Published online before print February 5, 2007, doi: 10.1161/CIRCULATIONAHA.106.638569
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2007;115:888-895.)
© 2007 American Heart Association, Inc.
Heart Failure |
Diastolic Heart Failure
Evidence of Increased Myocardial Collagen Turnover Linked to Diastolic Dysfunction
From the Heart Failure Unit (R.M., M.L., C.O., C.C., A.P., K.M.), St Vincent’s University Hospital, Dublin, Ireland, and School of Medicine & Medical Science, St Vincent’s University Hospital and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin (J.B., S.C.D.), Dublin, Ireland.
Correspondence to Dr Kenneth McDonald, Heart Failure Unit, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. E-mail kenneth.mcdonald{at}ucd.ie
Received May 16, 2005; accepted November 27, 2006.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Background— The pathophysiology of diastolic heart failure (DHF) is poorly understood. One potential explanation is an active fibrotic process that produces increased ventricular stiffness, which compromises filling. The present study investigates collagen metabolism in hypertensive patients in different phases of diastolic function with and without proven DHF.
Methods and Results— We studied 86 hypertensive patients divided into groups according to the presence of DHF (32 with, 54 without) and phase of diastolic function (20 with normal function, 38 with impaired relaxation, 10 with pseudonormalization, and 16 with restrictive-like filling). Serum carboxy-terminal, amino-terminal, and carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, matrix metalloproteinases (MMPs; total MMP-1, active MMP-2, and MMP-9), and tissue inhibitor of MMPs levels were assayed by radioimmunoassay and ELISA. Doppler-echocardiographic assessment of diastolic filling was made with measurements of E/A ratio, E-wave deceleration time, and isovolumic relaxation time. Serum carboxy-terminal telopeptide of procollagen type I, carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 levels (P<0.001 for all, controlled for age and gender) were greater in patients with DHF than in those without. When we controlled for age and gender, levels of serum carboxy-terminal telopeptide of procollagen type I, tissue inhibitor of MMP-1, amino-terminal propeptide of procollagen type III (all P<0.001), carboxy-terminal telopeptide of procollagen type I(P=0.008), and MMP-2 (P=0.03) were greater in more severe phases of diastolic dysfunction. Within phases of diastolic dysfunction, serum carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 were elevated in those with DHF compared with those without DHF (all P<0.001).
Conclusions— These data demonstrate serological evidence of an active fibrotic process in DHF, which is more marked in more severe diastolic dysfunction. This observation may help explain the pathophysiology of DHF and may suggest new avenues for diagnostic and therapeutic intervention.
Key Words: heart failure • diastole • hypertension • myocardium • metalloproteinases • collagen
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Diastolic heart failure (DHF) is an important contributor to the heart failure syndrome, with reported prevalence rates ranging from 20% to 50% of the total heart failure population in clinical practice.1,2 The central disturbance in DHF involves abnormalities in myocardial relaxation and ventricular compliance.3 Although still poorly understood, a Clinical Perspective p 895 growing body of data has laid the foundation for a better understanding of the pathophysiological mechanisms that underlie DHF.4–9 A primary cause of DHF is hypertensive heart disease (HHD),10 a syndrome characterized by structural and functional abnormalities of the heart as a result of the hypertensive process. Experimental5,6 and clinical7–9 data have demonstrated serological and morphometric evidence of increased myocardial fibrosis in HHD. These observations have been directly linked to abnormalities in diastolic function and myocardial stiffness.7 Furthermore, therapies that reduce the fibrosis content of ventricles have been shown to improve diastolic function.8,9 These observations support the hypothesis that a change in the extracellular matrix of the myocardium, characterized by the formation of excess collagen tissue, is a cause of worsening diastolic dysfunction (DD), eventually leading to DHF. Although there has been considerable work done on collagen turnover in HHD,8,9,11–14 there are no data linking the extent of abnormalities of collagen turnover to the severity of DD and DHF. Recently, important work by Ahmed et al15 has demonstrated an association between elevated levels of tissue inhibitor of matrix metalloproteinase (TIMP)-1 with DD. Moreover, this work identified higher levels in patients with DHF than in those without.
