Angela J. Woodiwiss

Reduction in Myocardial Collagen Cross-Linking Parallels Left Ventricular Dilatation in Rat Models of Systolic Chamber Dysfunction

Background—The transition from compensated left ventricular hypertrophy (LVH) to heart failure is associated with alterations in the myocardial interstitium. We hypothesized that LV dilatation is associated with modifications in collagen cross-linking. Methods and Results—We studied 2 rat models of LV dilatation: (1) pressure-overload hypertrophy with heart failure (POH-F) induced by suprarenal abdominal aortic banding and (2) LVH induced by 7 months of isoproterenol (ISO, 0.04 mg · kg−1 · d−1) administration. In POH-F rats and in rats receiving ISO, LV dilatation and a reduced systolic chamber performance were noted. Myocardial hydroxyproline concentrations ([HPRO]) were increased in the POH-F rats, whereas in rats receiving ISO, [HPRO] was decreased. In POH-F rats, the ratio of myocardial collagen type I to type III was increased, but in rats receiving ISO, myocardial collagen I/III was unchanged. In contrast to the diverse changes in myocardial collagen concentrations and phenotypes observed in the 2 models of LV dilatation, the ratio of myocardial insoluble to soluble (relationship between cross-linked and non–cross-linked) collagen was decreased in both the POH-F and ISO groups. Moreover, administration of captopril (0.22 mmol · kg−1 · d−1), which inhibited the ISO-induced reduction in myocardial insoluble/soluble collagen but not the reduction in [HPRO], prevented the ISO-induced alterations in LV dimensions and performance. Conclusions—Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.

Myocardial stiffness is attributed to alterations in cross-linked collagen rather than total collagen or phenotypes in spontaneously hypertensive rats.

BACKGROUND The relative contributions of increases in myocardial collagen, collagen cross-linking, and the ratio of type I to type III collagen to the stiff myocardium in hypertension were determined. METHODS AND RESULTS We compared the action of hydralazine (0.07 mmol x kg(-1) x d(-1)) with that of captopril (0.22 mmol x kg(-1) x d(-1)) on the left ventricular end-diastolic (LVED) myocardial stiffness constant, k (g x cm(-2)) and LV myocardial interstitial characteristics in spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) control rats. LVED k (SHR, 27.9+/-1; WKY, 19.5+/-1.2; P<.01), myocardial hydroxyproline concentrations (HPRO; microg/mg dry wt) (SHR, 4.19+/-0.16; WKY, 3.17+/-0.09; P<.001), and collagen type I/III ratios (SHR, 7.1+/-0.7; WKY, 2.1+/-0.2; P<.001) were increased, whereas the percentage of myocardial collagen extracted after cyanogen bromide digestion (an index of cross-linked collagen) was decreased (SHR, 17+/-3; WKY, 41+/-4; P<.001) in SHRs compared with WKY controls. Captopril therapy reduced LVED k, myocardial HPRO, collagen type I/III, and augmented collagen solubility (43+/-4) in SHRs to values similar to those measured in WKY controls. Hydralazine therapy, despite a favorable effect on LVED k in SHRs (20.+/-1.6, P<.01 compared with untreated SHRs), failed to influence either myocardial HPRO (4.18+/-0.18) or collagen type I/III (8+/-1) but did improve collagen solubility (31+/-2). CONCLUSIONS An association between alterations in LVED k and collagen solubility but not between changes in LVED k and total collagen or phenotype ratios after antihypertensive therapy in SHRs suggests that myocardial stiffness in hypertension is the consequence of an enhanced myocardial collagen cross-linking rather than of an increase in total collagen or type I phenotype concentrations.

Aminoguanidine Prevents the Decreased Myocardial Compliance Produced by Streptozotocin-Induced Diabetes Mellitus in Rats

