Diastolic Heart Failure Group Research Articles

Abstract 672: Long-Term Inhibition of Rho-kinase Ameliorates Diastolic Heart Failure in Hypertensive Rats

Background: Diastolic heart failure (DHF) is a major cardiovascular disorder with poor prognosis; however, its molecular mechanism remains to be fully elucidated. We have previously demonstrated that activation of Rho-kinase pathway is substantially involved in the pathogenesis of oxidative stress and cardiac remodeling. In this study, we thus examined whether Rho-kinase pathway is also involved in the pathogenesis of DHF. Methods: We maintained male Dahl salt-sensitive rats for 10 weeks, starting from 7 weeks of age, with either 0.5% NaCl (control) or 8% NaCl (DHF) with or without oral treatment with fasudil, a selective Rho-kinase inhibitor (30 and 100 mg/kg/day) (n=13–31). We serially measured hemodynamic variables and cardiac function by echocardiography, followed by histological analysis. Results: At week 17, the untreated DHF group exhibited overt heart failure (e.g. lung edema) associated with diastolic dysfunction but with preserved systolic function, characterized by increased myocardial stiffness, cardiomyocyte hypertrophy, and enhanced cardiac fibrosis and superoxide production (all P<0.01 vs. control). By contrast, in the fasudil-treated group, those myocardial changes associated with DHF were significantly and dose-dependently ameliorated, independent of the changes in blood pressure, with a resultant inhibition of the transition to decompensated heart failure. Western blot analysis showed that cardiac Rho-kinase activity, as evaluated by the extent of phosphorylation of ERM, a downstream substrate of Rho-kinase, was significantly increased in the untreated DHF group and was dose-dependently inhibited in the fasudil-treated group. Importantly, there was a highly significant correlation between the extent of myocardial stiffness and that of cardiac Rho-kinase activity (R=0.74 for the posterior wall and R=0.63 for the septum, both P<0.001). Cardiac Rho-kinase activity also significantly correlated with cardiac superoxide production. Conclusions: These results indicate that activation of Rho-kinase pathway plays an important role in the pathogenesis of DHF through cardiomyocyte hypertrophy and interstitial fibrosis, suggesting the therapeutic importance of Rho-kinase for the treatment of DHF in humans.

Coexistence and exercise exacerbation of intraleft ventricular contractile dyssynchrony in hypertensive patients with diastolic heart failure

Patients with heart failure (HF) and a normal left ventricular ejection fraction usually present with diastolic dysfunction (DD). Whether intraleft ventricular contractile dyssynchrony (IVCD) coexists with DD and contributes to the clinical manifestations of HF remains unclear. The study investigated the IVCD at rest and after exercise in hypertensive patients with diastolic HF (DHF). Echocardiography was performed in 60 hypertensive patients with narrow QRS, left ventricular ejection fraction > or = 50%, and no active ischemia. Patients were grouped as having DD (mitral E/A < 1 plus E deceleration time > 200 milliseconds, or mitral annular early diastolic velocity < 8 cm/s; n = 26), DD plus HF symptoms/signs (DHF, n = 13), or as non-DD (n = 21). At rest, the IVCD index (SD of 12 left ventricular segmental electromechanical delays) was greater in the DHF and DD groups than that in the non-DD group (52.2 +/- 10.7 and 39.1 +/- 23.6 vs 23.1 +/- 19.9 milliseconds; P < .05 for both comparisons). Six-minute treadmill exercise induced exacerbation of dyssynchrony in the DHF group (67.0 +/- 12.9 vs 52.2 +/- 10.7 milliseconds; P < .001). Multivariate analysis revealed that the combination of IVCD index > or = 35 milliseconds at rest and > or = 50 milliseconds after exercise was independently associated with DHF (odds ratio = 20, 95% CI = 2-199, P = .009). Postexercise IVCD index correlated positively with plasma N-terminal pro-brain natriuretic peptide (r = 0.37, P = .004). Exercise would aggravate intraventricular dyssynchrony in hypertensive patients with DHF, implicating a potential contribution of systolic dyssynchrony to clinical manifestations.

