Hypertensive Heart Failure

Abstract

Despite overwhelming epidemiological evidence, the contribution of hypertension (HTN) to heart failure (HF) development has been undermined in current clinical practice. This is because approximately half of HF patients have been labeled as suffering from HF with preserved left ventricular (LV) ejection fraction (EF) (HFpEF), with HTN, obesity, and diabetes mellitus (DM) being considered virtually equally responsible for its development. However, this suggestion is obviously inaccurate, since HTN is by far the most frequent and devastating morbidity present in HFpEF. Further, HF development in obesity or DM is rare in the absence of HTN or coronary artery disease (CAD), whereas HTN often causes HF per se. Finally, unlike HTN, for most major comorbidities present in HFpEF, including anemia, chronic kidney disease, pulmonary disease, DM, atrial fibrillation, sleep apnea, and depression, it is unknown whether they precede HF or result from it. The purpose of this paper is to provide a contemporary overview on hypertensive HF, with a special emphasis on its inflammatory nature and association with autonomic nervous system (ANS) imbalance, since both are of pathophysiologic and therapeutic interest.

Keywords: autonomic imbalance; ejection fraction; heart failure; hypertension; sympathetic nervous system.

Figure 1

The importance of hypertension (HTN) in heart failure (HF) pathogenesis. A patient with HTN may develop concentric left ventricular (LV) hypertrophy (LVH), which is a risk factor for HF with preserved ejection fraction (HFpEF) that may progress to eccentric LVH and HF with reduced ejection fraction (HFrEF). Alternatively, as HTN is a major risk factor for coronary artery disease (CAD), the patient may suffer an acute myocardial infarction (MI). Following MI, primary coronary angioplasty (PCI) and medications (Medical Rx) attenuate myocardial damage and favorably affect prognosis. Eventually, however, eccentric LVH and HFrEF may develop, and the outcome may be further compromised by incident atrial fibrillation (AF), which frequently appears in the setting of LV dysfunction and, in turn, adversely affects LV structure, function, and outcome. With permission from Ref. [21].

Figure 2

Interaction between microbiota-derived metabolites and blood pressure. SCFAs—short-chain fatty acids; RAAS—renin–angiotensin–aldosterone system; Ang II—angiotensin II; TMA—trimethylamine; TMAO—trimethylamine N-oxide, Olfr78—olfactory receptor 78, ↑—increase. With permission from Ref. [29].

Figure 3

Cardiac remodeling in hypertensive heart failure (HHF). According to the spectrum theory, each HF phenotype results from a patient-specific trajectory where the heart remodels towards concentric left ventricular hypertrophy (LVH), eccentric LVH, or a combination of the two. In the case of hypertension (HTN), the port of entry in the HF spectrum (HHF entry phenotype) depends on (a) HTN severity, duration and antihypertensive treatment effectiveness; (b) the balance between LV pressure and LV volume overload; (c) the coexistence of morbidities such as obesity, diabetes mellitus, and coronary artery disease; and (d) disease modifiers (age, sex, genes, other). The eventual HHF phenotype results from transitions across the HF spectrum, whose direction predominantly depends on disease severity and antihypertensive treatment, which shift towards the lower end of upper end of the HF spectrum, respectively.

Figure 4

The parasympathetic nervous system-mediated anti-inflammatory reflex. Vagal afferents respond to inflammation mediators and send signals to the brainstem, where a signal is produced and transmitted by vagal efferents to the splenic nerve, causing noradrenaline (NA) release in the spleen. CD4+ T lymphocytes, which express the β2- adrenaline receptor (β2AR), uptake NA and release acetylcholine (ACh). Acetylcholine inhibits the synthesis of proinflammatory cytokines in the macrophages that express the α7nAChR receptor (α7 nicotinic acetylcholine receptors). Further, the anti-inflammatory reflex diminishes CD11b expression on neutrophils, augments the release of pro-resolving mediators (SPMs), and reduces antibody secretion and migration of B lymphocytes. In the intestine, ACh stimulates antigen-presenting cells (APCs) through muscarinic receptors (mAChR), contributing to the maintenance of regulatory T cells (Treg). With permission from Ref. [67].

Figure 5

Renal and cardiac damage induced by mineralocorticoid receptor (MR) overactivity. MR overactivity stimulates NADPH oxidase and enhances ROS accumulation in VSMCs and ECs, increasing oxidative stress. MR agonists (e.g., aldosterone) promote endothelial dysfunction, macrophage infiltration and T cell activation, as well as cytokine collection, leading to VSMC fibrosis and stiffening. MR overactivity adversely affects kidney function, by aggravating podocyte damage and effacement, injuring the glomerulus injury, and promoting VSMC proliferation and endothelial damage, which lead to vascular remodeling. Regarding the heart, MR overactivity pro-motes myocardial remodeling and fibrosis, thereby exacerbating heart failure. In contrast, the nonsteroidal MR antagonist finerenone blocks the binding of aldosterone and MR, and attenuates the cardiac derangements induced by MR overactivity. MR, mineralocorticoid receptor. EC, endothelial cells. VSMC, vascular smooth muscle cells. ROS, reactive oxygen species. NADPH, nicotinamide adenine dinucleotide phosphate. With permission from Ref. [98].

Figure 6

Filtrates reabsorbed by the sodium–glucose co-transporter (SGLT) 2, which operates at the glomerular proximal tubule. SGLT2, bicarbonate reabsorption, and the Na⁺/K⁺ ATPase, which provides energy to drive both, are depicted. The active reuptake of bicarbonate and of other solutes, coupled with Na⁺, drives the high tissue O₂ consumption in the kidney. Na⁺ escaping the reabsorption at the proximal section tubule is sensed by the juxtaglomerular apparatus and sets the afferent arteriole tone. GLUT2 = glucose transporter 2; SGLT2 = sodium–glucose co-transporter 2. With permission from Ref. [102].

Figure 7

Implementation of medical treatment in hypertensive heart failure (HHF). The presence of elevated BP in HHF as well as the renoprotective effects of finerenone, which rarely causes early hyperkalemia, allows ultra-fast up-titration of HF medications. Treatment should start with the simultaneous use of sacubitril/valsartan, sodium glucose cotransporter 2 inhibitors (SGLT-2i), and mineralocorticoid receptor antagonists (MRAs, preferably finerenone). In HFF patients with eccentric left ventricular hypertrophy (LVH), BBs (preferably vasodilatory) should be started from the beginning, whereas in HHF patients with concentric LVH, BBs should be considered in those with atrial fibrillation, coronary artery disease, or resistant hypertension. A target systolic blood pressure of 110–130 mmHg should be achieved within 45 days, and thereafter, systolic blood pressure should be within the target range.

Figure 8

The protective effects of exercise on the cardiovascular system. Abbreviations: eNOS: endothelial nitric oxide synthase; NO: nitric oxide; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol. With permission from Ref. [130].