BACKGROUND A decreased cardiac compliance is a major feature of the cardiomyopathy of diabetes mellitus. Either an increase in the resistance afterload to the LV or an increase in collagen cross-linking induced by the formation of advanced glycosylation end products (AGEs) of collagen may be responsible for the stiff myocardium. To evaluate these hypotheses, we examined the effect of captopril, an afterload-reducing agent, and aminoguanidine, a nucleophilic hydrazine that prevents the accumulation of collagen AGEs, on left ventricular end-diastolic (LVED) compliance after 4 months of streptozotocin (0.26 mmol/kg)-induced diabetes mellitus in rats. METHODS AND RESULTS Diabetes mellitus produced a decrease in LV chamber compliance as a result of an increased myocardial stiffness (slope of the linearized LVED stress-LVED strain relation [unitless]: diabetes mellitus, 47+/-4; control, 27+/-3; P<.001) and an increase in blood pressure as a result of an elevated vascular resistance. LV end-systolic elastance was unaltered by diabetes mellitus. The stiff myocardium was not associated with changes in the myocardial collagen volume fraction or total hydroxyproline concentration but was associated with an increased myocardial collagen fluorescence (fluorescence units/microg hydroxyproline) (diabetes mellitus, 11+/-1.1; control, 6.6+/-0.7; P<.01). Captopril therapy (0.22 mmol x kg(-1) x d(-1)), despite producing a decrease in blood pressure through alterations in vascular resistance, failed to decrease myocardial stiffness in rats with diabetes mellitus. Alternatively, administration of aminoguanidine (7.35 mmol x kg(-1) x d(-1)) prevented both the enhanced myocardial collagen fluorescence (7.1+/-1.2) and the increased slope of the linearized LVED stress-LVED strain relation (29+/-2) but did not change markers of blood glucose control. CONCLUSIONS These results demonstrate that diabetes mellitus can produce a stiff myocardium before the development of myocardial fibrosis. The stiff myocardium in the early stages of the development of the cardiomyopathy of diabetes mellitus is not a consequence of an increase in ventricular resistance afterload and in these circumstances is associated with the formation of collagen AGEs.

Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats

OBJECTIVE To assess whether the variable impact of quantitative changes in myocardial collagen on left ventricular (LV) diastolic myocardial stiffness (myocardial k) and remodelling (increased volume intercept of diastolic pressure-volume relations) in LV hypertrophy (LVH) is associated with alterations in myocardial collagen cross-linking. METHODS We evaluated myocardial collagen content (hydroxyproline concentrations [HPRO]) and the degree of myocardial collagen cross-linking (solubility to cyanogen bromide digestion) in 14-15- and 21-22-month-old spontaneously hypertensive rats (SHRs), and in aortic-banded rats with pressure overload hypertrophy (POH). RESULTS In rats with POH and in SHRs irrespective of age, increases in myocardial [HPRO] were noted. However, hypertensive rats differed in the material and geometric properties of the myocardium, and in qualitative aspects of fibrosis. In 14-15-month-old SHRs myocardial k (determined from diastolic stress-strain relations) and insoluble (cross-linked) [HPRO] were increased, but no LV remodelling or increases in myocardial soluble (non-cross-linked) [HPRO] were noted. In rats with POH, LV remodelling and increases in soluble myocardial [HPRO] occurred, but no increase in k or insoluble myocardial [HPRO] were observed. In 21-22-month-old SHRs, increases in k, soluble and insoluble myocardial [HPRO], as well as LV remodelling occurred. CONCLUSIONS Collagen cross-linking may determine the diverse relation that exists between increases in myocardial collagen concentrations and either myocardial stiffness or chamber remodelling in hypertension. These findings support the notion that fibrosis contributes to myocardial stiffness as well as LV dilatation in LVH, albeit an effect that is modulated by collagen quality.

Heart failure in pressure overload hypertrophy ☆: The relative roles of ventricularremodeling and myocardial dysfunction

OBJECTIVES We sought to explore the relative contributions of ventricular remodeling and myocardial dysfunction to heart failure in pressure overload hypertrophy (POH). BACKGROUND The mechanism that underlies heart failure in POH is adverse left ventricular (LV) chamber remodeling or decreased myocardial function, or a combination of these. METHODS Twenty weeks after suprarenal aortic banding in rats, animals with POH were classified as those with heart failure (POH-HF) or those with no heart failure (POH-NHF). The LV chamber and myocardial systolic and diastolic functions were determined from in vivo and ex vivo experiments. RESULTS The LV mass was similar in both POH groups. Chamber remodeling in the POH-HF group was characterized by marked LV enlargement with a normal relative wall thickness (eccentric remodeling), whereas remodeling in the POH-NHF group was characterized by a normal chamber size and increased relative wall thickness (concentric remodeling). The LV systolic function, as determined in vivo from the end-systolic pressure-diameter relationship and ex vivo from the pressure-volume relationship, was lower in the POH-HF group than in the POH-NHF and sham-operated control groups. In contrast, myocardial function was similar in both POH groups, as determined in vivo from the stress-midwall fractional shortening relationship and myocardial systolic stiffness, and ex vivo from the slope of the LV systolic stress-strain relationship. The diastolic chamber stiffness constant was lower in the POH-HF group than in the POH-NHF group, but the myocardial stiffness constant was similar in the two POH groups. CONCLUSIONS The two POH groups differed primarily in their remodeling process, which led to a chronically compensated state in one group and to heart failure in the other. Hence, heart failure in POH is more closely related to deleterious LV remodeling than to depressed myocardial function.

