The splanchnic reservoir: an oasis for blood volume in heart failure with preserved ejection fraction?

Although its pathogenesis is multifaceted, heart failure (HF) with preserved ejection fraction (HFpEF) is defined as a syndrome of elevated left ventricular (LV) filling pressures at rest or with exertion, leading to pulmonary and systemic venous congestion. Patients with HFpEF can have normal or mildly elevated pulmonary capillary wedge pressure (PCWP) at rest, but exhibit steep increases with minimal levels of exertion, reflecting an inability of the left heart to tolerate the increase in central blood volume that occurs with exercise.¹ As such, therapies aimed to decongest the left atrium may improve exercise tolerance and symptoms among patients with HFpEF. However, left atrial (LA) decongestion has proven more challenging in HFpEF as compared with HF with reduced ejection fraction (HFrEF). While diuretics are a mainstay of therapy for this purpose in both syndromes, patients with HF across the ejection fraction spectrum may often present with LA congestion (i.e. elevated PCWP) without overt venous congestion (i.e. normal right atrial pressure). In this setting, diuretic up-titration may be met with both symptomatic hypotension and acute kidney injury. In HFrEF, such clinical situations are often effectively treated with afterload reducing agents, including angiotensin receptor-neprilysin inhibitors or nitroprusside, which promote decrease in systemic vascular resistance and subsequent improvement in stroke volume. However, medical therapies aimed to reduce afterload have been ineffective at improving symptoms of LA congestion in HFpEF and may lead to hypotension and paradoxical reduction in stroke volume.² Thus, there is an unmet need to identify therapies for LA decongestion in patients with HFpEF.

The potential of redistribution of blood volume away from the heart offers promise to decongest the left atrium in HFpEF without the side effects related to arterial vasodilatation. At rest, 70% of total blood volume lies within the venous system because of its large capacitance compared with the arterial system.³ Most of this blood volume lies in the splanchnic veins, which contain highly vascular organs including the liver, spleen, and intestines. Capacitance of the splanchnic venous circulation is regulated by the sympathetic nervous system via the greater splanchnic nerve (GSN), and sympathetic activation results in venoconstriction and rapid shifts of blood volume from the splanchnic circulation to the heart and lungs.⁴ This volume redistribution from ‘unstressed’ (i.e. splanchnic) to ‘stressed’ (i.e. arterial) reservoirs is an important compensatory mechanism in situations of relative intravascular hypovolaemia, including orthostasis, exercise, or acute blood loss. However, rapid volume shifts may be poorly tolerated in HFpEF due to LA and LV non-compliance, leading to acute rise in LV filling pressure. Human and animal studies have demonstrated GSN stimulation increases preload and blood pressure.^5,6 Thus, modulation of the splanchnic nervous system may be a promising target for cardiac decongestion in HFpEF. Importantly, modulation of the GSN to increase splanchnic venous capacitance offers an advantage over venodilatory medications, such as nitrates, which have not demonstrated efficacy in improving symptoms or exercise capacity in HFpEF despite their ability to increase splanchnic venous blood volume.⁷ Specifically, GSN modulation targets splanchnic venous capacity in isolation, rather than the systemic circulation. The systemic vasodilatation of nitrates may result in side effects (e.g. headaches) that likely counteract potential benefit to the splanchnic reservoir.⁸ This is supported by the fact that isosorbide mononitrate resulted in decreased physical activity levels in HFpEF compared with placebo in the NEAT-HFpEF trial.⁹

In this issue of the Journal, Málek et al.¹⁰ further investigated the role of splanchnic nerve modulation in HFpEF through a proof-of-concept, single-arm trial of surgical GSN ablation. HFpEF patients with left-sided congestion at rest or with exertion underwent right-sided GSN ablation using video-assisted thoracoscopy. The trial population was high-risk, with elevated natriuretic peptides and evidence of right- and left-sided congestion at baseline (median resting right atrial and pulmonary capillary wedge pressures: 10.5 mmHg and 16.5 mmHg, respectively). Over 12-month follow-up, adverse events related to GSN ablation were minor, including transient hypotension, and the majority of side effects reported in the trial were related to the surgical procedure itself. At 3-month follow-up, GSN ablation resulted in a reduction in PCWP of ~5 mmHg during exercise, which corresponded to an improvement in New York Heart Association class in 7 of 10 participants. Importantly, while GSN ablation resulted in peri-procedural decrease in blood pressure, this was a transient phenomenon and not sustained at long-term follow-up. The lack of reduction in N-terminal pro-B-type natriuretic peptide after GSN ablation is somewhat perplexing but may be related to the small sample size of the trial. In aggregate, the findings of this study suggest that GSN ablation is feasible, and HFpEF patients may derive a haemodynamic benefit. Additionally, these findings expand upon the current understanding of GSN modulation in HF. Temporary GSN block has demonstrated acute improvements in PCWP in hospitalized HF and chronic HFrEF.^11,12 The current study establishes that the reduction in PCWP may be sustained via a long-term modality of GSN modulation, and such favourable alterations in haemodynamics are also noted in HFpEF (Figure 1).¹³

Figure 1.

