Diffuse Myocardial Fibrosis Is Associated With Diastolic Dysfunction in HF with Preserved EF

Cardiology Review® Online, December 2014, Volume 30, Issue 6

Is degree of diffuse myocardial fibrosis associated with severity of diastolic dysfunction in heart failure with preserved ejection fraction?

Mushabbar A. Syed, MD

Review

Su MYM, Lin LY, Tseng YHE, et al. CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF. J Am Coll Cardiol Img. 2014;7:991-997.

Heart failure (HF) is generally categorized as either HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). Despite similar clinical presentations, the 2 conditions are distinctly different in their pathophysiology and treatment. The hallmark of HFpEF is the presence of left ventricular (LV) diastolic dysfunction, to which several experimental studies have shown an association with myocardial fibrosis. This study by Su and colleagues examined whether the degree of diffuse myocardial fibrosis, as shown by cardiac magnetic resonance imaging (CMR), is associated with severity of diastolic dysfunction in patients with HFpEF.

Study Details

Inclusion criteria for study enrollment were symptoms of HF (NYHA class II to III) or symptoms/signs of HF persisting for more than 3 months. Subjects were excluded if they had known significant valvular heart disease, chronic atrial fibrillation, chronic pulmonary disease, positive stress test or unrevascularized significant (70%) coronary stenosis, or an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2. Of 106 patients who met the study’s enrollment criteria, 66 with EF greater than 45% and LV diastolic dysfunction confirmed by tissue Doppler echocardiography (defined as the mean of septal and lateral mitral annular early diastolic velocity <8 cm/s) were assigned to the HFpEF group and 40 with EF less than 45% were assigned to the HFrEF group. Another 22 subjects without current or previous HF were enrolled as the non-HF group.

CMR was performed on a 3-T system with cine imaging, pre- and post gadolinium myocardial T1 mapping, and late gadolinium enhancement. Severity of diffuse myocardial fibrosis was quantified by analysis of extracellular volume fraction (ECV) from T1 maps. Late gadolinium enhancement was used to identify focal fibrosis or scarring; cine images were used to quantify LV volumes, EF, and mass; and rate of change of LV volume (dV/dt) was used to determine systolic and diastolic functional indexes by peak ejection rate (PER) and peak filling rate (PFR), respectively. Four patients in the HFpEF group could not undergo CMR because of severe arrhythmia and were excluded from image analysis.

There were few differences among the study groups with respect to demographics: in the HFrEF group, there were more men and a higher number of patients with prior myocardial infarction, whereas in the group with HFpEF there were more patients with hypertension and coronary artery disease (CAD). There were no differences in age and other risk factors among the groups.

The myocardial ECV was significantly higher in patients with HFrEF than in those with HFpEF (31.2% vs 28.9%; P = .001) and in the non-HF group (31.2% vs 27.9%; P <.0001). Patients with HFpEF also had a higher ECV than those in the non-HF group (28.9% vs 27.9%; P = .006). There were no significant differences between the groups for precontrast T1 time; however, post contrast T1 time was significantly shorter in the HFrEF group compared with the HFpEF and non-HF groups. Patients with HFpEF also had significantly shorter postcontrast T1 time than the non-HF group (613 ms vs 649 ms; P = .016). There were no significant differences in myocardial ECV, precontrast T1, and postcontrast T1 between patients with and without CAD in both HF groups.

LV functional indexes, including LV volumes, EF, mass, PER, and PFR were all significantly different in the HFrEF group compared with the HFpEF and non-HF groups. Patients with HFrEF had dilated LV with eccentric remodeling. Conversely, patients with HFpEF showed concentric remodeling. Comparison of HFpEF and non-HF groups showed that only PFR was significantly lower (P <.001) in the HFpEF group.

In a correlation analysis between myocardial ECV and the LV functional index for each group, the myocardial ECV was significantly correlated with LV volumes, EF, mass, PER, and PFR. However, there was no significant correlation between myocardial ECV and LV functional indexes in the HFrEF group.