Obesity promotes left ventricular concentric rather than eccentric geometric remodeling and hypertrophy independent of blood pressure.

BACKGROUND As it is uncertain whether excess adiposity promotes primarily concentric or eccentric left ventricular hypertrophy (LVH), we aimed to determine at a population level, the independent relationship between waist circumference (WC) and LV geometric changes and the potential hemodynamic mechanisms thereof. METHODS We assessed the relations between WC and LV end-diastolic diameter (EDD), LV mean wall thickness (MWT = posterior + septal wall thickness/2), LV relative wall thickness (RWT = MWT/EDD), LV mass index (LVMI), concentric LVH (LVMI > 51 g/m2.7 and RWT > 0.45), eccentric LVH (LVMI > 51 g/m2.7 and RWT < 0.45), or concentric LV remodeling (normal LVMI and RWT > 0.45), in 309 never treated for hypertension, randomly recruited adult participants with a high prevalence of excess adiposity ( approximately 25% overweight; 38% obese). Pulse-wave analysis was performed to determine central artery blood pressures (BPs). Two hundred and thirty-one participants had high-quality ambulatory BP monitoring. RESULTS Approximately 7% of participants had concentric LVH, approximately 16% concentric LV remodeling, and approximately 15% eccentric LVH. After adjustments for potential confounders including conventional systolic BP (SBP), WC was related to MWT (partial r = 0.23, P = 0.0001), RWT (partial r = 0.13, P = 0.03), concentric LVH (P < 0.04), concentric LV remodeling (P = 0.02), but not with EDD or eccentric LVH (P = 0.91). Similar outcomes were noted after adjustments for central or 24-h SBP, and for conventional, central, or 24-h pulse pressure. Separate analysis in normotensive subjects revealed similar outcomes. CONCLUSIONS In a population sample with a high prevalence of obesity, excess adiposity promotes concentric, rather than eccentric LV geometric changes, effects which are independent of conventional, central artery or 24-h BP measured on a single occasion.

Ethnic Differences in Arterial Wave Reflections and Normative Equations for Augmentation Index

Data regarding ethnic differences in wave reflections, which markedly affect the central pressure profile, are very limited. Furthermore, because age, heart rate, and body height are strong determinants of augmentation index, relating single measurements to normative data (in which augmentation index values correspond with average population values of its determinants) is challenging. We studied subject-level data from 10 550 adults enrolled in large population-based studies. In a healthy reference sample (n=3497), we assessed ethnic differences in augmentation index (ratio of second/first systolic peaks) and generated equations for adjusted z scores, allowing for a standardized comparison between individual augmentation index measurements and the normative population mean from subjects of the same age, sex, ethnic population, body height, and heart rate. After adjustment for age, body height, heart rate, and mean arterial pressure, African blacks (women: 154%; men: 138%) and Andean Hispanics (women: 152%; men: 133%) demonstrated higher central (aortic) augmentation index values than British whites (women: 140%; men: 128%), whereas American Indians (women: 133%; men: 122%) demonstrated lower augmentation index (all P<0.0001), without significant differences between Chinese and British whites. Similar results were found for radial augmentation index. Nonlinear ethnic/sex-specific equations for z scores were successfully generated to adjust individual augmentation index values for age, body height, and heart rate. Marked ethnic differences in augmentation index exist, which may contribute to ethnic differences in hypertensive organ damage. Our study provides normative data that can be used to complement the interpretation of individual hemodynamic assessments among men and women of various ethnic populations, after removing the effect of various physiological determinants.

Relationship Between Urinary Salt Excretion and Pulse Pressure and Central Aortic Hemodynamics Independent of Steady State Pressure in the General Population