Greater splanchnic nerve ablation in heart failure with preserved ejection fraction (HFpEF). In HFpEF, an acute precipitant (e.g. exercise) leads to a cascade of sympathetic nervous system activation, mobilization of blood volume from the splanchnic circulation, and left atrial (LA) congestion. Ablation of the greater splanchnic nerve (GSN) decreases sympathetic activity and may increase capacitance of the splanchnic venous circulation to reduce ‘stressed’ blood volume during exertion. Such volume redistribution has potential to decrease pulmonary capillary wedge pressure (PCWP) with exercise. CV, cardiovascular; RF, radiofrequency. Portions of this figure were adapted with permission from Amer et al.¹³ (https://creativecommons.org/licenses/by/4.0/).

Despite demonstration of feasibility of surgical GSN ablation, less invasive methods of GSN modulation may provide potential for similar efficacy without accompanying side effects of surgery. Recently, an endovascular method for right GSN ablation in HFpEF has been developed, which involves catheter placement into an intercostal vein that sits adjacent to the right GSN, and subsequent radiofrequency ablation. An open-label, single-arm, first-in-human trial of endovascular GSN ablation of 11 patients with HFpEF demonstrated improvement in quality of life, reduction in natriuretic peptides, and increased exercise capacity at 3 months.¹⁴ The consistent signal of both surgical and endovascular GSN ablation approaches in these early phase trials further demonstrates promise of this therapy in HFpEF and serves as a nidus for randomized trials of GSN modulation. As a result of the findings from the first-in-human study, a feasibility study of endovascular GSN ablation in HFpEF is currently underway (REBALANCE-HF trial; NCT04592445). REBALANCE-HF is a randomized, multicentre, sham-controlled trial of endovascular ablation of the right GSN among patients with HFpEF. The primary efficacy endpoint is change in mean PCWP at rest, after passive leg raise, and after 20 W of exercise at 1 month. Secondary endpoints include changes in quality-of-life assessment, 6-min walk test distance, and HF hospitalizations over the 12-month study period.

Despite current understanding of the interplay between the GSN and splanchnic capacitance in HFpEF, several mechanistic questions remain. The effect of GSN ablation on LA and LV mechanics is unclear. It is possible that increased splanchnic capacitance and reduction in LV filling pressures may mitigate pressure-induced myocardial remodelling, thus slowing the HFpEF progression. Given the partial contribution of the GSN to the renal plexus, it is possible that GSN ablation may have a multifaceted effect upon both the splanchnic and renal sympathetic nervous systems. Further investigation regarding changes to renal sympathetic activity and the renin–angiotensin–aldosterone axis after GSN ablation would be particularly important to understand. The effect of splanchnic ablation upon capacitance of regional vascular beds may provide insight toward mechanisms of LA congestion in HFpEF. Splanchnic blood flow and capacitance can be measured by multiple imaging techniques, including Doppler ultrasound, blood pool scintigraphy, or magnetic resonance venography. The specific vascular beds (i.e. intestinal, splenic, hepatic) that are most affected by GSN ablation may identify regions for future, targeted therapies.

It will also be important to determine the long-term effects of GSN ablation in HF. While GSN ablation for pain control appears safe when performed for individuals with cancer and intractable abdominal pain,³ long-term follow-up within HF populations is critical. Additionally, optimal HFpEF patient selection for GSN ablation requires further elucidation. HFpEF patients with one of several phenotypes, including exercise-induced PCWP elevation, resting congestion, pulmonary hypertension, or right ventricular failure and renal venous congestion, may experience differential haemodynamic effects to GSN ablation. Likewise, there may be HFpEF populations in which preload reduction may be harmful (e.g. amyloid cardiomyopathy), and GSN ablation should be avoided. Finally, for endovascular GSN ablation, objective evidence of procedural success may be challenging due to lack of direct visualization of the right-sided GSN. One potential option would be to indirectly demonstrate reduction in nerve activity by examining the effects of GSN stimulation on physiological parameters before and after ablation.⁶ The ongoing REBALANCE-HF trial will provide insight into these questions by examining endovascular GSN ablation in the setting of a randomized, sham-controlled trial.

Left atrial congestion in HFpEF leads to a cycle of progressive LA myopathy, resulting in adverse haemodynamics, increased symptoms, and poor prognosis.¹⁵ Efforts to decongest the left atrium are particularly important to improve symptoms and break the cycle of worsening LA dysfunction in HFpEF. Modulation of splanchnic venous capacitance via GSN ablation offers promise of creating a reservoir to prevent rapid volume shifts with exercise, and the current study adds to a growing body of evidence suggesting a haemodynamic benefit of this therapeutic intervention. Given the vast desert of previously investigated therapies for HFpEF, further investigation is required to determine whether GSN ablation is the much-needed therapeutic oasis for this highly symptomatic patient population.