In conclusion, diffuse myocardial fibrosis,as measured by ECV, was increased in patients with HFand more severe in patients with HFrEF; however, an association of myocardial fibrosis with ventricular functional indexes was present only in HFpEF. These data support the study hypothesis that diffuse myocardial fibrosis is a key factor in pathophysiology of HFpEF leading to diastolic dysfunction.

CommentaryHFpEF: Is there more than meets the eye?

HF is a clinical diagnosis that requires further characterization for therapeutic and prognostic decision making. Although EF is preserved in HFpEF compared with HFrEF, the mortality and morbidity is not significantly different between the 2 conditions.1 Established HF treatments that have been shown to decrease morbidity and mortality in HFrEF have not shown the same treatment effect in HFpEF. In clinical practice, the presence of HF with relatively preserved EF and an absence of significant valvular abnormalities is generally considered HFpEF; however, the hallmark of HFpEF is the presence of diastolic dysfunction. Studies have differed in their definition of preserved EF (>35%, >40%, >45%, or >50%).

The present study by Su et al used EF greater than 45% as their cutoff value for HFpEF. This heterogeneity in cutoff points adds to the challenges of data interpretation. For example, patients with EF of 35% to 50% in these reports may, in fact, belong to the HFrEF group rather than HFpEF. Most authors believe that HFpEF should be diagnosed only when EF is greater than 50%, along with the presence of diastolic dysfunction and symptoms and signs of HF. HFpEF generally implies diastolic heart failure, although the presence of valvular heart disease may also cause HFpEF. Most patients with HFpEF have hypertensive heart disease, although the presence of coronary artery disease, infiltrative myocardial diseases, diabetes mellitus, advanced age, and obesity also contribute to diastolic HF.

Cardiac structural and functional abnormalities associated with HFpEF have been described with the use of noninvasive imaging, and include normal LV end-diastolic volume, left ventricular hypertrophy, or concentric remodeling (elevated relative wall thickness). Experimental studies have more recently focused on changes at the microscopic level in cardiomyocytes and extracellular matrix. Two studies using endomyocardial biopsy specimens from patients with HFpEF found increased cardiomyocyte diameter and stiffness, as well as evidence of extracellular matrix remodeling with elevated collagen volume fraction compared with the control group and patients who were similar to HFrEF patients.2,3 There is also biomarker evidence of an active fibrotic process in HFpEF, which correlates with the severity of diastolic dysfunction.4

The CMR technique of late gadolinium enhancement has been shown to accurately detect localized fibrosis in the heart. The 2 commonly observed forms of localized fibrosis include myocardial infarction (includes the subendocardium) and replacement fibrosis, seen in nonischemic dilated cardiomyopathy or hypertrophic cardiomyopathy (spares the subendocardium and involves midwall or subepicardial regions).5 More recent technical developments have led to increasing interest in characterizing the myocardial interstitial space in diffuse myocardial diseases. The 2 quantitative CMR techniques developed for this purpose are6:

  • Native (noncontrast) T1 can detect myocardial edema, inflammation, diffuse fibrosis, and deposition of protein, lipids, or iron. The disease processes with these pathophysiologies include acute coronary syndrome, acute myocardial infarction, myocarditis, diffuse fibrosis, cardiac amyloid (all with high T1), Anderson-Fabry disease (low T1), and siderosis (low T1). No gadolinium contrast is required for this technique.
  • ECV fraction with the use of gadolinium contrast agent is the extracellular volume of the myocardium that is not taken up by cells and is a direct measurement of the size of extracellular space, reflecting interstitial disease. In the absence of amyloid or edema, the expansion of interstitial space is largely due to collagen volume fraction. ECV has robust histological validation of its correlation with collagen volume fraction.7,8 Therefore, ECV has been termed the CMR biomarker of fibrosis. Diffuse myocardial fibrosis is associated with a number of conditions and may represent a final common pathway of diastolic dysfunction from a variety of disease processes.

