Efficacy and Safety of an Orally Administered Selective Prostacyclin Receptor Agonist, Selexipag, in Japanese Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.Methods and Results:Selexipag was administered at 200 µg twice daily and titrated up to 1,600 µg by increments of 200 µg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm5(P<0.0001). For the secondary endpoint, the 6-min walk distance (6MWD) increased from 445.0±102.2 to 459.1±112.8 m (P=0.0324); World Health Organization functional class improved in 4 patients (12.1%), and was maintained in 29 patients (87.9%). A decrease in PVR was also shown in patients treated with selexipag, on top of a phosphodiesterase inhibitor and endothelin receptor antagonist. Most of the commonly reported adverse events were consistent with those reported for other PGI2formulations. Thirty-four patients attained the individual maximum tolerated dose (maintenance dose). CONCLUSIONS: The efficacy and tolerability of selexipag in Japanese PAH patients was confirmed by improvement in pulmonary hemodynamics, exercise capacity, symptoms. Selexipag is an efficacious treatment option for Japanese PAH patients. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111532].).

Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODS AND RESULTS: Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P<0.0001). 6MWD increased from 427±128 to 494±116 m (P<0.0001). WHO functional class improved in 13 patients (46.4%) and was maintained in 15 patients (53.6%), and NT-pro-BNP was reduced by 18% (P<0.0001). The favorable treatment effect on PVR was apparent regardless of concomitant therapy for PAH. CONCLUSIONS: Macitentan was efficacious and well tolerated and improved the hemodynamic parameters, exercise capacity, symptoms, and clinical biomarkers in Japanese PAH patients. Macitentan can be a valuable therapeutic option for Japanese patients with PAH. ( TRIAL REGISTRATION: JAPIC Clinical Trials Information [JapicCTI-121986].) (Circ J 2016; 80: 1478-1483).

Effects of nocturnal oxygen therapy in patients with chronic heart failure and central sleep apnea: CHF-HOT study.

It was previously reported that nocturnal home oxygen therapy (HOT) significantly improved not only sleep disordered breathing (SDB), but also quality of life (QOL) and left ventricular ejection fraction (LVEF) in two trials. To strengthen the statistical reliability of the above efficacies of HOT and to assess the effects of 12-week nocturnal HOT on suppression of ventricular arrhythmias, we combined the two trials and undertook a post hoc analysis. Ninety-seven patients with chronic heart failure (CHF) and central sleep apnea were assigned to receive HOT (45 patients) or not (52 patients). HOT resulted in greater reduction in the apnea-hypopnea index (AHI) (-11.4 ± 11.0 vs. -0.2 ± 7.6 events/h, p < 0.01), which is associated with greater improvement in the Specific Activity Scale (0.8 ± 1.2 vs. 0.0 ± 0.6, p < 0.01), New York Heart Association (NYHA) functional class (p < 0.01), and LVEF (p = 0.06). Median number of premature ventricular contraction (PVC) at baseline was 17 beats per hour in both the HOT and the control groups. Overall improvements of PVCs were not different either in the HOT group or in the control. However, in 12 patients with NYHA >III and AHI >20 events/h, PVC was significantly improved by HOT with a marked reduction in AHI and a substantial increase in LVEF. In conclusion, among patients with CHF and CSA, HOT improves SDB, QOL, and cardiac function. The effectiveness of HOT for ventricular arrhythmias was not observed in the overall analysis, but only in a limited number of patients with severe CHF and SDB. To clarify the effects of HOT on ventricular arrhythmias in patients with CHF and SDB, a further study is needed.

