Coronary microvascular dysfunction in HFpEF: pathophysiologic mechanisms, diagnosis, treatments, and the amplifying potential of sepsis

Figures

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  Figure 1. Epicardial versus microvascular contributions to coronary circulation. Schematic comparison of the coronary vasculature visualized by conventional angiography versus the full coronary tree. The left side shows the epicardial arteries alone, which are the vessels resolved on invasive coronary angiography and which account for only a small fraction of total coronary resistance. The right side superimposes the pre-arterioles, arterioles, and capillaries, which lie below the spatial resolution of angiography yet constitute the principal site of coronary flow regulation.

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  Figure 2. Coronary microvascular dysfunction in HFpEF: five key mechanisms and sepsis exacerbation. Conceptual overview of the mechanisms linking coronary microvascular dysfunction (CMD) and HFpEF, with the proposed amplifying role of sepsis. CMD and HFpEF occupy the centre in a bidirectional relationship, each reinforcing the other. Five mechanistic domains converge on this axis: systemic inflammation (elevated inflammatory markers, including interleukin-6, tumour necrosis factor-alpha, and C-reactive protein, with chronic low-grade inflammation); impaired nitric oxide–cyclic GMP–protein kinase G (NO–cGMP–PKG) signalling, with reduced vasodilation and impaired diastolic relaxation; microvascular rarefaction and fibrosis (capillary loss, collagen deposition, scarring, and reduced tissue perfusion); mitochondrial dysfunction (energy starvation, reduced ATP, oxidative stress, and reactive oxygen species); and ventriculoarterial decoupling (increased arterial and ventricular stiffness with impaired cardiac performance). Sepsis is depicted as a superimposed insult acting upon these mechanisms, representing the hypothesized “second hit” upon an already-injured microvasculature. CRP, C-reactive…

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  Figure 3. Multimodal diagnostic approaches to HFpEF and CMD, ranging from non-invasive to invasive. Spectrum of diagnostic modalities used to evaluate HFpEF and coronary microvascular dysfunction, arranged along a continuum from non-invasive (left) to invasive (right). Modalities shown are the H₂FPEF score, which estimates HFpEF probability from clinical and echocardiographic data; biomarkers, which assess haemodynamic stress and inflammation; tissue Doppler imaging, which evaluates diastolic function indices; two-dimensional speckle-tracking echocardiography, which defines global longitudinal strain to phenotypically differentiate; computed tomography perfusion, which provides anatomic coronary evaluation and perfusion data via the volume-to-mass ratio; cardiac magnetic resonance imaging, which assesses structure, function, and fibrosis; OCTA imaging, which evaluates myocardial blood flow through retinal microvascular imaging; cardiopulmonary exercise testing with or without right heart catheterization, which assesses microvascular blood flow through exercise testing; and functional angiography, which uses acetylcholine and adenosine challenge to determine coronary flow reserve and the…

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  Figure 4. Therapeutic strategies in HFpEF relevant to coronary microvascular dysfunction. Overview of therapeutic options for HFpEF, organized around a central node of HFpEF treatment options and divided into medical or biologic therapies and device or surgical interventions. Medical and biologic therapies are grouped by mechanism: cardiorenal and metabolic agents (SGLT2 inhibitors; GLP-1 and GLP-1 receptor agonists and amylin agents; angiotensin receptor–neprilysin inhibitors; ACE inhibitors and ARBs; mineralocorticoid receptor antagonists; beta blockers, such as nebivolol); vasoactive and endothelial agents (calcium-channel blockers; soluble guanylate cyclase stimulators; phosphodiesterase inhibitors; nitrates; endothelin antagonists; oral prostacyclins); mitochondrial agents (the HU6 metabolic stimulator; nicotinamide riboside); and anti-inflammatory, antifibrotic, and other agents (colchicine; CD34+ cell therapy; urate transporter-1 inhibition; myosin inhibitors; and interleukin-6 inhibition). Device and surgical interventions comprise coronary sinus reducers, cardiac contractility modulation, atrial shunting devices, and structural devices, including pericardial resection devices and…