Left ventricular hypertrophy (LVH) is the major risk factor associated with myocardial failure. An explanation for why a presumptive adaptation such as LVH would prove pathological has been elusive. Insights into the impairment in contractility of the hypertrophied myocardium have been sought in the biochemistry of cardiac myocyte contraction. Equally compelling is a consideration of abnormalities in myocardial structure that impair organ contractile function while preserving myocyte contractility. For example, in the LVH that accompanies hypertension, the extracellular space is frequently the site of an abnormal accumulation of fibrillar collagen. This reactive and progressive interstitial and perivascular fibrosis accounts for abnormal myocardial stiffness and ultimately ventricular dysfunction and is likely a result of cardiac fibroblast growth and enhanced collagen synthesis. The disproportionate involvement of this nonmyocyte cell, however, is not a uniform accompaniment to myocyte hypertrophy and LVH, suggesting that the growth of myocyte and nonmyocyte cells is independent of each other. This has now been demonstrated in in vivo studies of experimental hypertension in which the abnormal fibrous tissue response was found in the hypertensive, hypertrophied left ventricle as well as in the normotensive, nonhypertrophied right ventricle. These findings further suggest that a circulating substance that gained access to the common coronary circulation of the ventricles was involved. This hypothesis has been tested in various animal models in which plasma concentrations of angiotensin II and aldosterone were varied. Based on morphometric and morphological findings, it can be concluded that arterial hypertension (i.e., an elevation in coronary perfusion pressure) together with elevated circulating aldosterone are associated with cardiac fibroblast involvement and the resultant heterogeneity in tissue structure. Nonmyocyte cells of the cardiac interstitium represent an important determinant of pathological LVH. The mechanisms that invoke short- (e.g., collagen metabolism) and long-term (e.g., mitosis) responses of cardiac fibroblasts require further investigation and integration of in vitro with in vivo studies. The stage is set, however, to prevent pathological LVH resulting from myocardial fibrosis as well as to reverse it.

Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system.

Cardiac interstitium in health and disease: the fibrillar collagen network

This study was undertaken to determine the prevalence and significance of diastolic left ventricular (LV) dysfunction in mild to moderate systemic hypertension. Rest and exercise equilibrium blood pool scintigraphy was performed in 39 hypertensive subjects (mean systolic blood pressure [BP] 156 ± 14 mm Hg [± standard deviation];mean diastolic BP 103 ± 5 mm Hg ) and 11 normal control subjects. These studies were analyzed for ejection fraction (EF), segmental wall motion, peak filling rate (PFR), time to PFR and filling fraction in the first third of diastole normalized for cycle length (first-third filling fraction). EF at rest was similar in the hypertensive patients and control subjects (0.63 ± 0.09 versus 0.65 ± 0.07);only 2 patients had a reduced EF. The EF response to exercise was normal in every hypertensive patient (increasing to a mean of 0.74 ± 0.08);only 1 patient had asynergy. In contrast, even when the 2 patients with abnormal systolic function were excluded, each index of diastolic filling was significantly different from the control group. PFR was lower (2.29 ± 0.49 vs 2.63 ± 0.39 end-diastolic volumes per second [EDV/s], p These findings indicate that diastolic abnormalities may be an early finding in hypertensive heart disease and that they are, at least in part, related to the degree of LV hypertrophy.

Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension.

This study tested the hypothesis that with hypertrophy, the proportion, distribution, and structural alignment of fibrillar collagen are important determinants of myocardial stiffness. Toward this end, the collagen volume fraction (morphometry), the transmural or subendocardial distribution of collagen, and the structural arrangement of fibrillar collagens (picrosirius red) were examined in the hypertrophied ventricle secondary to pressure overload (abdominal aorta banding or perinephritis), isoproterenol, and pressure overload plus isoproterenol. In the same hearts, the slopes of the systolic and diastolic stress-strain relations of the left ventricle, representing its active and passive stiffness, respectively, were obtained. In comparison with controls, we found 1) for a moderate rise in transmural collagen, active and passive stiffness increased with pressure-overload hypertrophy; 2) following isoproterenol alone there was a marked increase in subendocardial collagen, and active and passive stiffness increased; 3) in pressure-overload hypertrophy plus isoproterenol, active stiffness declined. Passive stiffness was increased except when fibrosis and thinning of the interventricular septum occurred, in which case it decreased; and 4) fibrillar collagens involved in remodeling included the formation of either collagen strands and fibers in a greater number of previously collagen-free intermuscular spaces in pressure-overload hypertrophy, or a dense crisscrossing latticework of fibers that encircled muscle fibers after isoproterenol. Thus, an increase in fibrillar collagen in pressure-overload hypertrophy is partially adaptive in that it enhances the tensile strength and three-dimensional delivery of force by the myocardium, but at the expense of reducing distensibility. The appearance of a dense collagen meshwork within the subendocardium after isoproterenol can be considered pathological in that it entraps muscle fibers causing active stiffness to fall while impairing distensibility. Finally, fibrosis may paradoxically reduce passive stiffness if it leads to a thinning of the interventricular septum.

Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle.