CMR is increasingly used in the assessment of HF and cardiomyopathies for accurate quantitation of ventricular volume, EF, and identification of scar/fibrosis. Presence of scarring/fibrosis in ischemic and nonischemic cardiomyopathies has both diagnostic and prognostic value. However, as described above, the established technique of late gadolinium enhancement can only detect regional fibrosis and is not suitable for the detection of diffuse myocardial fibrosis. Mascherbauer et al studied 100 patients with suspected HFpEF, 61 of whom had a confirmed diagnosis.9 All patients underwent postcontrast T1 mapping and invasive hemodynamics. Over a mean follow-up of 22.9 ± 5.0 months, 16 outcome events (3 cardiovascular deaths, 13 HF hospitalizations) occurred in confirmed HFpEF patients; none occurred in nonconfirmed patients. Postcontrast T1 time, left atrial area, and pulmonary vascular resistance were significantly associated with outcome events. Patients with T1 times below the median were at a greater risk of cardiac events than the rest of the group, suggesting its role as a possible prognostic biomarker of HFpEF.

The physiological link between diffuse myocardial fibrosis ,as assessed by postcontrast T1 mapping and invasively determined index of LV diastolic stiffness, was recently studied in 20 cardiac transplant recipients.10 All patients underwent CMR postcontrast T1 mapping, echocardiography, and invasive measurement of LV pressure-volume measurements. Postcontrast T1 time significantly correlated with the passive ventricular stiffness constant, suggesting that abnormal passive ventricular stiffness is likely the major contributor to diastolic dysfunction from diffuse myocardial fibrosis.

The current study by Su et al adds to our knowledge of the critical role played by diffuse myocardial fibrosis in the pathogenesis of HFpEF. This understanding can potentially open up new avenues of research in diagnostics and therapeutics of this disease entity for which there are currently no evidence-based therapies available. It is unclear at this time whether diffuse myocardial fibrosis can be detected at an early disease stage before development of HF symptoms. Additionally, the CMR methodology of T1 mapping and ECV quantitation continues to evolve. There are numerous variations of these methods with different accuracies and precision. However, none of these methods is currently available for clinical use on a commercial MRI scanner. Further advances are needed to develop a robust and well-validated methodology for routine clinical application.

References

Own TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251-259.

Borbély A, van der Velden J, Papp Z, et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005;111:774-781.

van Heerebeek L, Borbély A, Niessen HW, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113:1966.

Martos R, Baugh J, Ledwidge M, et al. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation. 2007;115(7):888-895.

Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular magnetic resonance, fibrosis and prognosis in dilated cardiomyopathy. J Am Coll Cardiol. 2006;48:1977-1985.

Moon JC, Messroghli DR, Kellman P, et al. Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement. J Cardiovasc Magnetic Resonance. 2013;15:92.

Flett AS, Hayward MP, Ashworth MT et al. Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation. 2010;122:138-144.

Miller CA, Naish J, Bishop P, et al. Comprehensive validation of cardiovascular magnetic resonance techniques for the assessment of myocardial extracellular volume. Cir Cardiovasc Imaging. 2013;6:373-383.

Mascherbauer J, Mazluf BA, Tufaro C, et al. Cardiac magnetic resonance postcontrast T1 time is associated with outcome in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging. 2013;6:1056-1065.

Ellims AH, Shaw JA, Stub D, et al. Diffuse myocardial fibrosis evaluated by post-contrast T1 mapping correlates with left ventricular stiffness. J Am Coll Cardiol. 2014;63:1112-1128.

About the Author

Mushabbar A. Syed, MD, FACC, is director of cardiovascular imaging and Rolf and Merian Gunner Professor of Medicine (Cardiology), Radiology and Cell & Molecular Physiology at Loyola University of Chicago’s Stritch School of Medicine. He received his MD from King Edward Medical College, Lahore, Pakistan, and completed residencies in Pakistan, Great Britain, and at Henry Ford Hospital in Detroit, Michigan, where he also completed fellowships in cardiology and echocardiography. He also completed a fellowship in cardiovascular MRI at the National Institutes of Health. His areas of interest include cardiovascular imaging, structural heart disease, and coronary artery disease.