BISOPROLOL INHIBITS SODIUM CURRENT IN VENTRICULAR MYOCYTES OF RATS WITH DIASTOLIC HEART FAILURE

1. Changes in sodium currents (I(Na)) in heart failure contribute to cardiac electrophysiological alterations and, thereby, to ventricular arrhythmias. Bisoprolol has anti-arrhythmic effects, but its direct effect on I(Na) in cardiac cells remains unclear. Accordingly, in the present study we investigated the effects of bisoprolol on ventricular I(Na) in diastolic heart failure (DHF) and normal rats. 2. The DHF model was produced by abdominal aortic coarctation for 4 weeks and single ventricular myocytes were isolated by enzymatic dissociation. The electrophysiological actions of bisoprolol on I(Na) currents were investigated using a whole-cell patch-clamp technique. 3. The membrane capacitance of rats in the DHF group was significantly greater than that of the control group and the current-voltage curve was simultaneously shifted downward. Bisoprolol concentration-dependently decreased I(Na) in ventricular myocytes of both groups (at -45 mV), with IC(50) values of 19.53 +/- 0.06 and 40.78 +/- 0.03 micromol/L in the control and DHF groups, respectively. 4. In both groups, the current-voltage curves were shifted upwards, whereas activation potentials, peak currents and reversal potentials showed no significant changes. At -45 mV, the descent ratio of current densities in the DHF group was lower than that of the control group. In both groups, inactivation curves were shifted to more negative potentials, but activation curves and recovery curves were not altered. Changes in the half-inactivation voltage, V(0.5), and the slope of the inactivation curve, S, were similar for both groups. 5. In conclusion, bisoprolol concentration-dependently decreases I(Na) in ventricular myocytes of DHF and normal rats, which could be responsible, at least in part, for its anti-arrhythmic effects.

Diastolic and Systolic Asynchrony in Patients With Diastolic Heart Failure: A Common But Ignored Condition

The present study aimed to examine whether diastolic and systolic asynchrony exist in diastolic heart failure (DHF) and their prevalence and relationship to systolic heart failure (SHF) patients. Few data exist on mechanical asynchrony in DHF. Tissue Doppler echocardiography was performed in 373 heart failure patients (281 with SHF and 92 with DHF) and 100 normal subjects. Diastolic and systolic asynchrony was determined by measuring the standard deviation of time to peak myocardial systolic (Ts-SD) and peak early diastolic (Te-SD) velocity using a 6-basal, 6-mid-segmental model, respectively. Both heart failure groups had prolonged Te-SD (DHF vs. SHF vs. controls subjects: 32.2 ± 18.0 ms vs. 38.0 ± 25.2 ms vs. 19.5 ± 7.1 ms) and Ts-SD (31.8 ± 17.0 ms vs. 36.7 ± 15.2 ms vs. 17.6 ± 7.9 ms) compared with the control group (all p < 0.001 vs. control subjects). Based on normal values, the DHF group had comparable diastolic (35.9% vs. 43.1%; chi-square = 1.48, p = NS), but less systolic asynchrony than the SHF group (39.1% vs. 56.9%; chi-square = 8.82, p = 0.003). Normal synchrony, isolated systolic, isolated diastolic, and combined asynchrony were observed in 39.1%, 25.0%, 21.7%, and 14.1% of DHF patients, respectively, and these were 25.6%, 31.3%, 17.4%, and 25.6%, correspondingly, in SHF (chi-square = 10.01, p = 0.019). The correlation between systolic and diastolic asynchrony, and between the myocardial velocities and corresponding mechanical asynchrony appeared weak. A wide QRS duration (>120 ms) was rare in DHF (10.9% vs. 37.7% in SHF) (chi-square = 16.69, p < 0.001). Diastolic and/or systolic asynchrony was common in 61% of DHF patients despite narrow QRS complex. The presence of asynchrony was not related to myocardial systolic or diastolic function. Systolic and diastolic asynchrony were not tightly coupled, implying distinct mechanisms.