Clinical Perspective p 895
Myocardial interstitial collagen content, historically measured by endomyocardial biopsy, can now be assessed with serum analysis of breakdown products of collagen I and collagen III, the major myocardial collagens.11,16 Enzymes that control collagen turnover, specifically, matrix metalloproteinase (MMP) and TIMP, can also be measured with serum analysis.15,16 Using similar methods, the present study aims to investigate the relationship between serum markers of collagen turnover, the extent of DD, and DHF.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Subjects
All subjects gave written informed consent to participate in the study. The Ethics Committee at St Vincent’s University Hospital approved the study protocol, which conformed to the principles of the Helsinki Declaration. The study population consisted of 86 white hypertensive patients, referred from the cardiology service at St Vincent’s University Hospital and subdivided by previously defined criteria into those with normal diastolic function and the following phases of DD: impaired relaxation, pseudonormalization, and restrictive-like filling.17 Furthermore, the study population was categorized according to the presence (DHF group, n=32) or absence (No-DHF group, n=54) of DHF. The diagnosis of DHF was based on the presence of all of the following criteria: 1 hospitalization for proven New York Heart Association class IV heart failure (confirmed by a consultant cardiologist) with continued signs or symptoms of heart failure (at least New York Heart Association class II level) as defined by European Society of Cardiology guidelines,18 left ventricular ejection fraction >45% with Doppler abnormalities of DD, and no significant evidence of valvular disease.
Patients were excluded if they had established pulmonary disease or anemia, which may make the diagnosis of DHF more difficult. We also excluded patients with renal insufficiency (serum creatinine >130 mmol) and conditions known to alter collagen turnover, including chronic liver disease, connective tissue disorders, metabolic bone diseases, and malignancy, and those who underwent recent trauma or surgery (<6 months).
A prerequisite of the present study dictated that all patients were clinically stable for 1 month (as defined by freedom from hospitalization or change in medication) before enrolment. All patients had appropriate clinical and laboratory evaluation to identify exclusion criteria and suitability for the study.
Biochemical Measurements of Indices of Collagen Metabolism
Peripheral venous blood samples were drawn during clinical assessment and immediately underwent serum isolation. Each sample was centrifuged for 10 minutes at 4°C. The serum was then separated into aliquots and stored at –80°C before simultaneous analysis of collagen turnover markers as described below.
Amino-terminal propeptide of procollagen type I (PINP) and type III (PIIINP) and carboxy-terminal telopeptide of collagen type I (CITP) were measured by radioimmunoassay with commercial antiserum kits (Orion Diagnostica, Espoo, Finland). The intraassay variations for determining PINP, PIINP, and CITP were 7%, <5%, and <8% respectively. The sensitivity (lower detection limit) of the assays was 13 µg/L for PINP, 1.9 µg/L for PIIINP, and 0.5 µg/L for CITP, respectively. Carboxy-terminal propeptide of procollagen type I (PICP) was measured with a specific ELISA according to the manufacturer’s method (Takara Biochemicals Co, Osaka, Japan). The sensitivity for PICP was 2 ng/mL.
All plasma MMP and TIMP levels were measured with 2-site sandwich ELISAs (Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom) per the manufacturer’s protocol. The MMP-1 assay (RPN2610; sensitivity 1.7 ng/mL) detects both free MMP-1 and that complexed with inhibitors such as TIMP-1. The MMP-2 assay (RPN 2617; sensitivity 0.37 ng/mL) detects the proform of MMP-2 and that complexed with TIMP-2; the MMP-9 assay (RPN 2614; sensitivity 0.6 ng/mL) detects the proform of MMP-9 and that complexed with TIMP-1; the TIMP-1 assay (RPN 2611; sensitivity 1.25 ng/mL) detects both free TIMP-1 and that complexed with MMPs. Duplicate measurements were performed, and the intra-assay coefficients of variation were <10% for all assays. Plasma B-type natriuretic peptide (BNP) levels were also measured with the Biosite Triage BNP test (Biosite, San Diego, Calif) in all patients.