Background Fibrosis is commonly found in association with cardiac hypertrophy and failure, but the relation of the connective tissue response to the development of impaired cardiac function remains unclear We examined passive myocardial stiffness, active contractile function, and fibrosis in the spontaneously hypertensive rat (SHR), a model of chronic pressure overload in which impaired cardiac function follows a long period of stable hypertrophy Methods and Results We studied the passive and active mechanical properties of left ventricular (LV) papillary muscles isolated from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) at the ages of 12 months and 20 to 23 months Seven of 15 SHR between 20 and 23 months of age had findings consistent with heart failure (SHR-F) In comparison to preparations from WKY rats and nonfailing SHR (SHR-NF), papillary muscles from the SHR-F group demonstrated increased passive stiffness (central segment exponential stiffness constant, kcs: SH

Myocardial Fibrosis and Stiffness With Hypertrophy and Heart Failure in the Spontaneously Hypertensive Rat

Diastolic myocardial stiffness and viscosity were determined in 40 patients with myocardial hypertrophy by combined echo-pressure measurements. These diastolic measurements were compared with left ventricular muscle fiber diameter and interstitial fibrosis as obtained from left ventricular endomyocardial biopsies at catheterization. The patients were divided into four groups: group 1 eight control patients; group 2–10 patients with moderate-to-severe aortic stenosis; group 3–10 patients with moderate-to-severe aortic insufficiency; and group 4–12 patients with congestive cardiomyopathy. Myocardial stiffness and viscosity were assessed using a viscoelastic stress-strain model. For the interpatient comparison, a normalization of the stress-strain relationship was performed by calculating a reference midwall circumference (11) at a transmural stress of 1000 dyn/cm2. The light microscopic evaluation of the left ventricular biopsies included the quantitative assessment of interstitial fibrosis by the point-counting system and of muscle fiber diameter by direct measurement. The normalized viscoelastic constant of myocardial stiffness (Kn) was slightly, but not significantly, increased in patients with aortic stenosis and insufficiency (13.3 and 13.0), whereas Kn was significantly (p < 0.05) higher in patients with congestive cardiomyopathy (33.8) than in the control subjects (8.8). The constant of myocardial viscosity (Yn) was elevated slightly in patients with aortic valve disease and moderately in patients with congestive cardiomyopathy. In contrast, 1, was significantly increased in all three groups with myocardial hypertrophy compared with group 1. Left ventricular interstitial fibrosis amounted to 2% in seven control patients, 15% in patients with aortic stenosis, 11% in patients with aortic insufficiency and 28% in patients with congestive cardiomyopathy. Muscle fiber diameter (control patients 13.7 μ) was largest in patients with aortic stenosis (26.8 μ) and was somewhat smaller in patients with aortic insufficiency (21.7 μ) or congestive cardiomyopathy (23.6 μ). The comparison of functional and structural properties of the left ventricle showed a significant correlation between myocardial stiffness and interstitial fibrosis (r = 0.59; p < 0.001), whereas there was no correlation between myocardial stiffness and angiographic muscle mass or muscle fiber size. In summary, normalized myocardial stiffness is normal in most patients with aortic valve disease, but is significantly higher in patients with congestive cardiomyopathy. Myocardial stiffness appears not to be influenced by left ventricular muscle mass or muscle fiber size, but is increased in the presence of massive left ventricular interstitial fibrosis. These findings suggest that diastolic myocardial stiffness in myocardial hypertrophy is related more to the interstitial than to the muscular tissue.

Diastolic function and myocardial structure in patients with myocardial hypertrophy. Special reference to normalized viscoelastic data.

In eight anaesthetized closed-chest dogs, acute myocardial ischaemia was produced for 30 to 90 s by inflating a small balloon-catheter, which had been advanced transaortically into the periphery of the left anterior descending coronary artery. Left ventricular high-fidelity pressure measurements and simultaneous angiocardiography were carried out at control and during ischaemia. Left ventricular systolic function was assessed by the left ventricular ejection fraction (EF) as well as by regional shortening in a basal (SH M1), middle (SH M2 and apical (SH M3) segment. Diastolic function was evaluated by the stress-strain relationship using a viscoelastic model. Regional wall stiffness (Kn) was determined in the same three segments (basal, middle and apical), which were used for the evaluation of regional systolic function. For the interindividual comparison of the diastolic stiffness parameters normalization of the strain data was performed by calculating a reference wall circumference (I) at a common wall stress of 1000 dynes/cm2.

During localized myocardial ischaemia left ventricular end-diastolic pressure remained essentially unchanged (7.2 v. 8.3 mm Hg: NS). Left ventricular EF (47 v. 31% P < 0.001), SH M2 (27 v. 14 % P < 0.005) and SH M3 (22 v. 2% P < 0.02) decreased during ischaemia. Kn in the middle (10.0 v. 14.2; P < 0.02) and the apical (9.8 v. 12.7, P < 0.005) segment increased during ischaemia whereas Kn in the non-ischaemic basal segment remained unchanged (9.6 v. 11.8; NS). During ischaemia I increased in the middle segment (15.7 v. 17.3 cm; P < 0.005).

Our data indicate that during acute ischaemia regional myocardial wall stiffness is increased in the ischaemic segment, but is normal in the non-ischaemic segment. Reference midwall circumference at a common wall stress of 1000 dynes/cm2 is enhanced during acute ischaemia (creep) and corresponds with the increased sarcomere length reported in ischaemic myocardium. Thus, it is suggested that the changes in regional myocardial wall stiffness are related to changes in reference midwall circumference with creep.

/pdf/regional-wall-stiffness-during-acute-myocardial-ischaemia-in-4bqg4fkhvr.pdf

Regional wall stiffness during acute myocardial ischaemia in the canine left ventricle.

[Computer-assisted evaluation of echo pressure curves of the left ventricle in patients with myocardial hypertrophy; importance of myocardial morphology].

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Diastolic function and myocardial structure in patients with myocardial hypertrophy. Special reference to normalized viscoelastic data.

Regional wall stiffness during acute myocardial ischaemia in the canine left ventricle.

[Computer-assisted evaluation of echo pressure curves of the left ventricle in patients with myocardial hypertrophy; importance of myocardial morphology].