The Relationship of a 6-min Walk to V̇O2peak and VT in Older Heart Failure Patients

To evaluate the relationship between a 6-min walk test (6-MWT) to peak oxygen consumption (VO(2 peak)) and ventilatory threshold (VT) in older heart failure (HF) patients, to validate the equation by Cahalin et al., and to develop a new equation to improve the prediction of VO(2 peak) from 6-MWT. Older patients (>65 yr) with systolic or diastolic HF (N=97) performed an exercise test to peak exertion on an upright bicycle ergometer using an incremental protocol. Gas exchange measures were collected along with continuous electrocardiograph monitoring. 6-MWT was performed on an indoor track at a self-selected pace under standardized conditions. The formula of Cahalin et al. was used to predict VO(2 peak) from 6-MWT, and a new equation was generated from the measured VO(2 peak)-6-MWT relationship from this investigation. The correlation between 6-MWT and measured VO(2 peak) was moderate (r=0.54) with a standard error of estimate (SEE) of 2.48 mL.kg.min. The correlation between 6-MWT and VT was weak (r=0.23), whereas the correlation between VO(2 peak) and VT was strong (r=0.74). Correlations between the measured and predicted VO(2 peak) values were moderate (r=0.54) for both prediction equations, and the SEE was 2.83 versus 1.34 mL.kg.min for the Cahalin et al. and the new equation, respectively. These results indicate that 6-MWT does not accurately predict functional capacity in older HF patients, and questions the validity of using this test to determine functional capacity in older HF patients. Predicting VO(2 peak) from equations using 6-MWT also results in substantial variability and, consequently, should not be used in older HF patients where an accurate determination of functional capacity is essential.

Role of B-type Natriuretic Peptide in Diagnosis and Follow-up of Diastolic Heart Failure

Background and Objectives:Although Doppler echocardiography has been used to identify left ventricular (LV) diastolic dysfunction, its limitations suggest there is a need for new biomarkers to measure the diastolic dysfunction. Because the B-type natriuretic peptide (BNP) levels correlate with the LV diastolic pressure, we hypothesized that the BNP would be useful for diagnosing and monitoring the patients with diastolic heart failure. Subjects and Methods:We prospectively studied a total of 69 consecutive patients (mean age: 68±12 yrs, 31 men and 38 women) who presented to the emergency room with suspected dyspnea of a cardiac origin from November 2003 to May 2004. BNP sampling and Doppler echocardiography were performed for all the study patients. We diagnosed the systolic heart failure (SHF) and diastolic heart failure (DHF) on the conditions that both the clinical and echocardiographic criteria for systolic and diastolic dysfunction were fulfilled. From June 2004 to May 2005, we also performed clinical examinations, measurement of the tissue Doppler derived E/E’ and the BNP level at baseline and at 1 year after pharmacologic treatment for 42 consecutive patients who were diagnosed with DHF in the ER and the outpatient clinic. Results:We diagnosed SHF in 37 patients, DHF in 19 patients and we excluded HF in 13 patients (the control group). The mean BNP levels of the SHF and DHF groups were 716±532 pg/mL and 390±446 pg/mL, respectively, and these values were significantly higher than that of the control group (13±14 pg/mL, p<0.01). The area under the receiver-operating characteristic (ROC) curve for BNP to diagnose DHF was 0.94 (95% CI: 0.86 to 1.02, p<0.001). We also compared the BNP levels with the E/E’ in terms of the changes of the functional status for the 42 patients suffering with DHF. After treatment, the blood pressure (BP) was significantly decreased from 162±26/91±15 to 141±16/80±12 mmHg (p<0.001), the New York Heart Association (NYHA) functional class was decreased from 2.3±0.7 to 1.7±0.6 (p<0.001), and the E/E’ was decreased from 15.9±5.7 to 13.8±5.1 (p<0.01), but there were no significant changes of the BNP levels, from 213±404 to 208±464 pg/mL, following treatment. Conclusion:A BNP assay is clinically useful for diagnosing DHF, and a cut-off value of BNP can be suggested for screening DHF. However, the tissue doppler derived E/E’ is the better index for monitoring changes in the functional status of DHF patients than is the BNP level. (Korean Circulation J 2006;36:359-365)

Cardiopulmonary Exercise Testing in the Clinical and Prognostic Assessment of Diastolic Heart Failure

