Microenvironment and Macroenvironment in Hypertensive Hearts
Boundaries and Silos–Can We Pick and Treat Diastolic Heart Failure?
Diastolic heart failure has had a troubled past, with years of uncertainty over its very existence as a specific clinical entity. However, clinicians are seeing growing numbers of patients in our ageing populations where no other adequate and plausible explanation appears to be appropriate. Understandably, a whole literature has grown in attempts to improve sensitivity, specificity, and precision of diagnosis. Heart failure with normal ejection fraction (HFNEF) is the cumbersome term that is now agreed to describe the condition. With progress in availability and capability of echocardiography, HFNEF has attracted the interest of investigators wishing to better understand more basic cellular and molecular mechanisms involved in the development and maintenance of HFNEF, with the aim of developing targeted and effective therapies.
Changes in muscle mass, size, and heart shape classically describe cardiac remodeling, but this process is being increasingly linked to dysfunction at the subcellular level, including the extracellular matrix, where alterations in biochemical composition and molecular structure may eventually transition from hypertrophy to heart failure. Activation of different proteases and phospholipases and alterations in gene expression are suggested as the basis for these changes.1
The article by Gonzalez et al2 in this issue of Hypertension makes a bold attempt to unravel some of the complex pathways leading to heart failure with normal ejection fraction, with an emphasis on collagen and the proteolytic tissue digesting matrix metalloproteinases (MMPs) and their antagonists, the tissue inhibitor of metalloproteinases (TIMPs), in the heart of hypertensive subjects. This scenario is reminiscent of the “push-pull” effect of sympathetic/parasympathetic activity in the autonomic nervous system, which rings true to all those managing hypertension. The authors examined a cohort of 2 sets of 78 hypertensive patients with elevations in left ventricular end-diastolic pressure and normal left ventricular ejection fraction that categorized them as having heart failure with normal ejection fraction and measured circulating levels of biomarkers, more specifically MMP-1/TIMP-1 levels, and PICP (procollagen type I carboxyterminal propeptide) as a measure of collagen synthesis. In contrast to controls, levels of all 3 of the biomarkers were found to be increased in both heart failure with normal ejection fraction groups. However, the balance between extracellular matrix–degrading MMPs and their antagonists the TIMPs differed according to the elevation in left ventricular end-diastolic pressure with a cutoff of 15 mm Hg. Those with the higher left ventricular filling pressure (LVFP) were found to have higher levels of matrix degrading inhibitor TIMP-1 so that the ratio of MMP-1:TIMP-1 was less. An independent association of left ventricular end-diastolic pressure with TIMP-1 and the MMP-1:TIMP-1 ratio was also found.
On the whole, the measurement of MMPs and TIMPs is relatively simple and is likely to become even more so with newer analytic technologies, such as combined microarray and 3D fluorophore activity assays. But there are potential pitfalls, so interpretation of results also needs caveats. The daunting number of MMPs (currently 24 human forms) and the variety of TIMPs (n=4) mean that choices need to be made between the different bioactive species according to the organ or tissue of interest. Gonzalez et al2 chose to measure MMP-1 and TIMP-1, which are 2 of the species represented in the human heart. Understandably in these clinical studies, tissue analysis was not an option, and plasma levels were chosen that might not mirror tissue levels. The scale of temporal and spatial MMP activation in a chronic condition such as hypertension introduces another variable,2–5 as does the possible confounding effect of antihypertensive treatment and inflammatory conditions, such as rheumatoid arthritis, diabetes mellitus, and other conditions common in the elderly. Whether plasma levels truly mirror metabolic activity or potential activity of MMPs/TIMPs has echoes of the situation with plasma epinephrine and norepinephrine levels, where only metabolic clearance was found to be a reliable measure of their activity. Another consideration that often bedevils MMP assays is the dichotomy between MMP activity as opposed to plasma or tissue levels. The species most relevant to heart extracellular matrix digestion exists predominantly in the metabolically inactive proform. Interestingly, the 10-fold plasma MMP-1 elevation seen by Gonzalez et al2 in their chronic, mostly treated hypertensive patients is comparable to that found in the acute phase of myocardial infarction in sheep heart by Gallagher et al.5
The thrust of the conclusions by Gonzalez et al2 is premised on reliable measures of LVFP, which they have attempted to derive as estimated pulmonary capillary wedge pressure (ePCWP), using the echocardiographically obtained E/E′ ratio with a figure of >15 predicting elevated ePCWP levels.6 A regression equation7 was applied in a way that risks overestimation of LVFP, because originally E′ values had been taken from the lateral mitral annulus alone. The choice of patients also differed in the study by Nagueh et al,7 which was composed of subjects with elevated LVFP among whom a great majority had depressed left ventricular systolic function. Thus, the use of this regression equation would tend to alter the threshold for predicting elevated LVFP using the E/E′ ratio.8 The behavior of LVFP under situations of cardiac stress, such as atrial pacing and/or handgrip exercise, as used by Westermann et al,9 could provide additional information on the dynamic behavior of this parameter, although it would still remain subject to loading conditions. The latter are largely accounted for by their measurements of left ventricular pressure-volume loops, which are currently not readily applicable with available technology to larger patient cohorts.
Gonzalez et al2 have added another dimension to the categorization of heart failure with normal ejection fraction, raising the possibility of a useful “biomarker’” akin to B-type natriuretic peptide in heart failure. However, selection of patient cohorts tightly matched for age, sex, treatment, hypertensive history, and current blood pressure status could add sensitivity and specificity to such a biomarker. In the future it may also be of interest to measure myocardial collagen content by currently evolving MRI techniques.
Boundaries and even silos that exist in studies on heart remodeling tend sometimes to inhibit the cross-disciplinary discourse that can be so beneficial in the biomedical sciences. The principal boundary is often the translation of knowledge from rodent experiments to the human condition, bypassing the insights provided by larger animal species.10 There are also some silos despite common themes, such as mechanical wall stress and the relative ischemia of hypertensive hypertrophied hearts. The challenge of meaningful clinical studies, particularly in chronic conditions prevalent in the elderly, such as hypertension, is always daunting. Gonzalez et al2 should be congratulated for shedding new light on the added dimension of subcellular mechanisms and for proposing a hypothesis that may lead to clinicians regarding diastolic hypertension through different glasses.
The valuable contribution of Dr Christopher Choong in analyzing the conclusions of echocardiographic data in the article by Gonzalez et al2 in light of the referenced work6 on which it relies for ePCWP measurement is gratefully acknowledged.
Sources of Funding
This work was supported by the National Health and Medical Research Council of Australia and the North Shore Heart Research Foundation.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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