Mark H. Drazner
Circulation. 2011;123:327-334
doi: 10.1161/CIRCULATIONAHA.108.845792
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From the Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Correspondence to Dr Mark Drazner, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9047. E-mail
Mark.Drazner@utsouthwestern.edu
(Circulation. 2011;123:327-334.)
2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.845792
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Variation in neurohormonal activation in hypertension is
another putative factor influencing the development of either
concentric or eccentric hypertrophy. Differences in plasma
renin activity are widespread in hypertensive subjects,45,46
and some investigators equate high- versus low-renin states
with concentric versus eccentric hypertrophy, respectively.47
Patients with eccentric hypertrophy have been shown to have
low plasma renin activity.48 Other neurohormones, including
angiotensin II and aldosterone, have also been associated with
LV geometry in small cross-sectional studies.49 51 However,
the Framingham Offspring Study recently reported that an
increased aldosterone-to-renin ratio was associated with both
concentric and eccentric hypertrophy in multivariable models.52 Their sample was by far the largest to date (n2119),
and these data question whether variability in the renin-angiotensin-aldosterone axis will be a key factor in the predilection to develop increased LV wall thickness versus ventricular dilation in hypertension.
Alterations in the extracellular matrix are suspected to be
critical mediators in the development of LV chamber dilation.
In a study of hypertensive subjects with heart failure in which
coronary artery disease was excluded by angiography, endomyocardial biopsy of the right ventricular septum was performed in16 subjects with dilated cardiac failure and 23 with
a preserved LVEF.53 Those with dilated cardiac failure had a
lower amount of collagen surrounding the cardiomyocytes, a
higher amount of perivascular and scar-related collagen, and
a higher ratio of matrix metalloproteinase-1 to tissue inhibitor
of matrix metalloproteinase-1, highlighting the importance of
alterations of the extracellular matrix in leading to LV
dilation.
As with LV mass (see above), there likely will be genetic
influences discovered that affect the pattern of the hypertrophic response (wall thickening or dilation).2,21,24,54 In a canine
model of aortic constriction, dogs that had a higher baseline
indexed LV mass and lower systolic wall stress before
placement of the aortic band had a larger increase in LV mass
and preservation of cardiac function compared with dogs with
baseline lower LV mass and higher systolic wall stress.55
Similarly, approximately one half of rats who underwent
suprarenal aortic banding remodeled concentrically and one
half eccentrically at 20 weeks.56 These data suggest that
intrinsic factors, possibly genetic, that are operative before
exposure to injury can modulate the hypertrophic response.
This hypothesis is supported by the murine model of transverse aortic constriction, in which the background mouse
strain influenced whether concentric or eccentric hypertrophy
developed.57 Potential molecular pathways affecting the ability of the ventricle to tolerate pressure overload have been
delineated.58,59 In total, these data suggest that genetic factors
may influence the response to pressure overload and, specifically, whether concentric or eccentric hypertrophy develops.
Regression of LV Mass
The pathway from hypertension to concentric LVH is not
unidirectional. With pharmacological control of blood pressure, LV mass decreases60 and is associated with reduced risk
of clinical events including cardiovascular death, myocardial
infarction, and stroke.61 However, whether a strategy tailored
329
330
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Drazner
has been reviewed recently.89 Thus, this review will focus on
the progression from concentric LVH to symptomatic heart
failure with a normal LVEF (pathway 6, Figure 1).
One factor that appears to be associated with the development of heart failure in those with LVH and a normal LVEF
is a progressive change in the extracellular matrix. In an
elderly canine model of hypertension, exogenous mineralocorticoid (deoxycorticosterone acetate) administration was
associated with progressive cardiac fibrosis and increased LV
stiffness,90 suggesting that mineralocorticoid receptor activation may be important in this progression. Others have
demonstrated a shift in serum levels of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases with
progression in the continuum of hypertensive heart disease.91
Higher tissue inhibitor of matrix metalloproteinase-1 levels,
which are associated with increased collagen accumulation,
were observed in patients with LVH and clinical heart failure
compared with patients with hypertension and LVH but no
clinical heart failure. In a study of 85 hypertensive patients,
serum levels of matrix metalloproteinase-2 and -9 and amino
peptide of procollagen type 3 were independent predictors of
identifying those with heart failure with a preserved LVEF,
and matrix metalloproteinase-2 had a better diagnostic utility
than B-type natriuretic peptide for this purpose.92 Together,
these studies suggest that progressive changes in the extracellular matrix may be responsible for the transition from
LVH to symptomatic heart failure with a preserved LVEF.
Another key component in the development of clinical
heart failure with a preserved LVEF appears to be elevation
in LV filling pressures. Data from implantable hemodynamic
monitors demonstrate that such filling pressures appear elevated in both the chronically compensated and acutely decompensated state of heart failure with preserved LVEF.93
Consistent with this hypothesis are echocardiographic data
that demonstrate an enlarged left atrium in patients with heart
failure and preserved LVEF94,95 as well as elevated pulmonary artery pressures, which are themselves correlated with
LV filling pressures.96
Conclusion
Hypertensive heart disease encompasses a broad spectrum
including asymptomatic LVH (either a concentric or an
eccentric pattern) and clinical heart failure (with either a
preserved or a reduced LVEF). There is considerable interindividual variability in the progression from hypertension to
LVH in both the magnitude of the increase in LV mass and its
geometric pattern (ventricular dilation or wall thickening).
Some of these differences are likely attributable to differences in the pressure load (which may not be discernable by
office measurements of blood pressure), concomitant medical
conditions, and the underlying neurohormonal milieu. However, these differences in LV geometry also suggest the
likelihood of operative genetic influences that are only
beginning to be uncovered. The classic paradigm of the
progression from hypertension to concentric hypertrophy and
then dilated cardiac failure has been established in animal
models, but recent data have challenged several of its components. First, in animal models of pressure overload, concentric hypertrophy, which normalizes wall stress, is not
331
Acknowledgments
I appreciate the assistance of Dr James de Lemos for his critical
review of this manuscript.
Sources of Funding
Dr Drazner was supported by the James M. Wooten Chair in
Cardiology.
Disclosures
None.
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KEY WORDS: heart failure
hypertension
hypertrophy
remodeling