This study sought to define the relative prognostic value of cardiopulmonary exercise testing (CPET) variables in heart failure (HF) patients with preserved versus reduced systolic function. Cardiopulmonary exercise testing has an established role in the assessment of patients with systolic heart failure (SHF). Two variables, peak Vo2 and, more recently, the VE/VCO2 slope, have been shown to be extremely valuable in risk stratification. However, data are lacking in terms of the prognostic value of CPET in patients with diastolic heart failure (DHF). A total of 409 HF patients underwent CPET. Patients were divided into three groups according to the following left ventricular ejection fraction (LVEF) cutoffs: > or =40%, > or =45%, and > or =50%. The CPET response and the ability of peak VO2 and the VE/VCO2 slope to predict total mortality and hospitalization were examined. At univariate Cox regression analysis, both the peak VO2 and the VE/VCO2 slope were significant predictors in SHF and DHF. Multivariate analysis documented a similar prognostic power of VE/VCO2 slope and peak VO2 in all SHF groups. Conversely, in DHF patients, VE/VCO2 slope outnumbered peak VO2, remaining the only predictor regardless of LVEF. In DHF, the area under the receiver operating characteristic curve for the VE/VCO2slope identified a cutoff of 32.6 (74% sensitivity, 52% specificity), 33.1 (76% sensitivity, 62% specificity), and 33.3 (97% sensitivity, 40% specificity) for an LVEF cutoff of > or =40%, > or =45%, and > or =50%, respectively. These results extend the clinical and prognostic applicability of CPET to DHF. An impairment in exercise ventilation rather than peak VO2 holds clinical and prognostic impact in this increasing subset of patients.

Elevation of plasma brain natriuretic peptide is a hallmark of diastolic heart failure independent of ventricular hypertrophy

ObjectivesWe tested a hypothesis that elevation of the plasma level of brain natriuretic peptide (BNP) is one of the characteristics of patients with diastolic heart failure (DHF) independent of left ventricular (LV) hypertrophy. BackgroundThe clinical characteristics of DHF are not well acknowledged, although DHF has become a great social burden. Such a lack of clinical information leads to inaccuracy in the diagnosis of DHF. We have demonstrated enhancement of ventricular production of BNP with progression of maladaptive ventricular hypertrophy, but not with development of compensatory hypertrophy in an animal DHF model. MethodsOf 372 patients who presented to the emergency department because of acute pulmonary congestion without acute coronary syndrome between January 1996 and May 2002, those with an ejection fraction ≥45% upon admission, who were stably controlled at least for a year in our outpatient clinics, comprised the DHF group (n = 19). A control group consisted of 22 hypertensive patients with a LV mass index greater than or equal to its minimum value of the DHF group and an ejection fraction ≥45%, in whom cardiac symptoms had not occurred. ResultsDespite a similar distribution of LV mass index, the BNP level was higher in the DHF group than in the control group (149 ± 38 vs. 31 ± 5 pg/ml, p < 0.01). There was no difference in LV cavity size or parameters derived from pulsed Doppler transmitral flow velocity curves. ConclusionsAn elevation of BNP may be a hallmark of patients with or at risk of DHF among subjects with preserved systolic function independent of LV hypertrophy.

Differentiation of Systolic and Diastolic Heart Failure using Strain and Strain Rate Echocardiography

Background and Objectives:Diastolic heart failure (DHF) is defined as clinical evidences of heart failure, with a normal ejection fraction (EF) and abnormal diastolic function. However, the distinction between DHF and SHF is often difficult. Strain (S) and strain rate (SR) echocardiography can measure the regional myocardial function as a magnitude and rate of deformation. The hypothesis“myocardial velocity (Vel), S & SR can provide additional information for differentiation DHF from SHF”was assessed. Subjects and Methods: 30 patients with symptomatic HF and low EF (SHF group) and 27 with symptomatic HF, and normal EF and diastolic dysfunction (DHF group) were enrolled. 37 age-and sex-matched control subjects were recruited. Conventional echo and regional indices (Vel, S and SR), measured at the mid septum and posterior wall, were obtained. Results:Almost all clinical and echo indices of control were different between the two HF groups. The EF, LV mass, S’ and DT in DHF were greater than those with SHF. The LA size, diastolic dysfunction grades; E, A, E/A, E’, A’ and E/E’, were not different between the two HF groups. In the regional indices, the peak S (long axis: 12.0±5.4 vs. 17.6±5.9%, radial axis: 26.4±12.7 vs. 46.0±16.7%) and systolic Vel (long axis: 2.6±0.8 vs. 3.6±0.9 cm/s, radial axis: 2.1 (1.2 vs. 3.7±1.4 cm/s) with SHF were significantly lower than those with DHF. However, the SR of the two groups was not different. The best cutoff values of peak S were 13.7% (long axis) and 32.9% (radial axis), and the systolic Vel were 3.0 cm/s (long axis) and 2.8 cm/s (radial axis). Conclusion:The peak S and systolic Vel may be useful indices for differentiating DHF from SHF. A similarly decreased SR in the two HF groups suggests that DHF has decreased myocardial contractility, despite the normal EF. (Korean Circulation J 2004; 34(11):1090-1098)

Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure

Background The presence of signs and symptoms of heart failure (HF), abnormal diastolic function and an ejection fraction > 45%, have been defined as diastolic HF (DHF). However, a cut-off value of 45% for ejection fraction seems arbitrary as mild systolic dysfunction may be overlooked. It was the goal of this study to assess the additive information derived from Doppler tissue imaging for patients with DHF. Methods As a measure of left ventricular (LV) long-axis function, systolic and diastolic velocities of the mitral annulus (peak, peak early, and peak late) derived from pulsed Doppler tissue imaging were assessed in 36 asymptomatic control subjects, 36 patients with DHF, and 35 patients with systolic HF (SHF). As a measure of overall LV performance, the Tei index (isovolumic contraction time and isovolumic relaxation time divided by ejection time) was assessed. Results In the DHF group, peak systolic annular velocity was reduced (7.1 ± 1.2 cm/s) as compared with the control group (9.0 ± 1.2 cm/s, P < .05), and was even lower in the SHF group (5.0 ± 0.7 cm/s, P < .01 SHF group vs DHF/control groups). The Tei index was increased in the DHF group (0.53 ± 0.14) in comparison with the control group (0.39 ± 0.07, P < .05), and was highest in the SHF group (0.94 ± 0.43, P < .01 SHF group vs control/DHF groups). Using peak systolic annular velocity < 7.95 cm/s as a cut-off value (derived from receiver operating characteristic curve analysis), patients with DHF were separated from control subjects with a sensitivity of 83% and a specificity of 83%. A Tei index > 0.43 separated patients with DHF and control subjects with a sensitivity of 79% and a specificity of 72%. Conclusion Systolic long-axis LV function is also impaired in patients with DHF, resulting in feasible diagnosis of DHF by Doppler tissue imaging analysis of LV long-axis function and overall LV function with the Tei index.

Hypoalbuminemia in elderly patients with acute diastolic heart failure

ObjectivesThis study evaluated the relative contribution of serum colloid osmotic pressure (COP) lowering and pulmonary artery wedge pressure (PAWP) elevation in the pathogenesis of pulmonary edema in patients with systolic or isolated diastolic heart failure (DHF). BackgroundThe role of hypoalbuminemia and the resulting low COP have been shown in some patients with acute systolic heart failure (SHF). MethodsColloid osmotic pressure and PAWP were determined in 100 patients with acute heart failure (HF) (56 with DHF and 44 with SHF; mean age, 78 ± 12 years), in 35 patients with acute dyspnea from pulmonary origin, and in 15 normal controls. Pulmonary artery wedge pressure was estimated using transthoracic Doppler echocardiography. ResultsColloid osmotic pressure was significantly lower in the DHF group (20.5 ± 5 mm Hg) than in the SHF group (24.2 ± 3.7 mm Hg, p < 0.001), pulmonary disease group (25.1 ± 4.2 mm Hg, p < 0.001), or normal control group (24.7 ± 3 mm Hg). Low COP resulted from hypoalbuminemia due to age, malnutrition, and sepsis. Pulmonary artery wedge pressure was significantly higher in patients with SHF (26 ± 6.3 mm Hg) than in the patients with DHF (20.3 ± 7 mm Hg, p < 0.001) and was significantly higher in the patients with DHF than in the patients with pulmonary disease (13 ± 4.2 mm Hg, p < 0.001). The COP–PAWP gradient was similar in patients with SHF (−1.6 ± 7.1 mm Hg) and patients with DHF (0.7 ± 6 mm Hg). ConclusionsFrequent hypoalbuminemia resulting in low COP facilitates the onset of pulmonary edema in patients with DHF who usually have lower PAWP than patients with SHF.

Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure.

