to as preload reserve.

    Preload Reserve Across Disease States

    Beyond normal physiology during exercise and gravitational stress, the importance of venous capacitance beds is likely of importance in disease states where active and passive regulation of preload reserve is impaired. We speculate that relevant diseases range on a spectrum from over-recruitment to under-recruitment of blood volume from venous reservoirs (central figure/Figure 2).

    Figure 2.

    Figure 2. Concept of preload reserve across the cardiovascular disease spectrum. Two proposed extremes of preload reserve are presented. To the left indicates the state of increased vascular congestion. This state is hypothesized to be driven by a decreased vascular capacitance, specifically in the central venous compartment28,29 and venous reservoirs.30,31 These effects are driven by active and passive volume redistribution into the central venous compartment which is deleterious to cardiac performance. To the right the case of vascular underfilling is presented. Exercise limitation is driven by pooling of blood in venous reservoirs or inability to recruit due to mechanical obstruction (transhepatic or major venous obstruction). The intent here is to show a simplistic concept of volume redistribution, but the actual blood volume can vary significantly between and within a disease state.32 NMS indicates neurally mediated syncope; and POTS, postural orthostatic tachycardia syndrome.

    Impaired Preload Reserve—Autonomic Dysfunction

    Disease states characterized by impaired preload reserve are perhaps the easiest to conceptualize. These disorders are commonly labeled as autonomic dysfunction and include diagnoses such as neurally mediated syncope, vasovagal syncope, and postural orthostatic tachycardia syndrome. Following a change in position from supine to standing, gravity shifts blood away from the thorax to below the diaphragm (splanchnic >> lower extremities).33,34 Failure of preload reserve mechanisms to compensate for the hydrostatic fall in filling volume results in a drop in cardiac filling volume and pressures, and the resulting lack of cardiac output augmentation during orthostatic stress can cause symptoms of cerebral under-perfusion. In the absence of active recruitment of the venous reservoir, conditions that require further augmentation of preload such as exercise can become severely limited by hypotension.35,36 Countermeasures intended to expand total blood volume or limit splanchnic (and to a lesser degree lower extremity venous) capacitance can prevent or attenuate orthostatic symptoms.37 Potential measures to decrease venous pooling include compressions stockings, abdominal binders, and even attempts at neuromodulation of the splanchnic nerves to actively decrease splanchnic vascular capacitance.38 Clinically, this is supported by the common failure of cardiocentric interventions alone to ameliorate tilt-table induced syncope.39

    Impaired Venous Capacitance and Preload Reserve in Heart Failure: Volume Redistribution Concept

    HF is characterized by resting or exercise-related symptoms commonly in the setting of structural cardiac abnormalities. HF is accompanied by abnormal arterial and venous capacitance, driven at least in part by abnormal baroreflex and chemoreflex function with resultant sympatho-activation.29,40,41 Experimentally induced acute HF in dogs leads to profound baroreflex-mediated venoconstriction accounting for roughly 80% of increased left ventricular end-diastolic pressure, with left ventricular dysfunction accounting for only 20% of increased left ventricular end-diastolic pressure.31,42 In HF, an elevated left ventricular end-diastolic pressure due to venoconstriction may result in a fall rather than a rise in stroke volume based on the fact that the heart often operates on the downward slope of the Starling curve.43 Using a modeling approach to cardiovascular hemodynamics in patients with HF, Burkhoff and Tyberg44 demonstrated that with decrease of left ventricular contractile strength by 50%, the arterial pressure dropped and wedge pressure increased from 12 to ≈15 mmHg. An increase in heart rate and total peripheral resistance improved cardiac output and arterial pressures, but the wedge pressure did not rise. The one intervention that did result in a substantial increase in left-sided filling pressures was an increase in stressed blood volume with increased cardiac preload from increases in predominantly venous tone. A decrease in unstressed blood volume (by 15%–20%) through simulated venous constriction increased the wedge pressure to >25 mmHg from a baseline of 12 to 15 mmHg. The restrictive function of the pericardium could play an additional role in this physiology.45

    In HF, reduced splanchnic vascular capacitance46,47 likely contributes to symptoms of exercise intolerance and promotes decompensation.48–53 A compromised vascular reservoir is unable to buffer shifts of fluid and actively contributes to the acute or chronic expulsion of fluid from the splanchnic vascular compartment to the central thoracic compartment. Evidence for reduced splanchnic vascular capacitance in HF has been shown repeatedly in preclinical models of HF.31,42 In humans with HF direct evidence of decreased splanchnic blood volume in a state of total blood volume excess is limited to a report from the 1950s in 12 patients.46 Many HF patients have normal hemodynamics at rest54 but profoundly abnormal hemodynamic response to exercise characterized by rapid and marked elevation in filling pressures.51,52 The redistribution of splanchnic blood volume into the central circulation may lead to sudden increases in pulmonary and left-sided cardiac pressures in HF.44,48,49 The main regulatory system for splanchnic vascular capacitance (storage-space) is the group of postganglionic sympathetic fibers originating from the celiac plexus, which control vascular tone of both arterial and venous beds. These postganglionic sympathetic fibers receive input from preganglionic sympathetic fibers traveling via splanchnic nerves.55,56 Activation of splanchnic nerves results in vasoconstriction and reduced splanchnic capacitance in animals and humans, recruiting blood volume into the central circulation.4,38,55

