Right Ventricular Function Measures as Biomarkers of Diabetic Cardiomyopathy

In this issue of JASE , Tadic et al . report that normotensive diabetic and prediabetic patients have early abnormalities of right ventricular (RV) systolic and diastolic function, with reductions in global systolic strain and early diastolic strain in the absence of an increase in RV wall thickness or a reduction of RV ejection fraction detectable by echocardiography. The authors used three-dimensional echocardiography for RV volume measurement and speckle-tracking for myocardial strain measurement. Their findings indicate early impairments of both RV contractile function and early diastolic relaxation in patients with diabetes mellitus and prediabetes.

The pulmonary circulation is a low-pressure system, and it was thought that RV function is not important to maintain circulation. Starr et al . showed that RV ablation in dogs was compatible with life. In patients with univentricular physiology, a Fontan circulation can maintain resting hemodynamics for many years, though it may ultimately fail. However, increasing evidence over the past 25 years suggests that RV function not only is important but determines prognosis in a variety of cardiovascular disorders, including heart failure, congenital heart disease, ischemic heart disease, and valvular disorders. Tadic et al . provide evidence that RV function can be affected in systemic disorders such as diabetes mellitus. This raises many questions pertaining to possible mechanisms, clinical significance, therapeutic implications, techniques for early detection, and importance as a possible window for the detection of involvement of other organs, such as the kidney and the eyes.

The potential mechanisms of RV involvement in diabetes, as the authors discuss, include hyperinsulinemia causing RV hypertrophy, hyperglycemia resulting in myocardial deposition of advanced glycosylation products, hyperlipidemia causing myocardial steatosis, and diabetes-associated inflammatory state. There are other potential mechanisms as well. Diabetic left ventricular (LV) cardiomyopathy can affect the right ventricle through affecting the common wall (i.e., the ventricular septum), though RV free wall function was independently abnormal in patients with diabetes and those with prediabetes in this study. Another potential mechanism is abnormal LV diastolic mechanics causing higher ambulatory LV filling and pulmonary pressures, resulting in an increase in RV afterload, although resting pulmonary artery pressures were not elevated compared with controls. Higher ambulatory pulmonary artery pressures would result in RV hypertrophy and fibrosis. There is also increasing recognition that epigenetic mechanisms such as changes in intracellular micro–ribonucleic acid (miR) may play a role in diabetic cardiomyopathy and cardiac involvement in systemic diseases. The miRs are small ribonucleic acid molecules of about 20 nucleotides in length and are implicated in gene expression. These are remarkably stable, do spill over into the circulation because of their small size, and may selectively block translation of specific messenger ribonucleic acids. Cardiomyopathy involves multiple mechanisms, including myocyte apoptosis, myocyte hypertrophy, interstitial fibrosis, and endothelial cell dysfunction. The miRs are implicated in most of these mechanisms in patients with diabetes. Downregulation of miR-133a induces cardiomyocyte hypertrophy. Upregulation of miR-1 and miR-206 results in cardiomyocyte apoptosis. Upregulation of miR-141 causes impaired mitochondrial adenosine triphosphate production and hence both contractile and relaxation failure. Impaired myocardial phosphocreatinine production with stress has been demonstrated in patients with diabetes using 31 P spectroscopy. In other words, there are ample mechanisms by which the right ventricle can be involved in diabetes mellitus through metabolic, epigenetic, neurohormonal, and hemodynamic mechanisms, and these may offer potential opportunities for therapeutic or prophylactic intervention. Detection of early cardiac involvement using simple, noninvasive techniques would be critically important for the timing and institution of such potential interventional approaches.

Tadic et al . have looked at systolic and early diastolic strain as principal measures of RV systolic and diastolic function, respectively, as biomarkers of diabetic RV cardiomyopathy. Though strain measures are easy to obtain, they have important limitations. Systolic strain is a better measure of RV systolic function than ejection fraction but is affected not only by RV contractile function but by its afterload, preload, and inotropic state. Wall stress is the best measure of afterload and takes into account the systolic pressures against which the myocardium contracts, the wall thickness and radius of the chambers, as well as geometry. However, RV geometry is complex and varies by region, while regional and directional (circumferential and meridional) RV wall stresses are difficult to compute. Given that the RV size was smaller in the patients with diabetes compared with the controls, without an increase in RV wall thickness or systolic pressure, one can presume that the wall stress was lower. This should have resulted in higher strain for a given contractile state. The fact that RV myocardial strain was reduced despite a possible reduction in wall stress indicates true RV contractile dysfunction.

Two additional measures of RV systolic function would have given greater insights: RV contractile reserve with inotropic stimulation and calculation of RV maximum elastance (E max ) from the RV pressure-volume loop (generated using the three-dimensional RV volume data and the RV systolic pressure profile generated from the tricuspid regurgitation velocity signal). The gold standard of systolic performance is E max , which is the maximum value of pressure-to-volume ratio and is largely load insensitive. Arterial elastance, E a , can be calculated as the ratio of pressure at E max to stroke volume as a measure of afterload. Optimum ventriculoarterial coupling occurs at an E max /E a ratio of 1.5 to 2.0. These parameters are potentially measurable by echocardiography and may serve as better or additional markers of RV myocardial systolic performance.

The gold standards for diastolic function include measures of early diastolic relaxation and late diastolic stiffness. The constant of isovolumic relaxation, τ, is the gold standard for the measurement of relaxation, and the modulus of chamber stiffness, k , is the gold standard for chamber stiffness. These are well characterized for the left ventricle, but there are no reliable data for the right ventricle. In addition, these may also depend upon the pulmonary artery pressures and the response of the right ventricle to pulmonary artery pressure. Also, these are best obtained by simultaneous measurement of RV pressure and volume, the former with high-fidelity, manometer-tipped catheter systems, not by fluid-filled catheters, which do not have adequate frequency response. Early diastolic strain measured in this study is a reasonable measure of RV relaxation.

The other logical questions are the following: What are the prognostic implications of abnormal RV strain measures? How do these compare with other subclinical markers of myocardial involvement, such as LV strain, LV mass, abnormal LV diastolic function, increased left atrial volume, and E/E m ratio? Are markers of RV involvement better predictors of outcomes than markers of LV involvement? Can the RV signals be improved by using other purer measures of RV myocardial performance? What causes these signals, and what can be done to prevent or reverse adverse myocardial involvement? Does myocardial involvement parallel involvement of other organs, such as the kidney and the eyes, and can it be a window to assessing systemic involvement? These are some of the unanswered questions that merit careful evaluation given that diabetes mellitus and obesity have become global epidemics of major public health importance.

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Apr 21, 2018 | Posted by in CARDIOLOGY | Comments Off on Right Ventricular Function Measures as Biomarkers of Diabetic Cardiomyopathy

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