Many older patients with symptoms of congestive heart failure have a preserved left ventricular ejection fraction (LVEF). However, the pathophysiology of this disorder, presumptively termed diastolic heart failure (DHF), is not well characterized and it is unknown whether it represents true heart failure. To assess the 4 key pathophysiological domains that characterize classic heart failure by systematically performing measurements in older patients with presumed DHF and comparing these results with those from age-matched healthy volunteers and patients with classic systolic heart failure (SHF). Observational clinical investigation conducted in 1998 in a general community and teaching hospital in Winston-Salem, NC. A total of 147 subjects aged at least 60 years. Fifty-nine had isolated DHF defined as clinically presumed heart failure, LVEF of at least 50%, and no evidence of significant coronary, valvular, or pulmonary disease. Sixty had typical SHF (LVEF < or =35%). Twenty-eight were age-matched healthy volunteer controls. Left ventricular structure and function, exercise capacity, neuroendocrine function, and quality of life. By echocardiography, mean (SE) LVEF was 60% (2%) in patients with DHF vs 31% (2%) in those with SHF and 54% (2%) in controls. Mean (SE) LV mass-volume ratio was markedly increased in patients with DHF (2.12 [0.14] g/mL) vs those with SHF (1.22 [0.14] g/mL) (P<.001) and vs controls (1.49 [0.17] g/mL) (P =.002). Peak oxygen consumption by expired gas analysis during cycle ergometry was similar in the DHF and SHF groups (14.2 [0.5] and 13.1 [0.5] mL/kg per minute, respectively; P =.40) and in both was markedly reduced compared with healthy controls (19.9 [0.7] mL/kg per minute) (P =.001 for both). Ventilatory anaerobic threshold was similar in the DHF and SHF groups (9.1 [0.3] and 8.7 [0.3] mL/kg per minute, respectively; P<.001) and in both was reduced compared with healthy controls (11.5 [0.4] mL/kg per minute) (P<.001). Norepinephrine levels were similar in the DHF (306 [64] pg/mL) and SHF (287 [62] pg/mL) groups (P =.56) and in both were markedly increased vs healthy controls (169 [80] pg/mL) (P =.007 and.03, respectively). Brain natriuretic peptide was substantially increased in both the DHF (56 [30] pg/mL) and the SHF (154 [28] pg/mL) groups compared with healthy controls (3 [38] pg/mL) (P =.02 and.001, respectively). Quality-of-life decrement score as assessed by the Minnesota Living with Heart Failure Questionnaire was substantially increased from the benchmark score of 10 in both groups (SHF: 43.8 [3.9]; DHF: 24.8 [4.4]). Patients with isolated DHF have similar though not as severe pathophysiologic characteristics compared with patients with typical SHF, including severely reduced exercise capacity, neuroendocrine activation, and impaired quality of life.

Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats

OBJECTIVESWe assessed the effects of long-term amlodipine administration in a diastolic heart failure (DHF) rat model with preserved systolic function as well as the relationship between changes in left ventricular (LV) myocardial stiffening and alterations in extracellular matrix.BACKGROUNDAlthough the effect of long-term administration of amlodipine has been shown to be disappointing in patients with systolic failure, the effect is unknown in those with DHF.METHODSDahl salt-sensitive rats fed a high-salt diet for seven weeks were divided into three groups: eight untreated rats (DHF group), eight rats given high-dose amlodipine (10 mg/kg/day; HDA group) and seven rats given low-dose amlodipine (1 mg/kg/day; LDA group).RESULTSHigh-dose administration of amlodipine decreased systolic blood pressure and controlled excessive hypertrophy, without a decrease in the collagen content, and prevented the elevation of LV end-diastolic pressure at 19 weeks. Low-dose administration of amlodipine with subdeppressive effects did not control either hypertrophy or fibrosis; however, it prevented myocardial stiffening and, hence, the elevation of LV end-diastolic pressure. The ratio of type I to type III collagen messenger ribonucleic acid levels was significantly lower in both the HDA and LDA groups than in the DHF group.CONCLUSIONSLong-term administration of amlodipine prevented the transition to DHF both at the depressor and subdepressor doses. Amlodipine did not decrease the collagen content, but attenuated myocardial stiffness, with inhibition of the phenotype shift from type III to type I collagen. Thus, amlodipine may exert beneficial effects through amelioration of collagen remodeling in the treatment of DHF.