Echocardiography Study
Two-dimensional echocardiography imaging, targeted M-mode echocardiography, and Doppler ultrasound measurements were obtained. M-mode measurements were taken according to the guidelines laid down by the American Society of Echocardiography. All echocardiography data represent the mean of 3 measurements on different cardiac cycles. Left ventricular ejection fraction was calculated by the Teichholz method. All measurements were made by blinded observers, with archive images recorded in a blinded fashion. The following pulsed Doppler measurements were obtained in the apical view with a cursor at the mitral valve inflow: maximal early (E) and late (A) transmitral velocities in diastole and E-wave deceleration time. Isovolumic relaxation time was measured in the apical 4-chamber view by continuous-wave Doppler placed between the mitral inflow area and the left ventricular outflow tract. Left ventricular DD was defined by the presence of alterations in E/A ratio, isovolumic relaxation time, and deceleration time. Left ventricular diastolic filling patterns were classified as previously described by Lubien et al.17 None of the patients studied exhibited left ventricular systolic dysfunction, as assessed by an ejection fraction 
45%.
Statistical Analysis
Data are presented as the mean±SD for continuous variables, whereas frequencies and percentages (in parentheses) summarize categorical variables. Comparisons between No-DHF and DHF groups were conducted with independent sample t tests and ANCOVA for normally distributed continuous variables and Mann-Whitney U test and Kruskal-Wallis ANOVA for nonnormal distributions (
=0.05). We used 
2 analysis to compare categorical variables. Partial correlation coefficients, adjusted for age, were calculated to assess the relationship between echocardiographic Doppler parameters and biochemical markers. Variables with nonnormal distributions were log-transformed where appropriate. All statistical calculations were performed with SPSS software (version 11; Statistical Package for Social Sciences, Chicago, Ill, 2001).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Baseline Characteristics
The demographics of the study population are presented in Table 1. The DHF group was older (72±11 versus 67±9 years), with a larger number of females (47% versus 24%), and higher body mass index (29.8±6.1 versus 27.3±4.5 kg/m2) than the No-DHF group (P=0.03 for all). No differences were found in systolic or diastolic blood pressure between the groups. Pharmacotherapy was similar except for the anticipated higher use of loop diuretics (frusemide or bumetanide) in the DHF group. Patients with DHF had higher levels of blood urea (8.9±4.7 versus 6.1±1.6 mmol/L, P=0.002) and BNP (264.7±181.7 versus 101.8±129.7 pg/mL, P<0.001) than the No-DHF group. Table 1 also presents the demographics of the study population according to diastolic function. Two patients refused to complete echocardiography examination. As anticipated, more severe phases of DD were associated with older age and increased levels of BNP. The only significant medication difference noted was the anticipated higher use of loop diuretics in the restrictive-like filling group, in accordance with the higher prevalence of heart failure. Although not statistically significant, however, more patients with severe DD were prescribed angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy.
|
Markers of Collagen Turnover and DHF
PICP, CITP, PIIINP, MMP-2, and MMP-9 levels were greater in the DHF group than in the No-DHF group (P<0.001 for all; Figure 1), even when adjusted for the effects of age and gender. A trend toward higher levels of PINP in the DHF group (51.7±42.0 versus 42.0±22.1 µg/L, P=0.09) was also observed. There were no differences between the groups in measurements of MMP-1 (12.8±9.9 versus 10.4±6.7 ng/mL, P=0.42) or TIMP-1 levels (642.2±265.7 versus 562.4±157.2 ng/mL, P=0.30).
|
Relation Between Markers of Collagen Turnover and Phases of Diastolic Function
After adjustment for the effects of age and gender, patients in the restrictive-like filling group, most of whom had DHF, had shorter deceleration time and higher E/A ratios than those in the impaired relaxation and pseudonormal filling groups (P<0.001 for both; Table 2). No differences were found in isovolumic relaxation time between the groups (P=0.68).