Although central pulse pressure (PPc) is strongly related to central mean arterial pressure (MAPc), PPc predicts cardiovascular outcomes beyond MAPc. Whether modifiable risk factors for hypertension contribute to PPc and its determinants, independent of MAPc, is uncertain. In 635 randomly recruited participants, we assessed the independent relationship between 24-hour urinary sodium (Na+) or potassium (K+) excretion and brachial artery PP (in office or 24-hour; n=487), PPc, the forward (P1) and augmented (Paug) pressure wave components of PPc, central augmentation index, and determinants of central pressure waves, including aortic pulse wave velocity, effective reflecting distance, and reflective wave transit time. Central dynamics were determined using applanation tonometry of the carotid, femoral, and radial arteries. With adjustments for potential confounders, urinary Na+/K+ was independently associated with in-office, central, and 24-hour PP, as well as Paug, P1, and central augmentation index (P<0.05 to P<0.005). With further adjustments for MAPc (or diastolic BP), urinary Na+/K+ was independently associated with PPc, 24-hour PP, Paug, P1, and central augmentation index (P<0.05 to P=0.005) but not with in-office PP, pulse wave velocity, effective reflecting distance, or reflective wave transit time. In conclusion, in a population of African ancestry, urinary salt excretion is independently related to central and 24-hour PP independent of MAPc or diastolic BP, effects that are attributed to increases in both P1 and Paug but not to pulse wave velocity. Hence, modifying salt intake could influence cardiovascular risk through effects on 24-hour and central PPs, as well as P1 and Paug, independent of steady-state pressure (MAP or diastolic BP) or pulse wave velocity.

Nurse-recorded auscultatory blood pressure at a single visit predicts target organ changes as well as ambulatory blood pressure

Aim To determine whether high-quality nurse-recorded auscultatory blood pressure (BP) values obtained at a single visit predict cardiovascular target organ changes as closely as ambulatory BP measurements. Methods In a randomly selected population sample (n = 458, 21% receiving antihypertensive treatment; approximately 40% hypertensive), we compared high-quality single visit nurse-recorded auscultatory BP values to same-day 24-h ambulatory BP in their ability to predict multiple target organ changes [left ventricular mass index (LVMI), left ventricle (LV) mean wall thickness (MWT), early-to-late transmitral velocity ratios (E/A), (echocardiography); log of urinary albumin-to-creatinine ratios (log ACR) (24-h urine samples); large artery dysfunction [carotid-femoral pulse wave velocity (PWV) and central augmentation index (Alc) (applanation tonometry)]. Results Nurse-recorded systolic BP (SBP) measurements obtained at a single visit were as closely associated with LVMI (r = 0.44), LV MWT (r = 0.44), E/A (r = −0.55), log ACR (r = 0.20), PWV (r = 0.62) and AIc (r = 0.41) (P < 0.0001 for all relations) as was 24-h SBP (LVMI; r = 0.33, LV MWT; r = 0.37, E/A; r = −0.35, log ACR; r = 0.24, PWV; r = 0.41, and AIc; r = 0.18, P < 0.001 for all relations) and either day or night SBP. On multivariate regression analysis with both nurse-recorded SBP and 24-h SBP in the same model, nurse-recorded SBP was independently associated with LVMI (P = 0.006), LV MWT (P = 0.03), E/A (P < 0.02), PWV (P < 0.0001) and AIc (P = 0.0002), and 24-h SBP was independently and positively associated with log ACR (P < 0.005), and PWV (P = 0.01). Conclusion One or more, high-quality single visit nurse-recorded auscultatory BP measurements may be equally as effective as ambulatory BP in predicting target organ damage in a population sample of African ancestry.

Effects of pentoxifylline on cytokine profiles and left ventricular performance in patients with decompensated congestive heart failure secondary to idiopathic dilated cardiomyopathy.

Patients with severe heart failure have plasma cytokine concentrations that are more than twofold greater than those in patients with moderate heart failure. Although pentoxifylline, an immunomodulatory agent that inhibits tumour necrosis factor-alpha (TNF-alpha) production, improves pump function in mild-to-moderate heart failure, its effects on advanced heart failure have not been determined. In a prospective, randomized, double-blind, placebo-controlled study we compared the effects of 1-month therapy with pentoxifylline (400 mg 3 times daily) (n = 9) and placebo (n = 9) on left ventricular systolic function and dimensions as well as on plasma TNF-alpha (picograms per milliliter), interleukin-10 (IL-10), and the apoptosis-signaling receptor Fas/Apo-1 in patients with idiopathic dilated cardiomyopathy and advanced heart failure. All patients had New York Heart Association functional class IV heart failure, required intravenous inotropic agents for >72 hours at the beginning of the study, and received diuretics, digoxin, and an angiotensin-converting enzyme inhibitor for the duration of the study. Marked increases in TNF-alpha and Fas/Apo-1 concentrations were noted in the 18 patients compared with patients with functional class II to III heart failure and controls (p <0.001). Baseline characteristics were the same between the pentoxifylline and placebo groups. Pentoxifylline administration resulted in reduced TNF-alpha and Fas/Apo-1 concentrations, and an increase in ejection fraction at 1 month (p <0.05 compared with baseline and with placebo), effects that were not observed in the placebo-treated group. These data suggest that pentoxifylline may be a useful adjunct to conventional therapy in patients with severe heart failure.