Effects of the endothelin receptor antagonist bosentan on hemodynamics and exercise capacity in Japanese patients with mildly symptomatic pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) trial has mostly enrolled patients with World Health Organization functional class (WHO FC) III or IV. However, PAH is rapidly progressive in nature even in patients with less severe forms at diagnosis. Following the recent studies in Western population, here we assessed the efficacy of bosentan in Japanese patients with WHO FCII PAH. In this open-label trial, bosentan 125 mg twice daily was administered for 12 weeks in 16 patients, and a hemodynamic evaluation was performed. Treatment was continued for a further 12 weeks, where the effect on exercise capacity was assessed in 13 patients. In 16 patients, mean pulmonary arterial pressure decreased from 40.4 ± 10.4 to 35.6 ± 12.6 mmHg (p = 0.018) and cardiac index increased from 2.54 ± 0.73 to 2.96 ± 0.82 L/min/m(2) (p = 0.023). Thus, pulmonary vascular resistance decreased from 792 ± 565 to 598 ± 558 dyn·sec/cm(5) (p = 0.006). In 13 patients followed up for 24 weeks, 6-min walking distance increased from baseline at Week 12 (p = 0.003) and Week 24 (p = 0.011). All patients were mildly symptomatic at baseline with dyspnea index (Borg scale) of 2.50 ± 1.58 and the specific activity scale (SAS) of 5.0 ± 1.4 METs. These values remained unchanged throughout the study. These results suggest that bosentan treatment was beneficial for Japanese patients with WHO FC II PAH and treatment should be started in the early stage of the disease.

Evidence for a role of mast cells in the evolution to congestive heart failure.

Mast cells are believed to be involved in the pathophysiology of heart failure, but their precise role in the process is unknown. This study examined the role of mast cells in the progression of heart failure, using mast cell-deficient (WBB6F1-W/W(v)) mice and their congenic controls (wild-type [WT] mice). Systolic pressure overload was produced by banding of the abdominal aorta, and cardiac function was monitored over 15 wk. At 4 wk after aortic constriction, cardiac hypertrophy with preserved left ventricular performance (compensated hypertrophy) was observed in both W/W(v) and WT mice. Thereafter, left ventricular performance gradually decreased in WT mice, and pulmonary congestion became apparent at 15 wk (decompensated hypertrophy). In contrast, decompensation of cardiac function did not occur in W/W(v) mice; left ventricular performance was preserved throughout, and pulmonary congestion was not observed. Perivascular fibrosis and upregulation of mast cell chymase were all less apparent in W/W(v) mice. Treatment with tranilast, a mast cell-stabilizing agent, also prevented the evolution from compensated hypertrophy to heart failure. These observations suggest that mast cells play a critical role in the progression of heart failure. Stabilization of mast cells may represent a new approach in the management of heart failure.

Coronary collateral growth and its therapeutic application to coronary artery disease.

There is a tremendous body of data concerning the coronary collateral circulation in both experimental animals and humans. The functional importance of a well-developed coronary collateral circulation has now been documented. The paradigm regarding the principal stimulus for coronary collateral growth has shifted from myocardial ischemia to increased shear stress at the site of pre-existing collateral arterioles. Numerous experimental and clinical studies have contributed to elucidation of the mechanisms of coronary collateral growth. Stimulation of coronary collateral growth is an alternative therapeutic approach to patients with intractable angina pectoris who are not indicated for percutaneous coronary intervention and/or coronary artery bypass grafting. Pharmacological and mechanical modulations accelerating coronary collateral growth have been challenged. Because it is conceivable that a well-developed coronary collateral circulation attenuates myocardial ischemia upon exercise, further research addressing coronary collateral growth is needed in both experimental models of myocardial ischemia and human coronary artery disease.

Reappraisal of functional importance of coronary collateral circulation.

Coronary collateral circulation (CCC) is defined as an alternative blood-conveying circuit to the ischemic myocardium supplied by a jeopardized coronary artery. Accumulating evidence on CCC and its functional role has been derived from basic and clinical studies over several decades. Progress in molecular biology and genetic engineering has enabled us to elucidate the mechanisms of collateral growth on the basis of the development of new experimental models and methods for accurate assessment of CCC. These achievements in basic research have been promptly translated into the clinical setting. Interaction between basic and clinical sciences in the fascinating field of CCC will contribute to the establishment of innovative collateral-promoting therapy for severe coronary artery disease.

Treatment effects of renin-angiotensin system inhibitor and calcium channel blocker in patients with coronary artery narrowing (from the Japanese Coronary Artery Disease Study).