|
The data demonstrate increases in PICP, CITP, PIIINP, MMP-2, and BNP across the phases of diastolic function. These differences remained significant when adjusted for age and gender effects. Although the numbers were small, it is also of interest that within similar phases of DD, several markers of collagen turnover (PICP, CITP, PIIINP, MMP-2, and MMP-9) were more elevated in the presence of heart failure (Table 3). There was a significant correlation (age-adjusted) observed between left atrial volume index and PICP (r=0.50, P<0.001; Figure 2), PINP (r=0.37, P=0.003), PIIINP (r=0.35, P=0.006), CITP (r=0.37, P=0.004), and MMP-2 (r=0.40, P=0.001; Figure 2).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
The results of the present study provide further information on collagen metabolism in patients with asymptomatic DD and DHF. Elevated levels of PICP and PIIINP and a trend toward an increase in PINP levels indicate increased collagen synthesis in DHF. In addition, elevated serum levels of CITP, MMP-2, and MMP-9 suggest increased degradation of myocardial collagen and other components of the extracellular matrix. Furthermore, greater collagen turnover is seen in more severe phases of DD, which suggests a direct relationship between DD and collagen excess. Finally, within a given phase of DD, several markers of collagen turnover are more elevated in the presence of heart failure.
It is generally accepted that the central problem of DHF is a stiff, noncompliant ventricle.3,19 The cause of this remains unknown, but earlier data from experimental and clinical studies in HHD,5,6,9,12,20–22 a frequent cause of DHF, provide some insight into this unresolved question. Studies using postmortem hearts20 or endomyocardial biopsy samples9,12,21,22 have demonstrated that myocardial interstitial fibrosis is one of the key pathological features of myocardial remodeling in HHD. These data have established the link between fibrillar collagen accumulation and tissue stiffness in HHD.
All of the above work was performed with tissue sampling, which presents an impediment to the clinical investigation of the fibrotic process in DD and heart failure. Recent work, however, has demonstrated that serum analysis of collagen-derived peptides and enzymes involved in their degradation provides a verified, noninvasive technique to measure this fibrotic process.9,11–16
With serum analysis, PICP has been one of the most widely studied procollagen markers.7,9,11–15 It is a breakdown product of fibrillar collagen type I, which accounts for 85% to 90% of myocardial collagen. A stoichiometric ratio of 1:1 exits between the numbers of collagen type I molecules produced and PICP released into blood stream and cleared by the liver.11,23 Type III collagen accounts for the majority of the remaining myocardial collagen. PIIINP is an extension peptide of procollagen type III, which is cleaved off during conversion from type III procollagen to type III collagen and then released into the blood stream. As with PICP, PIIINP is also eliminated from the blood by the liver. Although serum PIIINP has been proposed as a useful marker of fibrogenesis,1,24 this peptide is not completely removed from its procollagen precursor during the extracellular processing of collagen type III.24 In contrast, the removal of PICP is complete; hence, serum PICP may reflect fibrogenesis more accurately than serum PIIINP.
Other commonly assessed serum markers of myocardial collagen turnover include the metalloproteinase enzymes, their tissue inhibitors, and CITP, which is a breakdown product of type I collagen. Elevated levels of MMP-2, MMP-9, and TIMP-1 have been demonstrated in a population with HHD14,25,26 and in a population with hypertrophic obstructive cardiomyopathy.16
In a recent study examining a mixed heart failure population, Querejeta et al7 demonstrated a positive correlation between coronary sinus and peripheral serum levels of PICP in heart failure patients. Moreover, there was a significant increase in PICP levels when this heterogeneous heart failure population was compared with HHD patients. More recently, Ahmed et al15 have demonstrated elevated serum levels of TIMP-1 and MMP-9 in patients with left ventricular hypertrophy and DHF.
