W.H. Wilson Tang, MD; Gary S. Francis, MD

Disclosures

J Am Coll Cardiol. 2010;55(7):688-696. 

In This Article

Pathophysiology

Microribonucleic Acid (miRNA)

A growing body of literature has provided evidence of the potentially important role that miRNA may play in the pathophysiology of HF and cardiac hypertrophy.[8,9] The miRNAs are single-stranded noncoding ribonucleic acid molecules of 21 to 23 nucleotides in length that are transcribed from the genome, but serve to regulate gene expression and cross-talk via modulation of messenger ribonucleic acid signaling instead of translation into proteins.[10] Differential expressions of several miRNAs have been observed between normal and cardiomyopathy tissues,[11] and changes in miRNA expression have also been observed after ventricular unloading with mechanical assist devices.[12,13] Because each miRNA can be linked to an array of downstream processes, the potential for manipulating such signals to reverse pathologic phenotypes is promising, as has been demonstrated in proof-of-concept studies.[14] In essence, they may provide potential targets of therapy to delay or reverse cardiac remodeling or fibrosis.

Modified Natriuretic Peptides

Several important observations have also emerged regarding the dynamic adaptations that occur in HF, particularly regarding the great diversity of the natriuretic peptide system. An alternative-splicing protein modified from B-type natriuretic peptide has been identified in patients with advanced HF. These peptides have moderate vasodilatory effects, yet provide for preserved or enhanced renal natriuretic effects.[15] Another mutant atrial natriuretic peptide found in humans is noted to be associated with enhanced diuretic, natriuretic, and vasodilatory effects relative to the wild-type peptide.[16] As disease progresses, detection of endogenous natriuretic peptides may appear to be reduced in part because of the presence of alternative forms (many of which have reduced bioactivity). This may actually represent a relative deficiency rather than a surplus of natriuretic peptide function.[17] These observations have greatly expanded our understanding of the importance and diversity of the natriuretic peptide system (either adaptive or maladaptive), and we can expect more to come.

Stem Cell Therapy in HF

Recent interest in the stem cell field has involved resident cardiac stem cells that can differentiate into multiple cell types, including cardiac myocytes.[18] A small proportion or side population of stem cells express the cell surface markers Kit and Sca1,[19] and such cells can generate cardiomyocytes in vitro and in vivo. Another side population expresses the transcription factor Isl1, allowing the cell to differentiate into endothelial, endocardial, smooth muscle, conduction system, right ventricular, and atrial myogenic lineages during embryonic heart development.[20] The cardiac stem cells can now be isolated and expanded from human myocardial biopsy samples. So-called induced pluripotent stem cells can be created to resemble embryonic stem cells and offer potential autologous regenerative therapies.[21] Such cells require 3 or 4 specific transcription factors (a sort of reprogramming cocktail) and in principle can generate all mammalian cell types. The processes of isolation, delivery of cells, survival and proliferation, electromechanical integration, and stability with safety are proving to be a big challenge, but several new human protocols are currently underway in the U.S. under the National Institutes of Health clinical trials network model. Despite improvement in our understanding of the biology, clinical trials to date have provided very modest results. Clearly, much more work is needed, both at the bench and in the clinic.

New Insights in Cardiorenal Physiology

Observations from several groups have verified venous congestion to be an important contributor to the cardiorenal syndrome, both in stable patients with chronic HF[22] as well as in patients with advanced HF admitted to the hospital for acute decompensation.[23] The venous congestion concept is a complementary view that accompanies the traditional renal–arterial underperfusion doctrine. Recognition that increased right atrial pressure is driving at least some of the problem has catalyzed a closer interdisciplinary look at how to best relieve congestion. A balance of pharmacologic as well as extracorporeal fluid removal techniques, particularly when the natriuretic response to diuretic therapy has diminished,[24] has now emerged. Also, tubular function and renal perfusion have been subjects of interest, with an observed inverse relation between urinary excretion of amino-terminal pro–B-type natriuretic peptide (NT-proBNP) and plasma NT-proBNP, and a direct relation between urinary excretion of NT-proBNP and renal plasma flow (independent of glomerular filtration).[25]

Meanwhile, the concept of arterial underperfusion has not been forgotten, and delivery of natriuretic peptide via a specialized catheter has demonstrated enhancement of glomerular filtration and urinary sodium excretion.[26] Because the determinants of arterial underperfusion can be multifactorial, another important proof-of-concept human experiment recently has been performed.[27] This new procedure was performed using a selective renal sympathetic ablation technique with a localized catheter-based system in patients with severe, refractory hypertension, which resulted in a significant and sustained reduction in blood pressure. It would be of interest to explore these new techniques in patients with advanced HF unresponsive to aggressive diuretic therapy, because renal artery constriction is known to occur.

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