Rationale and study design of the GOREISAN for heart failure (GOREISAN-HF) trial: A randomized clinical trial.

BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.

Relationships between sodium levels, haemodynamics and metalloproteinases in heart failure patients.

To estimate the associations between dysnatraemia and inflammatory marker [including interleukin-6 (IL-6)], and tissue remodelling marker [matrix metalloproteinase (MMP)-9 and tissue inhibitor of MMP (TIMP)-1], the pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (PAP), and left ventricular end-diastolic pressure (EDP), and the prognostic relevance in patients with heart failure. The serum sodium level and circulating levels of IL-6, MMP-9, and TIMP-1 were measured in 173 heart failure patients. Dual heart catheterisation was performed to measure PCWP, mean PAP, and EDP. All-cause mortality was assessed during the follow-up period (mean 88 ± 49 months). Restricted cubic spline (RCS) regression showed a U-shaped association of serum sodium level with TIMP-1, with the lowest values in the 138-140 mmol/L range (P for effect = 0.042, P for non-linearity = 0.017). IL-6 and MMP-9 levels showed non-significant associations with serum sodium level. U-shaped associations of serum sodium level with PCWP (P for effect = 0.004, P for non-linearity = 0.001) and mean PAP (P for effect = 0.042, P for non-linearity = 0.017) were found with the RCS regression model. The random forest model revealed that TIMP-1, MMP-9, and IL-6 were important predictors for serum sodium levels. Restricted cubic spline Cox regressions demonstrated that TIMP-1 levels indicated a U-shaped, concaved, non-linear association with all-cause mortality (P for effect = 0.011, P for non-linearity = 0.022). Dysnatraemia is an index of TIMP-1 aggravation and elevated PCWP, mean PAP; hence, it is associated with worsening all-cause mortality.Clinical Trial Registration: UMIN000023840.

Association between matrix metalloproteinase-9 and worsening heart failure events in patients with chronic heart failure.

AIMS: Matrix metalloproteinase (MMP) is up-regulated during heart failure (HF) and influences ventricular remodeling. We hypothesized that disparity between MMP-9 and tissue inhibitors of MMP-1 (TIMP-1) results in clinical manifestations and is related to prognostic risk in patients with chronic HF. METHODS AND RESULTS: Plasma levels of MMP-9, TIMP-1, and brain natriuretic peptide (BNP) were measured in 173 patients with chronic HF. Combined endpoints of worsening HF events were assessed during follow-up (median 109 months). MMP-9 and TIMP-1 levels and the MMP-9/TIMP-1 ratio increased with increasing severity of the New York Heart Association class (P for trend = 0.003, 0.011, and 0.005, respectively). Patients with HF events (n = 35) had significantly higher MMP-9 than those without HF events (P = 0.004). Kaplan-Meier analysis demonstrated a higher probability of HF events with high MMP-9 values (>23.2 ng/mL; P = 0.005). A multivariate Cox proportional hazard model showed that high MMP-9 values were an independent predictor of HF events (hazard ratio, 3.73; 95% confidence interval (CI), 1.03-13.46; P = 0.043). In patients with lower BNP levels (≤210 pg/mL), the adjusted hazard ratio for HF events was 3.63 (95% CI, 1.20-11.02; P = 0.023) among patients with high MMP-9 values compared with patients with low BNP and low MMP-9 values. CONCLUSIONS: MMP-9 and TIMP-1 levels correlate with the severity of chronic HF. MMP-9 is a strong predictor of HF events, suggesting that a disparity between MMP-9 and TIMP-1 levels and increased MMP-9 levels may help predict HF events.

Temporal change of enhancement after gadolinium injection on contrast-enhanced CMR in reperfused acute myocardial infarction.

BACKGROUND: A recent report demonstrated that early enhancement on contrast-enhanced cardiac magnetic resonance (CE-CMR) correlated with myocardial edema detected by T2-weighted CMR in reperfused acute myocardial infarction (AMI). However, the time at which the enhancement in salvaged myocardium disappears is yet to be determined. We aimed to examine the time course of the enhancement with the use of different quantification techniques and to compare the extent of enhancement with the myocardial edema. METHODS AND RESULTS: CE-CMR was performed at 2-20 min after gadolinium administration in 32 AMI patients. The extent of enhancement (% myocardium) was quantified by manual delineation and the threshold methods of 2-5 SDs above remote myocardium. In subendocardial infarct, the enhancement was greatest at 2 min regardless of the quantification techniques and decreased with time, particularly in the first 6 min. In transmural infarct, the change in the size of enhancement was modest although the time course of enhancement varied according to the quantification techniques. The sizes of enhancement were not significantly different between 15 and 20 min regardless of the techniques and infarct transmurality. The best agreement with myocardial edema was found at 2 min with average differences of 0.5% and -1.2% and limits of agreement of ±20.2% and ±21.2% for the manual and 2-SD techniques, respectively. CONCLUSIONS: The optimal timing for delineation of salvaged myocardium on CE-CMR is at 2min when the manual or 2-SD technique was employed. Imaging needs to be completed in a short time (ideally within a minute) because of rapid reduction of enhancement in salvaged myocardium.

Effect of caffeine on intravenous adenosine-induced hyperemia in fractional flow reserve measurement.