The specific pattern of activation of collagen markers noted in the present study consisted of a significant increase in PICP and PIIINP in patients with established DHF, supportive of the hypothesis that a predominant pathophysiological process in DHF is abnormal accumulation of fibrous tissue. This observation is consistent with the recent data of Lopez et al,27 who demonstrated a significant increase in total collagen volume fraction in patients with DHF. We also noted elevated levels of MMP-2 and MMP-9 in the DHF population, similar to previous studies on HHD.25,26 On one level, this observation of elevated levels of enzymes known to be responsible for breakdown of interstitial proteins may seem counterintuitive in the setting of increased fibrosis. Elevated levels of metalloproteinase-2 and -9, however, have been associated with profibrotic remodeling.28,29 Furthermore, MMP-2 and MMP-9 have elastase activity and are associated with increased arterial stiffness in hypertensive patients.26 Therefore, increases in MMP-2 and MMP-9 in the present work may reflect loss of elastin and other components of the myocardial extracellular matrix, contributing to stiffness, more severe DD, and ultimately, DHF. The observation of increased MMP-2 is counter to the data of Ahmed et al,15 in which no change in this MMP was noted. The explanation for this difference is unclear, although the populations were not entirely similar and, in particular, the definition of DHF in the present study was more stringent and would have directed enrollment to older and more severely ill patients. Another notable result from the present study in the comparison of DHF and No-DHF groups was the lack of change in the MMP-1/TIMP-1 ratio. This observation is again consistent with the data of Lopez and colleagues,27 who noted no change in this ratio in DHF and an increase only in the presence of systolic heart failure.
The present study also demonstrated a close relationship between the extent of DD and increasing levels of many of the markers of collagen turnover, which supports the concept that this interstitial disease is responsible for diastolic impairment. This association was further supported by the close correlation between several of these markers and left atrial volume index, a continuous variable linked to diastolic function.30 Lubien et al17 demonstrated a relationship between BNP and phase of DD, a finding again confirmed in the present data. In fact, the increasing levels of BNP with worsening diastolic function may reflect a response to myocardial fibrosis, because several experimental data indicate that BNP has antifibrotic properties.31,32 Finally, we noted that within the more significant phases of DD, markers of collagen turnover were more elevated in those patients with a history of DHF. This suggests that a more established fibrotic process might explain the development of heart failure in those patients. These data, however, require further analysis, because numbers in these subgroups were small.
Effective management of DHF has been impeded to date by a paucity of proven therapies, which possibly reflects a poor understanding of the pathogenesis of this syndrome. The growing evidence that points to a role for abnormal collagen accumulation provides a rationale for the examination of several potential therapeutic approaches in this syndrome. This includes therapies that alter the renin-angiotensin-aldosterone system, which have been shown in several clinical studies to modify the myocardial fibrotic process and improve diastolic function.8,9,33,34 Furthermore, it has been demonstrated that torsemide, a loop diuretic, reduces PICP levels and reverses collagen volume fraction in patients with chronic heart failure.35
In interpreting these data, certain limitations of the present study need to be taken into consideration. First, the present study relied on peripheral markers of collagen turnover without supportive endomyocardial biopsy data or coronary sinus sampling. Second, strict criteria were used to diagnose DHF, with all diagnoses confirmed at the time of presentation by a staff cardiologist. This was done to ensure that the heart failure population was truly representative of DHF syndrome, although in doing so, we clearly excluded those with less severe manifestations of this syndrome. Furthermore, it is also possible that some of the asymptomatic group had subtle symptoms of heart failure, especially those with more severe manifestations of DD. Third, although we included Doppler echocardiographic evidence of DD, we did not perform tissue Doppler, pulmonary venous flow measurements, or invasive confirmation of DD. Fourth, differences in medicines that can attenuate fibrosis across the groups may be a potential limitation to the interpretation of the results; however, because there was greater usage of these medicines in DHF and more severe DD, it may serve to emphasize the role of these markers. Finally, sample sizes were small, and groups were of unequal size when mean levels of collagen turnover markers were compared across the patterns of DD in those with and without DHF, which may result in type II error.
|
Conclusions |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
These original findings demonstrate the presence of increased collagen turnover in patients with established DHF and DD. Furthermore, the demonstrated association between extent of collagen turnover and degree of DD strengthens the link between these 2 observations and may explain the reduced ventricular compliance characteristic of these syndromes. Finally, these data may support the development of new diagnostic and therapeutic strategies in DHF and DD.
|
Acknowledgments |
|---|
Disclosures
None.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
1. Senni M, Redfield MM. Heart failure with preserved systolic function: a different natural history? J Am Coll Cardiol. 2001; 38: 1277–1282.