Low-dose antihypertensive drugs in combination are prescribed frequently in clinical practice. Combination treatment is superior to monotherapy with higher doses of each drug in terms of blood pressure reduction and side effects. However, it is unclear whether combination treatment provides additional prognostic benefit beyond the blood pressure lowering effects. We assessed the usefulness of the combined treatment of a renin-angiotensin system inhibitor (RASI) and a calcium channel blocker (CCB) for all cardiovascular events in the Japanese Coronary Artery Disease (JCAD) Study population. In the JCAD Study, which is an observational and non-randomized trial, 13,812 patients with angiographically shown narrowing >50% in ≥1 of 3 major coronary arteries were followed up for a mean of 2.7 years. The primary endpoint of the study was all cardiovascular events. In the present study, baseline covariates possibly influencing the event rate were adjusted between the different treatment groups. There was no statistically significant difference in the event rate between the RASI monotherapy and combined treatment groups, although Kaplan-Meier analysis showed a 23% (p = 0.0003) relative risk reduction with an RASI monotherapy compared with the control group. In conclusion, there may be no additional benefit beyond blood pressure lowering effects in the combination of an RASI and a CCB in patients with angiographically documented CAD.

Prognostic effects of combined treatment with calcium channel blockers and statins in patients with coronary narrowing: from the Japanese Coronary Artery Disease study.

Calcium channel blockers (CCB) and statins are frequently prescribed for patients with coronary artery disease (CAD) complicated by hypertension and/or hypercholesterolemia. CCB have pleiotropic actions beyond their blood pressure-lowering effect, while statins have pleiotropic actions beyond their cholesterol-lowering effect. We assessed the hypothesis that combined treatment with CCB and statins has additional prognostic benefits resulting from potential additive or synergistic pleiotropic actions of both classes of drugs in the Japanese CAD (JCAD) study population. The JCAD study consisted of 13,812 patients with angiographically demonstrable significant coronary narrowing in at least 1 of 3 major coronary arteries who were followed-up for a mean of 2.7 years (follow-up rate, 88.4%). The primary endpoint of the present study was all cardiovascular events. We compared the event rate between patients receiving neither CCB nor statins and those receiving each drug alone or as a combination treatment using propensity score matching analysis. The rate of all events was 62.8 per 1,000 patient-years in the JCAD study. Kaplan-Meier analysis with the log-rank test showed no statistically significant difference in the event rate in each comparison. In conclusion, there may be no additional prognostic benefit beyond the blood-pressure-lowering and cholesterol-lowering effects in the combined treatment with CCB and statins for angiographically documented CAD patients.

Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients.

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.Methods: In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.Results: Macitentan was administered at a once-daily dose of 10 mg in 30 PAH patients with a median treatment period of 2.4 years (range, 229-1037 days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.Conclusions: This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.

Calcineurin-GATA-6 pathway is involved in smooth muscle-specific transcription.

Intracellular calcium is one of the important signals that initiates the myogenic program. The calcium-activated phosphatase calcineurin is necessary for the nuclear import of the nuclear factor of activated T cell (NFAT) family members, which interact with zinc finger GATA transcription factors. Whereas GATA-6 plays a role in the maintenance of the differentiated phenotype in vascular smooth muscle cells (VSMCs), it is unknown whether the calcineurin pathway is associated with GATA-6 and plays a role in the differentiation of VSMCs. The smooth muscle-myosin heavy chain (Sm-MHC) gene is a downstream target of GATA-6, and provides a highly specific marker for differentiated VSMCs. Using immunoprecipitation Western blotting, we showed that NFATc1 interacted with GATA-6. Consistent with this, NFATc1 further potentiated GATA-6-activated Sm-MHC transcription. Induction of VSMCs to the quiescent phenotype caused nuclear translocation of NFATc1. In differentiated VSMCs, blockage of calcineurin down-regulated the amount of GATA-6-DNA binding as well as the expression of Sm-MHC and its transcriptional activity. These findings demonstrate that the calcineurin pathway is associated with GATA-6 and is required for the maintenance of the differentiated phenotype in VSMCs.

[Home oxygen therapy (HOT) for patients with heart failure associated with sleep disturbed breathing].

Recently, there is increasing evidence that sleep apnea may adversely affect pathophysiology and outcomes of congestive heart failure (CHF). Repetitive nocturnal apneas may worsen CHF through a number of mechanisms including the repetitive arterial oxygen desaturation, increased left ventricular afterload, or an activation of sympathetic nervous system. Although central sleep apnea (CSA) is relatively rare, prospective studies revealed that 33 to 82 % of patients with CHF have evidence of CSA and characteristic Cheyne-Stokes respiration (CSR). We assessed an efficacy of nasal O2 therapy at night using a conventional O2 concentrator in ambulatory patients with stable CHF and CSR. O2 resulted in a significant improvement of sleep together with an increase in left ventricular function and quality of life. Therefore, home oxygen therapy(HOT) can be a valuable nonpharmacological option for the treatment of patients with CHF and CSR-CSA.