    By attenuating the signal to splanchnic beds, a targeted reduction of splanchnic sympathetic activity could provide benefit for HF patients with cardiopulmonary congestion at rest or with exertion. Preliminary proof-of-concept work in patients with acute decompensated and chronic HF has shown promise for the beneficial concept of splanchnic nerve modulation in HF.47,57,58 In patients hospitalized for decompensated HF (mostly with reduced ejection fraction), short-term splanchnic nerve blockade with lidocaine decreased right and left sided filling pressures.57 The findings from the resting study were extended to supine bike exercise in patients with chronic (mostly) HFrEF.58 Interruption of splanchnic nerve traffic resulted in improved resting and exercise filling pressures.58 Mean pulmonary arterial pressure at peak exercise decreased from 54.1±14.4 to 45.8±17.7 mm Hg (P<0.001). Peak exercise wedge pressure dropped from 34.8±10.0 to 25.1±10.7 mm Hg (P<0.001). Changes in intracardiac pressures were associated with improvement in cardiac index (at peak exercise increased from 3.4±1.2 to 3.8±1.1 L/minute per m2; P=0.011) and peak oxygen consumption VO2 (from pre-block: 9.1±2.5 to post-block: 9.8±2.7 mL/kg per minute; P=0.053). Additionally, a reduction in abdominal sympathetic tone has been observed via renal denervation.59 Interestingly, attenuation of splanchnic autotransfusion in the setting of the Valsalva maneuver was a good surrogate of procedural success of renal denervation. This study supports the role of the kidney and renal sympathetic nerves in modulation of vascular tone and cardiac preload. Additionally, renal dysfunction and activation of the renin-angiotensin-system in itself can promote volume retention and lead to increased preload.

    The potentially protective effects of increased splanchnic vascular capacitance can be seen in cardiac amyloidosis with associated neuropathy. Patients with hereditary ATTR have involvement of autonomic nerves, especially in the splanchnic compartment.60 The neuropathy impairs autonomic nerve function and leads to increased abdominal blood pooling limiting neurohormonal-mediated blood volume redistribution with exercise. These patients tend to develop orthostatic symptoms and lack of typical HF symptoms despite advanced cardiac involvement.61 It is likely that a latent or overt form of autonomic neuropathy in these patients delays the onset of central vascular congestion at rest and with exercise.

    While the above described blood volume redistribution concept likely contributes to a significant portion of patients with HF, other forms of preload reserve impairment also occur in the setting of cardiac dysfunction and HF.

    Impaired Preload Reserve As a Cause of Heart Failure Like Syndrome

    HF symptoms and pathophysiology marked by inability to augment cardiac output on demand can be due not only to over-recruitment of venous blood pools but also due to lack of blood volume recruitment. Recruitment of preload reserve from the splanchnic compartment and extremities depends on unobstructed passage of blood through the liver and central veins (iliac veins and vena cava; Figure 4). Limitation in exercise function and exercise-related symptoms such as shortness of breath could be related not only to what is considered to be HFpEF (an inability of the heart to pump blood to the body at a rate commensurate with its needs, or to do so only at the cost of high filling pressures)62 but could also be driven by abnormal preload reserve. Below, we discuss several novel concepts in which impaired preload reserve is likely the driving force underlying pathophysiology.

    Heart—Liver Preload Reserve Impairment via the Portal and Hepatic Veins

    In patients with unexplained exertional dyspnea and evidence of reduced exercise performance, 18% show isolated preload reserve limitation without evidence of HFpEF.63 It is likely that limitation of cardiac preload reserve with the inability to augment cardiac output with low/normal filling pressures is an unrecognized disease form, not related to HFpEF where traditional findings of wedge pressure and pulmonary arterial pressure elevations are singularly blamed for observed exercise impairment.

