Impaired Systemic Venous Capacitance: The Neglected Mechanism in Patients with Heart Failure and a Preserved Ejection Fraction?

A large proportion of patients with heart failure have a left ventricular (LV) ejection fraction that is normal or only mildly reduced. Although these patients are commonly grouped together as ‘heart failure with a preserved ejection fraction’ (HFpEF), they comprise a heterogeneous group.1 Their shared pathophysiological abnormality is an increase in LV filling pressure, which is a primary determinant of exercise tolerance.2 Yet, the mechanisms responsible for the increased LV filling pressures in HFpEF have not been elucidated. To understand the genesis of increased LV filling pressures, it is important to distinguish the most common phenotype of HFpEF (that associated with obesity or insulin resistance) from heart failure that is due to a hypertrophic or infiltrative cardiomyopathy (the latter most commonly related to cardiac amyloidosis) (Table 1). Markedly increased (especially in men) Often within the normal range or mildly increased Left ventricular end-diastolic volumes (indexed for age and sex) Often mildly or moderately increased Left ventricular ejection fraction Typically mildly reduced or normal Typically mildly reduced or normal Normal response (based on limited data) Impaired response (based on limited data) Patients with hypertrophic cardiomyopathy have encroachment of the LV walls into the cavity space, whereas wild-type transthyretin amyloid cardiomyopathy is characterized by amyloid accumulation in both ventricles. In both disorders, there is striking thickening of the LV walls with a meaningful reduction in LV cavity size.3 Natriuretic peptides are increased, and in cardiac amyloidosis, the increase is disproportionately greater than the increase in LV filling pressures.4 The LV end-diastolic pressure–volume relation is shifted upwards and to the left, without a concomitant shift in the end-systolic pressure–volume relation, resulting in a reduced stroke volume, cardiac output and blood pressure.1, 5, 6 This shift makes LV output exceptionally sensitive to underfilling, explaining why these patients are often intolerant of diuretics.5, 7 A key distinction between hypertrophic and amyloid cardiomyopathy is that the infiltrative process in the latter often involves the right ventricle; thus, right-sided filling pressures are typically increased in amyloid (but not in hypertrophic) cardiomyopathy. In contrast, most patients in clinical practice with HFpEF have an underlying systemic metabolic or inflammatory disorder (e.g. obesity, diabetes) that is accompanied by the expansion of dysfunctional visceral adipose tissue.8, 9 These patients (often women) show evidence of inflammation of the endothelium of the coronary microcirculation.8 It has been hypothesized that the resulting microvascular dysfunction and/or fibrosis impairs the ability of the left ventricle to accommodate increases in blood volume unless there is a meaningful rise in pressure.9 In contrast to hypertrophic/infiltrative cardiomyopathy, patients with inflammatory-metabolic HFpEF have LV walls that are not thickened or only mildly so. In addition, LV volumes (when indexed for age and sex) are often mildly or moderately increased,10 but because of the limitation of LV chamber stretch or concomitant obesity, circulating levels of natriuretic peptides are lower than expected for the increase in LV filling pressures.9 In these patients, the LV end-diastolic pressure–volume relation is not characteristically shifted upwards and to the left; instead, the mild LV dilatation indicates that the left ventricle is overfilled.1, 6 This LV overfilling may explain why (i) systolic blood pressures are typically increased; and (ii) unlike hypertrophic or infiltrative cardiomyopathy, these patients respond favourably to diuretics, and they are not at high risk of developing hypotensive events when plasma volume is reduced. In patients with the inflammatory-metabolic phenotype of HFpEF, the disease process causes structural myocardial changes that limit the ability of the left ventricle to tolerate increases in central blood volume. However, it is not clear why central blood volume is increased. There are two possibilities. First, central blood volume may be increased as a result of a general expansion of plasma volume due to sodium retention. Many of the systemic disorders that predispose to the inflammatory-metabolic form of HFpEF are accompanied by increases in aldosterone and leptin and by inappropriately low levels of or a decreased responsiveness to endogenous natriuretic peptides.11 The expanded mass of inflamed adipocytes is an important source of both aldosterone and leptin, and adipocytes accelerate the clearance of natriuretic peptides.11, 12 As a result, sodium reabsorption is increased along the span of the renal tubules, explaining why many patients with inflammatory-metabolic HFpEF (especially if obese) have an increased plasma volume.9 However, increases in central blood volume cannot be the sole determinant of increased LV filling pressures, since these remain increased even when hypervolaemia is treated with diuretics. Second, central blood volume may be increased in inflammatory-metabolic HFpEF because a decrease in systemic venous capacitance causes a redistribution of total blood volume from the periphery to the central compartment (which is bound by the pulmonary and aortic values); accordingly, changes in systemic venous function can have a profound