BACKGROUND: The interaction between caffeine and adenosine is still a matter of debate. AIMS: We examined whether caffeine attenuated intravenous adenosine-induced hyperemia in the measurement of fractional flow reserve (FFR) and whether an increased dose of adenosine overcame the caffeine antagonism. METHODS: FFR was measured using different adenosine doses (140, 175, and 210 µg/kg/min) and papaverine as a reference standard in patients with intermediate coronary stenoses, who refrained from caffeine for >24 h (no-caffeine group; n = 14) and those who consumed caffeine (caffeine group; n = 28). RESULTS: The median caffeine level in the caffeine group was 2.9 mg/L (interquartile range, 1.8-4.6 mg/L). In the no-caffeine group, FFR with adenosine did not decrease above the dose of 140 µg/kg/min (0.769, 0.771, and 0.770 at 140, 175, and 210 µg/kg/min, respectively) and was not significantly different from that with papaverine (0.765). In the caffeine group, adenosine overestimated FFR (140 µg/kg/min: 0.813, P<.001; 175 µg/kg/min: 0.806, P<.01; 210 µg/kg/min: 0.794, P=.01) compared with papaverine (0.779). The difference in FFR between papaverine and 140 µg/kg/min dose of adenosine was significantly greater in the caffeine group than in the no-caffeine group (0.034 vs 0.004; P<.05). CONCLUSION: Caffeine attenuates intravenous adenosine-induced hyperemia in FFR measurement. Even increased adenosine doses up to 210 µg/kg/min cannot fully surmount the antagonism.

Continuous administration of nicorandil decreases QT dispersion during the chronic phase of acute myocardial infarction.

We previously reported that continuous intravenous (IV) administration of nicorandil (NIC) inhibits QT dispersion (QTd). However, no prior study has evaluated the efficacy of NIC when administered orally to acute myocardial infarction (AMI) patients following continuous IV administration. Thirty patients with anteroseptal infarction in whom revascularization was performed successfully within 6 hours of AMI onset were included in the study and assigned to one of 3 groups: group A (continuous IV administration of NIC), group B (continuous IV and oral administration of NIC), and group C (no treatment with NIC). After 24 hours, QTd in groups A and B was significantly decreased compared to QTd in group C (P < 0.01) (group A, 58.1; group B, 58.2; and group C, 81.3). The QTd obtained 3 months later was significantly shorter in group B subjects who were orally administered NIC, and QTd before percutaneous coronary intervention (PCI) was restored in group A, in which no NIC had been administered orally [group A, 66.7; group B, 54.1; and group C, 73.9; P < 0.05 (group A versus group B) and P < 0.01 (group B versus group C)]. The effects were evaluated by comparing different routes of administration. Continuous IV and subsequent oral administration of NIC inhibited prolongation of QTd, suggesting that these effects may prevent the occurrence of cardiac events during both the acute and chronic phases of AMI.

Pravastatin suppresses the increase in matrix metalloproteinase-2 levels after acute myocardial infarction.

BACKGROUND: Matrix metalloproteinase (MMP) may contribute to myocardial remodeling after myocardial infarction. The goal of this study was to characterize the effects of pravastatin on circulating levels of MMP and on left ventricular dilatation after acute myocardial infarction (AMI). METHODS: Thirty-four consecutive patients with successful reperfusion following AMI were assigned to either pravastatin group (group P, n=12) or non-pravastatin group (group NP, n=22). Serum MMP-2 and tissue inhibitor of MMP (TIMP)-2 were measured immediately after reperfusion, on days 2, 3, 7, 30, and at 6 months after MI. Left ventriculography was performed after reperfusion and at 4 weeks and 6 months. RESULTS: MMP-2 levels were higher in patients with MI than control on days 1, 30, and at 6 months. Left ventricular end-diastolic volume index (LVEDVI) at 6 months correlated with MMP-2 levels on day 30 (r=0.47, p<0.01) and at 6 months (r=0.56, p<0.001). MMP-2 levels at 6 months were significantly lower in group P than group NP. Further, LVEDVI at 6 months tended to be smaller and DeltaLVEDVI was significantly smaller in group P when compared with group NP. CONCLUSION: Serum MMP-2 varied in a time-dependent manner following AMI and correlated with late changes in LVEDVI. Serum MMP-2 levels were significantly lower in treatment group than in non-treatment group and DeltaLVEDVI was significantly smaller in treatment group after long-term pravastatin administration. Use of statins in AMI patients may provide beneficial effects in terms of preventing heart failure over and above its lipid-lowering effects.

Circulating matrix metalloproteinase-2 is elevated in patients with congestive heart failure.

BACKGROUND AND AIMS: It has been reported that matrix metalloproteinase (MMP) protein concentration and activity are upregulated in the failing human heart. However, there are few reports describing the role of elevated level of circulating MMPs in congestive heart failure (CHF) patients. This study examined whether circulating matrix metalloproteinases (MMPs) are also related to the pathogenesis of CHF. METHODS: We measured circulating levels of matrix metalloproteinase-2 (MMP-2) in 52 patients with CHF (left ventricular ejection fraction (LVEF) <50%). The patients were also subdivided into two groups according to NYHA functional class; mild CHF (class II, n=43) and severe CHF (class III, n=9). RESULTS: The serum level of MMP-2 and MMP-2/TIMP-2 ratio were significantly higher in CHF than in controls (P<0.01). Among patient groups, serum levels of MMP-2 were significantly higher in patients with severe CHF than in patients with mild CHF (P<0.01). Plasma levels of BNP had a significant positive correlation with circulating levels of MMP-2 (r=0.78; P<0.01) and MMP-2/TIMP-2 ratio (r=0.60; P<0.01). CONCLUSIONS: Our data showed that the circulating MMP-2 concentration was increased in CHF patients and that the levels were related to the plasma levels of BNP in CHF, suggesting that the elevated levels are related to developing heart failure syndrome.