    The liver serves as gate-keeper between the splanchnic (abdominal) and central vascular (heart/lung) compartments. One-quarter of preload is derived from the hepatic artery and portal vein through the liver, which amount to <5% of the total body weight. Interference in venous return due to impaired transit through the liver can have a significant impact on cardiac filling and cardiovascular performance. Increased atrial pressures or a hepatic sinusoidal pressure gradient can result in significant impairment in venous return, since driving pressures from the splanchnic compartment to the right heart are low and not designed to overcome resistance. Thus, conditions that create resistance to blood flow across hepatic sinusoids can limit preload reserve. Such a disease is nonalcoholic fatty liver disease (NAFLD), which is a spectrum of diseases leading to hepatic fibrosis or cirrhosis. Cardiovascular disease is the number one cause of mortality among patients with NAFLD, and growing evidence suggests that NAFLD is an independent risk factor for cardiovascular disease.64 NAFLD and HFpEF have similar risk factors, prevalence, and clinical phenotypes. Both HFpEF and NAFLD are marked by high cardiovascular morbidity and mortality that have reached epidemic proportions.65 Both HFpEF and NAFLD share common pathophysiologic characteristics such as metabolic syndrome, insulin resistance, systemic inflammation, and altered cardiac energy metabolism. Moreover, both seem to have comparable cardiovascular dysfunction characteristics including abnormal left ventricular structure, impaired diastolic function, normal-to-high output state, and autonomic nervous system dysregulation (Figure 5).66,67 Finally, dyspnea with exertion and limited exercise performance are the predominant symptoms not only in patients with HFpEF but also in those with NAFLD without HFpEF.68,69 In population-wide association studies, patients with asymptomatic NAFLD tend to develop subclinical left ventricular remodeling, abnormal geometry, and impaired cardiac function.70 Further, patients with NAFLD are more likely to develop clinical HF and are at a 5-fold higher risk for rehospitalization for HF.71,72

    Figure 3.

    Figure 3. A concept of exercise-induced pressure elevation in heart failure.

    Figure 4.

    Figure 4. Concept of venous obstruction as limitation in preload reserve.

    Figure 5.

    Figure 5. The cardiovascular link between nonalcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF).

    We propose a mechanistic link between NAFLD and HFpEF beyond a common basis of inflammation, obesity, and metabolic derangement. We propose that HFpEF is not simply associated with NAFLD but that HFpEF is the common cardiovascular manifestation of NAFLD. There is evidence that trans-hepatic blood flow obstruction (portal hypertension) begins in early stages of NAFLD when fibrosis is far less advanced and in absence of frank cirrhosis.73 Hepatic hemodynamic changes and increased splenic stiffness are detectable at early stages of hepatic fibrosis (Stage 2/4). Orthostatic symptoms at rest (57% of NAFLD population tested with head up tilt) and cardiopulmonary exercise limitations often exist in patients with NALFD (peak VO2 in mL/minute in NAFLD 25.7 [23.6–27.2] versus controls 31.0 [26.0–42.7], P=0.036)74,75 and advanced liver disease.76 Evaluation of transhepatic pressures in patients with advanced liver disease points to the presence of dynamic splanchnic outflow obstruction with exercise as documented by an average increase of transhepatic venous gradient from 16.7±1.5 mm Hg at rest to 19.9±1.4 (P<0.01) with exercise.76 In early stages, clinically significant portal hypertension may be absent at rest but can be unmasked during activity.76 In patients with HF, increasing degrees of hepatic fibrosis is associated with a more progressive HF course.66 Acute and chronic congestion of the splanchnic vascular compartment results in sympathetic hyperactivation with downstream effects on the cardiovascular system.77,78 Thus, despite central vascular underfilling at rest and with exercise, the liver/HF phenotype can present with typical signs of chronic HFpEF such as hypertension, increased vascular stiffness, and impaired heart rate reserve. Portal hypertension is not only a proposed central extracardiac limitation to preload reserve during activity but also leads to the formation of intra- and extrahepatic shunts. Development of shunts could explain a high-normal output state at rest that does not augment adequately with activity as it is seen not only in many patients with liver disease but also in HFpEF.74,76 Extreme forms of high output states are commonly linked back to a (new) diagnosis of liver disease or vascular shunts,79 but we suggest that borderline cases remain commonly unexplored and underlying liver disease is overlooked. The relationship between liver disease and HF remains to be further explored.

