Do progenitor cells matter for patients with HF? First, what is a progenitor cell? A progenitor cell is a stem cell that has potential to differentiate into multiple different cell types. Progenitor cells are classified by cluster of differentiation surface markers, which act as receptors and ligands to their target tissue. CD34+ progenitor cells have been shown to play a role in vascular and myocardial regeneration and in this article are shown to be an important biomarker in heart failure.
Progenitor cells seem to do lots of good things. Decreased circulating progenitor cells are associated with vascular disease such as atherosclerosis and endothelial dysfunction. Low levels of progenitor cells are also associated with dysfunctional cellular regeneration and repair. Progenitor cells appear to mitigate adverse left ventricular remodeling, prevent cardiomyocyte apoptosis, and stimulate angiogenesis.
514 HF patients were analyzed (330 HFrEF and 184 HFpEF). The HFrEF cohort was further divided into ICM (286) and NICM (44). These patients were then compared to over 1400 non-HF controls. This represents the largest and most powerful study to date looking at levels of circulating progenitor cells in HF patients. A separate cohort of 582 patients (137 with HF) served as a validation cohort.
So what did they find? Patients with both HFpEF and HFrEF had decreased levels of circulating progenitor cells compared to controls without HF, and this directly correlated with NYHA symptoms. Individuals with NICM had the most depressed CD34+ counts. Interestingly, low endothelial-enriched progenitor cell counts correlated with poor outcomes in HFpEF but not in HFrEF.
In a heartbeat…
HF patients have lower circulating levels of progenitor cells compared to non-HF patients. Levels are predictive of HF outcomes and have distinct cellular patterns between HFpEF and HFrEF. Unlocking stem cells continues to be a promising, but unrealized, therapeutic strategy.
Relaxing can be hard in hypertensive heart disease (HHD). Specifically, for the stiff ventricle destined for HFpEF. Is it a problem with relaxation of myocytes, or is it due to stiffening from fibrosis?
Entry of Ca2+ into the myocyte begins a flood of stored Ca2+, stimulating contraction. The cell can relax only when this Ca2+ is taken away from the contractile apparatus. Along with SERCA and phospholamban, the sarcolemmal Na+/Ca2+ exchanger (NCX) handles this important duty.
In heart failure, this calcium handling system becomes deficient, and high intracellular Ca2+ causes longer myocyte contraction and slower myocyte relaxation.
How can we put this in a clinical perspective? Well, myocytes taken during coronary artery bypass graft surgery from (a) patients without hypertension or HF, and from patients with hypertensive heart disease (b) without, and (c) with clinical HFpEF were studied in a paper by Runte et al. These myocyte samples were then put in a beating prep in the laboratory while movements of Ca2+ and Na+ were measured. Turns out that despite the five-star laboratory accommodations, the myocytes from hypertensive patients (groups b and c) still could not relax normally.
Myocardial Ca2+ was elevated in cells from hypertensive patients, with and without HFpEF, but higher Ca2+ elevations were seen in HFpEF. When myocytes were made to go from 60-180 beats per minute Ca2+ elevations were particularly pronounced. Na+, on the other hand, was not elevated. In addition, drugs blocking Na+ influx, such as ranolazine, furosemide or amiloride, did not affect relaxation in these cells, which may have clinical implications.
In a heartbeat…
Myocytes from patients with hypertensive heart disease with and without HFpEF have impaired myocardial relaxation. In the same cells, myocardial Ca2+ was elevated during diastole while Na+ was not.
How does the heart clean up after a myocardial infarction? Autophagy. Wong et al identified the role of Cathespin D as a regulator of cardiac remodeling.
First, what is autophagy? Autophagy is derived from the Greek “auto” meaning self and “phagy” meaning eating. Pay close attention, as it is soon to be a familiar term in our field. Exciting new basic and translational research will be presented in CircHF in the coming months.
Healthy autophagy is a process by which the body removes damaged cellular components. As a standard housekeeping activity, autophagy is regulated through ubiquitin tagging of degraded proteins – “ubiquitination” – followed by appropriate proteosomal degradation. Other times it’s unregulated, such as when it is triggered by “starvation” or cellular energy depletion, and cells start literally eating themselves. So too much autophagy – starving cells eating themselves – or too little – degraded proteins remaining in cells and not being cleared – leaves debris that may contribute to myocardial dysfunction.
So, cathepsin D. It is a lysosomal protease that participates in removal of autophagosomes after an infarction. Autophagosomes are organelles involved in autophagy – delivering damaged goods and toxins to the lysosome for destruction.
Explanted hearts of patients with terminal ischemic cardiomyopathy have increased levels of a precursor of cathepsin D. Immediately post myocardial infarction, mice have elevated levels of both mature and precursor cathepsin D. With time, the mature form returns to normal in the mice; however, the precursor form stays elevated, as seen in the explanted human hearts. The pattern of elevated precursor cathepsin D is correlated with increased autophagy. Not just in the infarcted region, but throughout the entire myocardium.
In a heartbeat…
Elevated tissue levels of Cathespin D precursor are correlated with autophagic activity in ischemic cardiomyopathy, which may reduce adverse cardiac remodeling and help prevent subsequent cardiomyopathy. Perhaps in the future we will be prescribing pro-autophagy therapy to patients?