The right side of the circulation in not secondary heart failure with preserved ejection fraction: an elephant in the room?

‘The man of science in searching for the truth must ever be guided by the cold logic of facts, and be animated by scientific imagination’ Dr. Will Mayo Not secondary HFpEF, i.e. the actual public health burden of the western world, a still incurable disease often associated with disabling symptoms and morbi-mortality,2 can be thus interpreted as a condition exquisitely linked with cardiovascular ageing. Together with ageing, traditional risk factors and comorbidities concur to promote myocardial stiffening, mostly in terms of fibrosis,3 eventually leading to high left heart filling pressure at rest or a steep rise of filling pressure during exercise.4 One potential exception to this paradigm is represented by the ‘obese HFpEF phenotype’ which tends to present earlier in life5 and has been shown to be associated with excess blood volume as compared with non-obese HFpEF1 and with peculiar constrictive-like features, promoted by adipose tissue in the chest.6 Apart from this potentially distinct phenotype,5, 6 the traditionally reported HFpEF ‘heterogeneity’ could simply reflect the natural history of the disease,7 where multimorbidity and frailty associated with not secondary, ageing-induced HFpEF act as potential co-factors. But if we accept HFpEF as a disease of cardiovascular ageing, with a stiffer left ventricle being the net final result of extracellular matrix deposition through decades, we might easily capitulate from a therapeutic standpoint, since it seems still hard to rewind the clock of time and increase the compliance of a stiff and fibrotic left ventricle. Additionally, left ventricular diastolic dysfunction is just the starting point of the HFpEF syndrome,7 where left atrial failure,8 pulmonary hypertension9 and right heart failure10 may yet unpredictably occur, adding complexity to the HFpEF manifestations, and further contributing to its apparent heterogeneity. Thus, Sorimachi et al.1 have to be commended for their effort to translate an apparently abstracted concept such as stressed blood volume (SBV), to a clinical entity underlying the HFpEF syndrome, and to link with the neglected right side of the circulation. In doing so, they could fill a gap in our understanding of symptoms in apparently euvolaemic but breathless subjects with HFpEF.11 Indeed, left ventricular diastolic stiffness is a necessary but not sufficient condition for the development of pulmonary congestion during exercise: increased SBV can contribute, favoured by reduced venous compliance and capacitance. Stressed blood volume represents the quote of blood volume which actively contributes to generate tension and pressure within the cardiovascular system.11 It is a functional entity, which can be rapidly stored in or mobilized from the venous compartment, roughly approximating preload. For instance, during exercise adrenergic discharge promotes venoconstriction, shifting a quote of SBV from the (splanchnic) venous compartment into the chest. In healthy subjects, this physiological preload reserve drives stroke volume and pulmonary vessel recruitment at the beginning of exercise. However, according to the data presented by Sorimachi et al.,1 the systemic venous system, which represents the larger pool of (stressed) blood volume, is stiffer and ‘overfilled’ in HFpEF. Therefore, SBV is already increased at rest, and exercise-induced adrenergic activation further reduces venous capacitance, causing a large amount of SBV to be shifted from below the diaphragm into the chest. But high preload is eventually counterproductive for these stiff hearts, leading to a flat rise of cardiac output despite a steep increase of filling pressure. Additionally, this complex hydraulic modelling of the circulation incorporating SBV is well suited to describe the poor perspective of the right heart in HFpEF patients. Indeed, the right ventricle stands in between the poorly compliant venous system (input) and the stiff left heart (output). Accordingly, it can combine dysfunctional preload with increased afterload, potentially linking SBV to right heart failure. In order to give an idea of the contribution of SBV to filling pressure and, on the other side, how treatments aimed at reducing SBV could be ideally useful in HFpEF patients, it suffices to say that – if all the mathematical assumptions made by Sorimachi et al.1 hold true – a manoeuvre capable of reducing SBV by 30% during exercise could nearly normalize pulmonary artery wedge pressure (and pulmonary congestion) in spite of persistently increased left ventricular diastolic stiffness, as depicted in Figure 1. It might be anticipated that such a reduction in preload may occur without adverse consequence for cardiac output, since HFpEF patients lay on the flat portion of the Frank–Starling curve.1 Accordingly, preliminary proof-of-concept works have shown that attenuation of the adrenergic signal to the splanchnic bed through nerve blockade could acutely lower rest and exercise pulmonary artery wedge pressure in chronic HF,12 and that such results were maintained after several months in patients with HFpEF.13 Unless we can rewind the clock of time associated with diastolic stiffening, or to delay it through well-targeted cardiovascular prevention programmes, could splanchnic sympathetic modulation be viewed as the next Holy Grail for the treatment of HFpEF14? For sure, a selective modulation of the largest reservoir of SBV is highly attractive (Figure 1) and, hence, object of current clinical trials. On the other hand, this enthusiasm might be counterbalanced by remembering the neutral results obtained with venodilators such as nitrates in HFpEF.15 Furthermore, we cannot exclude that the theoretical favourable effects of splanchnic sympathetic modulation could lose their efficacy in the long term: the venous system, despite a rightward shift of its pressure–volume relationship, might be ‘refilled’ over time with progressively higher SBV, up to the point where it approaches its limit of capacitance and becomes dysfunctional again, unless diastolic dysfunction remains untreated. Might this suffice to palliate the breathlessness of this disease and to gain time, postponing disabling symptoms that afflict our patients? Or will long-term results of selective splanchnic nerve modulation consistently prove to have a favourable long-term risk–benefit balance for HFpEF, contributing to a paradigm shift for this disease, from the left ventricle back to the capacitance veins? Precise characterization of patients' pathophysiology, as it has been done by Sorimachi et al.,1 is crucial for our understanding of HFpEF and for the identification of possible common denominator(s) of this syndrome, that might be amenable to well-targeted treatments and a specific haemodynamic phenotype: in this perspective, SBV modulation holds promise (Figure 1). Only time and further rigorous research will eventually confirm us whether the venous side of the circulation is the elephant in the room we have long neglected in HFpEF. Conflict of interest: none declared.