    Obstruction of Venous Return From the Lower Extremities As an Alternative Explanation of Exercise Intolerance and Dyspnea

    Veins of the lower extremities have a dual role during exercise. Veins serve as passive conduit vessels returning deoxygenated lactic acid-laden blood from exercising muscles preventing symptoms associated with acid accumulation in exercising muscle. Venous return also serves to reduce blood volume in the exercising extremity preventing venous hypertension, edema, and in dire circumstances blood volume engorgement sufficient to interfere with arterial perfusion. These passive roles require adequate venous capacitance to respond to increase arterial blood flow of the exercising extremity. Arterial blood flow to the lower extremity increases as much as 8-fold at peak exercise,80 and the venous system must have adequate capacitance to accommodate and return that increased regional blood volume to the heart, thereby providing adequate evacuation of the byproducts of metabolism, reducing blood pooling during exercise in the extremity, and guaranteeing adequate preload to preserve stroke volume. Failure to return blood thus simultaneously contributes to muscle fatigue and pain, exertional edema, and limits preload reserve of the heart causing inadequate cardiac stroke response to exercise. This constellation of symptoms, in the absence of left ventricular systolic dysfunction, is often erroneously referred to as HFpEF but would be more accurately labeled “Preload Reserve Limitation”.

    Currently venous capacitance disorders are suspected only in the presence of resting venous signs and symptoms such as edema and varicosities. However, clinically important abnormalities of extremity venous capacitance may be unmasked only during exercise. Iliocaval obstructions could present a significant and underrecognized cause of exercise intolerance that may be confused with HFpEF. This can occur in the presence of typical symptoms including exertional leg pain, dyspnea, or fatigue even in the absence of underlying cardiac disorders.81

    Compression of iliac veins can be caused by intrinsic anatomic structures such as overriding arteries, ligaments, bones, and fat.81 Pregnancy presents a relatively common situation during which mechanical venous obstruction can lead to hypotension. A highly prevalent form of external venous compression is the May-Thurner syndrome in which the right common iliac artery crosses the left common iliac vein, typically at the level of L5. Studies using cross-sectional imaging suggest that about 25% of adults have up to 50% compression of the left common iliac vein.82

    While complete and incomplete compression of veins can cause stasis of blood and precipitate deep venous thrombosis formation, chronic symptoms of incomplete venous obstruction may often go undiagnosed in the absence of resting venous congestion, hypertension, or edema. Symptoms frequently attributed to HFpEF may be properly attributed to venous capacitance inadequacy. Sub-total obstruction of pelvic veins may be readily evaluated using passive straight leg raising during echocardiography or noninvasive hemodynamic monitoring, just as the maneuver of passive straight leg raising can identify dehydration as a cause of hypotension.83,84 For example, in a study of healthy adults, 96% (23 out of 24) had consistent evidence of fluid responsiveness with a passive leg raise as defined by an increase in stroke volume index of >10%.83 Similarly, Miller et al85 examined 40 healthy adults using passive leg raise. Ninety percent of the subjects (36/40) had an increase of stroke volume of 10% or more following passive leg raise. Intravenous infusion of 500 mL of saline mirrored the effect of the passive leg raise with a similar nonresponder rate. In patients with suspected preload reserve issues, a discrepant fluid responsiveness (intravenous fluid>passive leg raise) could raise concern for an outflow obstruction from the lower extremities.

    Obstruction of venous flow induces venous hypertension at rest and becomes even more accentuated during exercise.86 Venous congestion may lead to swelling and exercise-related pain aka venous claudication.87 Venous distension from ilio-caval obstruction can be a powerful stimulus for sympathoexcitation,88,89 with negative downstream effects despite only a local afferent trigger. A number of clinical studies have shown impaired cardiopulmonary exercise in patients with prior inferior vena cava ligation without effect on heart rate reserve or pulmonary gas exchange.35,90 Experimental studies of venous occlusion via lower extremity cuffs or lower body negative pressure do not identify any significant reduction in cardiopulmonary exercise performance. Interestingly, treatment of venous obstruction has been shown to improve functional capacity.91 In the presence of grossly normal heart function, symptoms of exertional intolerance or dyspnea with exercise—commonly labeled as HFpEF—may instead represent inadequate preload reserve due to abnormal venous reserve capacitance and inadequate venous return during exercise.


    Exercise limitation is a central hallmark of HF. While many of the cardiac and arterial limitations to exercise performance have been well-characterized previously,92,93 extracardiac limitations to exercise performance have been underrecognized but are nevertheless important. We propose that abnormalities in cardiac preload reserve represent an underrecognized and common cause of such exercise limitations. We further propose that mechanistic links exist between conditions as seemingly disparate as HFpEF, NAFLD, and pelvic venous compression/obstruction syndromes, and that extracardiac abnormalities of preload reserve serve as a major pathophysiologic mechanism underlying these and other disease states.

    Nonstandard Abbreviations and Acronyms


    nonalcoholic fatty liver disease

    Disclosures Dr Fudim consults for Axon Therapies, Daxor, Edwards Lifesciences, and Galvani. Dr Sobotka consults for V-Flow, Medical. Dr Dunlap consults for Axon Therapies.


    For Sources of Funding and Disclosures, see page 10.

    Correspondence to: Marat Fudim, MD, MHS, 2301 Erwin Rd, Durham, NC. Email


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