effect on left atrial and LV filling. The systemic veins (particularly the splanchnic venous system) normally act as a capacious reservoir, but changes in splanchnic venous tone can result in striking increases in central blood volume under physiological conditions (in response to acute hypovolaemia) or under pathological conditions (if systemic venous capacitance is impaired). Interestingly, inflammatory states (as well as both obesity and diabetes) are characterized by an impairment in systemic venous capacitance.13, 14 Additionally, inflammatory-metabolic HFpEF is a disease of elderly women, and both age and gender can further impair systemic venous function.15 Abnormalities of systemic venous capacitance may become particularly marked during exercise and contribute to effort-induced increases in LV filling pressures. Sympathetic activation (as occurs during exercise and in heart failure) causes constriction of the splanchnic venous system.16, 17 Interestingly, the inflammatory response that causes endothelial dysfunction of the coronary microvasculature in HFpEF may also impair the endothelial function of the systemic veins in these patients.18 This effect may explain the intriguing finding that the abnormalities in systemic venous capacitance are more pronounced in patients with HFpEF than in patients with heart failure and a reduced ejection fraction (HFrEF).19 The severity of this impairment is an important determinant of the increased LV filling pressures and exercise intolerance. In contrast, the responsiveness of venous capacitance vessels does not appear to be impaired in patients with hypertrophic cardiomyopathy.20 Many patients with HFpEF have increased circulating levels of aldosterone and neprilysin, raising the possibility that these contribute to the derangements in systemic venous capacitance. Levels of aldosterone are inversely related to systemic venous capacitance in patients with chronic heart failure,21 and abnormalities of venous endothelial function leading to increased venous stiffness can be reversed by treatment with spironolactone.22 Similarly, neprilysin inhibition leads to decreases in decreases in LV filling pressures and left atrial volume in patients with heart failure that are related to potentiation of the effects of endogenous natriuretic peptides on the peripheral circulation, and not to their effects to ameliorate sodium retention and hypervolaemia.23 Neprilysin inhibition may correct the apparent deficiency of natriuretic peptides in inflammatory-metabolic HFpEF;9 restoration of natriuretic peptide action increases systemic venous capacitance, particularly if there is pre-existing systemic venoconstriction (as in the case of heart failure).24 The cardinal feature of HFpEF is an increase in LV filling pressure in the face of a LV ejection fraction that is not meaningfully reduced. In patients with a hypertrophic or infiltrative cardiomyopathy, the increase in LV filling pressures is primarily driven by an upward and leftward shift of the LV end-diastolic pressure–volume relation. In contrast, in inflammatory-metabolic HFpEF, LV end-diastolic volumes (when indexed for age and sex) are not reduced; there is little evidence for a consistent shift in the end-diastolic pressure–volume relation; and LV filling pressures are increased because the left ventricle is overfilled. The mechanisms leading to the increase in LV filling pressures and central blood volume in HFpEF have not been fully elucidated. Sodium retention and plasma volume expansion often play a role and can be ameliorated with diuretics. However, abnormalities of systemic venous capacitance likely play a critical (and unappreciated) role in driving an increase in central blood volume in HFpEF,22 explaining why diuretics are typically insufficient to ameliorate the increase in LV filling pressures. Mineralocorticoid receptor antagonists and neprilysin inhibitors may exert favourable effects on systemic venous capacitance, thus contributing to their action to lower LV filling pressures and wall stress in HFpEF. Additionally, treatments that block sympathetically-mediated vasoconstriction of the splanchnic venous bed may also alleviate pulmonary congestion in patients with decompensated heart failure, a finding that also might be applicable to patients with HFpEF.16, 17 Admittedly, the assessment of the effects of drugs on systemic venous capacitance is challenging, since it is extremely difficult to reliably evaluate the function of the splanchnic venous system in the clinical setting. Despite its potential importance, little work has been dedicated to understanding the role of changes in the functions of the systemic venous system in HFpEF. In the 1970s, the systemic venous system was the focus of considerable work in understanding the pathogenesis of HFrEF. It is time that we understood that, as in the case of HFrEF, HFpEF is a disorder of the entire circulation, inclusive of the peripheral circulation, and not simply a disorder of LV structure and function. Dr. Maurer receives grant support from NIH R01HL139671-01, R21AG058348 and K24AG036778. Conflict of interest: M.S.M. has had consulting income from Pfizer, GSK, Eidos, Prothena, Akcea and Alnylam, and his institution received clinical trial funding from Pfizer, Prothena, Eidos and Alnylam. M.P. has recently consulted for Abbvie, Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, NovoNordisk, Pfizer, Sanofi, Synthetic Biologics and Theravance. None of these relationships are relevant to the topic of this manuscript.