2. Mandinov L, Eberli FR, Seiler C, Hess OM. Diastolic heart failure. Cardiovasc Res. 2000; 45: 813–825.
3. Oh JK, Hatle L, Tajik AJ, Little WC. Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol. 2006; 47: 500–506.
4. Baicu CF, Zile MR, Aurigemma GP, Gaasch WH. Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation. 2005; 111: 2306–2312.
5. Diez J, Panizo A, Gil MJ, Monreal I, Hernandez M, Pardo MJ. Serum markers of collagen type I metabolism in spontaneously hypertensive rats: relation to myocardial fibrosis. Circulation. 1996; 93: 1026–1032.
6. Brilla CG, Matsubara L, Weber KT. Advanced hypertensive heart disease in spontaneously hypertensive rats: lisinopril-mediated regression of myocardial fibrosis. Hypertension. 1996; 28: 269–275.
7. Querejeta R, Lopez B, Gonzalez A, Sanchez E, Larman M, Martinez Ubago JL, Diez J. Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation. 2004; 110: 1263–1268.
8. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation. 2000; 102: 1388–1393.
9. Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation. 2002; 105: 2512–2517.
10. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol. 2004; 43: 317–327.
11. Lopez B, Gonzalez A, Varo N, Laviades C, Querejeta R, Diez J. Biochemical assessment of myocardial fibrosis in hypertensive heart disease. Hypertension. 38: 1222–1226.
12. Querejeta R, Varo N, Lopez B, Larman M, Artinano E, Etayo JC, Martinez Ubago JL, Gutierrez-Stampa M, Emparanza JI, Gil MJ, Monreal I, Mindan JP, Diez J. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation. 2000; 101: 1729–1735.
13. Alla F, Kearney-Schwartz A, Radauceanu A, Das DS, Dousset B, Zannad F. Early changes in serum markers of cardiac extra-cellular matrix turnover in patients with uncomplicated hypertension and type II diabetes. Eur J Heart Fail. 2006; 8: 147–153.
14. Lindsay MM, Maxwell P, Dunn FG. TIMP-1: a marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension. 2002; 40: 136–141.
15. Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, McClure CD, Spinale FG, Zile MR. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006; 113: 2089–2096.
16. Lombardi R, Betocchi S, Losi MA, Tocchetti CG, Aversa M, Miranda M, D’Alessandro G, Cacace A, Ciampi Q, Chiariello M. Myocardial collagen turnover in hypertrophic cardiomyopathy. Circulation. 2003; 108: 1455–1460.
17. Lubien E, DeMaria A, Krishnaswamy P, Clopton P, Koon J, Kazanegra R, Gardetto N, Wanner E, Maisel AS. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation. 2002; 105: 595–601.
18. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, Tavazzi L, Smiseth OA, Gavazzi A, Haverich A, Hoes A, Jaarsma T, Korewicki J, Levy S, Linde C, Lopez-Sendon JL, Nieminen MS, Pierard L, Remme WJ. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J. 2005; 26: 1115–1140.
19. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure: abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004; 350: 1953–1959.
20. Rossi MA. Pathologic fibrosis and connective tissue matrix in left ventricular hypertrophy due to chronic arterial hypertension in humans. J Hypertens. 1998; 16: 1031–1041.[CrossRef][Medline] [Order article via Infotrieve]
21. Schwartzkopff B, Brehm M, Mundhenke M, Strauer BE. Repair of coronary arterioles after treatment with perindopril in hypertensive heart disease. Hypertension. 2000; 36: 220–225.
22. Ciulla M, Paliotti R, Hess DB, Tjahja E, Campbell SE, Magrini F, Weber KT. Echocardiographic patterns of myocardial fibrosis in hypertensive patients: endomyocardial biopsy versus ultrasonic tissue characterization. J Am Soc Echocardiogr. 1997; 10: 657–664.[CrossRef][Medline] [Order article via Infotrieve]
23. Nimni ME. Fibrillar collagens: their biosynthesis, molecular structure, and mode of assembly. In: Zern M, Reid L, eds. Extracellular Matrix. New York, NY: Marcel Decker; 1993: 121–148.
