The mechanism of heart failure and its primary symptom of shortness of breath due to pulmonary oedema are reasonably well understood. There is also increasing recognition of the delicate balance that is maintained in stable disease. In acute cardiac failure, this balance becomes disrupted, which may be due to any mechanism that places increased strain on the heart or one of the interlinked systems explored below (Johnson, 2014; Mentz & O’Connor, 2016).
During early disease, the renin-angiotensin-aldosterone system (RAAS) becomes activated, initiating physiological changes to maintain perfusion of systemic tissues: increased myocardial contractility, sodium and fluid retention, and peripheral vasoconstriction. What is helpful short-term, however, becomes detrimental long term, increasing fibrosis of myocardial tissues and leading to end organ damage (Mentz & O’Connor, 2016; Tania & Frantz, 2016).
Venous congestion is a core component in the pathophysiology of heart failure. It is influenced by neurohormonal activation, endothelial cell activation and worsening renal function. The clinical picture may vary significantly depending on the site of congestion. Predominantly right-sided heart failure is more likely to present with hepatic oedema and ascites, rather than the more classical left-heart failure – presenting with pulmonary oedema. Once fluid overload has begun, a positive feedback loop is initiated where the RAAS is activated to maintain peripheral perfusion, further increasing venous congestion (Schiff et al., 2003; Mentz & O’Connor, 2016).
An improved understanding of venous congestion of the splanchnic circulation, which may play a key role in the pathogenesis of right-sided heart failure, could lead to new therapeutic approaches. There are several possible mechanisms, centered around upregulation of sodium-hydrogen exchanger-3 (NHE3), which may form a causal link between right ventricular dysfunction, splanchnic congestion, and worsening HF. These include an anaerobic environment in enterocytes, resulting in reduced intracellular pH; increased sodium absorption by the gut via NHE3; decreased pH at the intestinal brush border thus altering the gut microbiome profile; increased bacterial synthesis of trimethylamine N-oxide; and decreased bacterial synthesis of short-chain fatty acids causing abnormal intestinal barrier function (Polsinelli et al., 2019).
Impairment of vascular endothelial function is another component of acute heart failure; the lack of effective nitric-oxide driven dilatation leads to increased oxidative stress and may lead to cardio-renal syndrome. The corresponding increase in venous pressure increases inflammation and neurohormonal stimulation – continuing the positive-feedback loop (Colombo et al., 2013; Mentz & O’Connor, 2016).
Renal dysfunction is contributed to by neurohormonal activation, inflammation and venous congestion. Hypertension is related to the loss of renal glomeruli and is often a comorbidity in heart failure, another reason for renal impairment and renal atherosclerosis. Previously it was believed that hypoperfusion secondary to arterial insufficiency was the predominant contributing factor, and more recently it has been suggested that venous congestion has a greater impact – but this is not definitive. Renal disease is often comorbid at admission for acute heart failure and is a negative prognostic factor (Mullens et al., 2009; Mentz & O’Connor, 2016).
Acute heart failure requiring admission is often accompanied by a raised serum troponin, indicating myocardial damage – this is the case even in the absence of ischaemia. This is likely to be reflective of increased myocardial wall stress, oxidative stress, inflammation, neurohormonal activation and altered calcium handling, although coronary heart disease involving small vessels can be a contributing factor (Kociol et al., 2010; Mentz & O’Connor, 2016).
Acute heart failure exacerbations can therefore be understood as a positive feedback loop, where the systems that usually increase tissue perfusion by raising cardiac output are all contributing to one another. Any metabolic, infective, ischaemic or other insult can create a tipping point for this cycle.