24. Risteli L, Risteli J. Non-invasive methods for detection of organ fibrosis. In: Rojkind M, ed. Connective Tissue in Health and Disease. Boca Raton, Fla: CRC Press; 1990: 61–98.
25. DeRosa G, D’Angelo A, Ciccarelli L, Piccinni MN, Pricolo F, Salvadeo S, Montagna L, Gravina A, Ferrari I, Galli S, Paniga S, Tinelli C, Cicero AF. Matrix metalloproteinase-2, -9, and tissue inhibitor of metalloproteinase-1 in patients with hypertension. Endothelium. 2006; 13: 227–231.[CrossRef][Medline] [Order article via Infotrieve]
26. Yasmin, McEniery CM, Wallace S, Dakham Z, Pulsalkar P, Maki-Petaja K, Ashby MJ, Cockcroft JR, Wilkinson IB. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness [published correction appears in Arterioscler Thromb Vasc Biol. 2005;25:875]. Arterioscler Thromb Vasc Biol. 2005; 25: 372.
27. Lopez B, Gonzalez A, Querejeta R, Larman M, Diez J. Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol. 2006; 48: 89–96.
28. Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K, Kinugawa S, Tsutsui H. Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension. 2006; 47: 711–717.
29. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000; 14: 163–176.
30. Moller JE, Hillis GS, Oh JK, Seward JB, Reeder GS, Wright RS, Park SW, Bailey KR, Pellikka PA. Left atrial volume: a powerful predictor of survival after acute myocardial infarction. Circulation. 2003; 107: 2207–2212.
31. Ogawa Y, Tamura N, Chusho H, Nakao K. Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart. Can J Physiol Pharmacol. 2001; 79: 723–729.[CrossRef][Medline] [Order article via Infotrieve]
32. Ito T, Yoshimura M, Nakamura S, Nakayama M, Shimasaki Y, Harada E, Mizuno Y, Yamamuro M, Harada M, Saito Y, Nakao K, Kurihara H, Yasue H, Ogawa H. Inhibitory effect of natriuretic peptides on aldosterone synthase gene expression in cultured neonatal rat cardiocytes. Circulation. 2003; 107: 807–810.
33. Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004; 110: 558–565.
34. Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone Evaluation Study (RALES): RALES Investigators. Circulation. 2000; 102: 2700–2706.
35. Lopez B, Querejeta R, Gonzalez A, Sanchez E, Larman M, Diez J. Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure. J Am Coll Cardiol. 2004; 43: 2028–2035.
 |
|
 |
|
  G. J. Mak, M. T. Ledwidge, C. J. Watson, D. M. Phelan, I. R. Dawkins, N. F. Murphy, A. K. Patle, J. A. Baugh, and K. M. McDonald Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone. J. Am. Coll. Cardiol., October 27, 2009; 54(18): 1674 - 1682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xie, A. Garfinkel, J. N. Weiss, and Z. Qu Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H775 - H784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. T. Phan, K. Abozguia, G. Nallur Shivu, G. Mahadevan, I. Ahmed, L. Williams, G. Dwivedi, K. Patel, P. Steendijk, H. Ashrafian, et al. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J. Am. Coll. Cardiol., July 28, 2009; 54(5): 402 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Barasch, J. S. Gottdiener, G. Aurigemma, D. W. Kitzman, J. Han, W. J. Kop, and R. P. Tracy Association Between Elevated Fibrosis Markers and Heart Failure in the Elderly: The Cardiovascular Health Study Circ Heart Fail, July 1, 2009; 2(4): 303 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N Achong, S Wahi, and T H Marwick Evolution and outcome of diastolic dysfunction Heart, May 1, 2009; 95(10): 813 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Borbely, I. Falcao-Pires, L. van Heerebeek, N. Hamdani, I. Edes, C. Gavina, A. F. Leite-Moreira, J. G.F. Bronzwaer, Z. Papp, J. van der Velden, et al. Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium Circ. Res., March 27, 2009; 104(6): 780 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Gonzalez, B. Lopez, S. Ravassa, J. Beaumont, T. Arias, N. Hermida, A. Zudaire, and J. Diez Biochemical markers of myocardial remodelling in hypertensive heart disease Cardiovasc Res, February 15, 2009; 81(3): 509 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Donal, L. H. Lund, C. Linde, M. Edner, S. Lafitte, H. Persson, F. Bauer, J. Ohrvik, P.-V. Ennezat, C. Hage, et al. Rationale and design of the Karolinska-Rennes (KaRen) prospective study of dyssynchrony in heart failure with preserved ejection fraction Eur J Heart Fail, February 1, 2009; 11(2): 198 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Martos, J. Baugh, M. Ledwidge, C. O'Loughlin, N. F. Murphy, C. Conlon, A. Patle, S. C. Donnelly, and K. McDonald Diagnosis of heart failure with preserved ejection fraction: improved accuracy with the use of markers of collagen turnover Eur J Heart Fail, February 1, 2009; 11(2): 191 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Kellogg, K. Converso, T. Wiggin, M. Stevens, and R. Pop-Busui Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H453 - H461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rudolph, H. Abdel-Aty, S. Bohl, P. Boye, A. Zagrosek, R. Dietz, and J. Schulz-Menger Noninvasive detection of fibrosis applying contrast-enhanced cardiac magnetic resonance in different forms of left ventricular hypertrophy relation to remodeling. J. Am. Coll. Cardiol., January 20, 2009; 53(3): 284 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Bradshaw, C. F. Baicu, T. J. Rentz, A. O. Van Laer, J. Boggs, J. M. Lacy, and M. R. Zile Pressure Overload-Induced Alterations in Fibrillar Collagen Content and Myocardial Diastolic Function: Role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in Post-Synthetic Procollagen Processing Circulation, January 20, 2009; 119(2): 269 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-G. Shyu Serotonin 5-HT2B Receptor in Cardiac Fibroblast Contributes to Cardiac Hypertrophy: A New Therapeutic Target for Heart Failure? Circ. Res., January 2, 2009; 104(1): 1 - 3. [Full Text] [PDF]
|
|
|
|
 |
|
 J. McMurray, M. Petrie, K. Swedberg, M. Komajda, S. Anker, and R. Gardner CHAPTER 23 Heart Failure ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Iles, H. Pfluger, A. Phrommintikul, J. Cherayath, P. Aksit, S. N. Gupta, D. M. Kaye, and A. J. Taylor Evaluation of Diffuse Myocardial Fibrosis in Heart Failure With Cardiac Magnetic Resonance Contrast-Enhanced T1 Mapping J. Am. Coll. Cardiol., November 4, 2008; 52(19): 1574 - 1580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Frantz, S. Stork, K. Michels, M. Eigenthaler, G. Ertl, J. Bauersachs, and C.E. Angermann Tissue inhibitor of metalloproteinases levels in patients with chronic heart failure: An independent predictor of mortality Eur J Heart Fail, April 1, 2008; 10(4): 388 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rohrbach, A. Martin, B. Niemann, and A. Cherubini Enhanced myocardial vitamin C accumulation in left ventricular hypertrophy in rats is not attenuated with transition to heart failure Eur J Heart Fail, March 1, 2008; 10(3): 226 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Lester, A. J. Tajik, R. A. Nishimura, J. K. Oh, B. K. Khandheria, and J. B. Seward Unlocking the Mysteries of Diastolic Function Deciphering the Rosetta Stone 10 Years Later. J. Am. Coll. Cardiol., February 19, 2008; 51(7): 679 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. LaCroix, J. Freeling, A. Giles, J. Wess, and Y.-F. Li Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H810 - H820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.H. W. Tang and G. S. Francis The Year in Heart Failure J. Am. Coll. Cardiol., December 11, 2007; 50(24): 2344 - 2351. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||