Thrombosis increases circulatory hepatocyte growth factor by degranulation of mast cells.

BACKGROUND: Plasma concentrations of hepatocyte growth factor (HGF), a powerful angiogenic growth factor inducible by heparin, increase in thrombus-associated disorders such as myocardial infarction and unstable angina. The mechanism of this thrombus-associated HGF release, however, is unknown. METHODS AND RESULTS: Wistar rats received through the tail vein (1) normal saline (NS), (2) 50 micro g of the mast cell-degranulating agent CP48/80, or (3) 1000 U/kg heparin. Blood samples were collected at 10 minutes or 30 minutes after the injections, or from untreated rats, for measurements of HGF. The same experiments were performed in mast cell-deficient white spotting (Ws) rats. Ws rats have a small deletion of the c-kit gene and are deficient in mast cells. Intravenous heparin immediately increased plasma HGF in both Wistar (38.02+/-2.08 ng/mL versus 1.11+/-0.70 ng/mL in untreated rats, P<0.0001) and Ws rats (36.39+/-4.15 ng/mL versus 0.66+/-0.18 ng/mL in NS-treated rats, P<0.0001). Injection of CP48/80 also increased plasma HGF in Wistar rats (9.12+/-1.11 ng/mL versus 0.65+/-0.24 ng/mL in NS group, P=0.004) but not in Ws rats (0.67+/-0.27 ng/mL versus 0.66+/-0.18 ng/mL in NS group, P=0.997). In a rat carotid artery microthrombus model, intra-arterial thrombus formation increased circulating HGF in Wistar rats (2.12+/-0.70 ng/mL versus sham 0.61+/-0.15 ng/mL in sham-operated Wistar rats, P=0.0064) but not in Ws rats (0.76+/-0.33 ng/mL versus 0.21+/-0.04 ng/mL in sham-operated Ws rats, P=0.29). In addition, in vitro stimulation of rat peritoneal mast cells with thrombin rapidly induced degranulation in a dose-dependent manner. CONCLUSIONS: These observations indicate that mast cell degranulation stimulated by thrombin is necessary for the rapid induction of plasma HGF in intravascular thrombus-associated disorders.

Augmented expression of neuronal nitric oxide synthase in the atria parasympathetically decreases heart rate during acute myocardial infarction in rats.

BACKGROUND: Nitric oxide (NO) synthesized within sinoatrial cells recently has been shown to participate in the autonomic control of heart rate. We hypothesized that NO in the neuronal cells in the heart was increased and parasympathetically regulated heart rate after myocardial infarction (MI). METHODS AND RESULTS: We examined heart rate dynamics and neuronal NO synthase (nNOS) expression and activities in the atria of rats with MI 1, 3, 7, and 14 days after MI (n=7 to 22 for each group). Both the mRNA levels of nNOS in the atria determined by competitive reverse transcriptase-polymerase chain reaction and the protein levels determined by Western blotting were significantly increased compared with controls 1, 3, and 7 days after MI. nNOS activity in the atria 1 day after infarction was also increased in MI rats. nNOS immunoreactivity was observed in nerve fibers in the atria. After infusion of a specific inhibitor of nNOS and iNOS, 1-(2-trifluoromethylphenyl) imidazole (TRIM) (50 mg/kg IV), heart rate was significantly (P<0.01) increased in MI rats compared with controls 1, 3, and 7 days after MI. The iNOS-specific inhibitor, 1400W (10 mg/kg SC), did not significantly affect the heart rate in rats with MI. The effect of TRIM was abolished by pretreatment with L-arginine (25 mg/kg IV) or by parasympathetic blockade with atropine but not by propranolol. There was a strong correlation (r=0.837, P<0.0001) between the nNOS protein expression and heart rate change after TRIM infusion. CONCLUSIONS: These results indicate that increased nNOS parasympathetically decreased heart rate via the production of NO in rats with acute MI.

Left ventricular pressure-volume relationship in a murine model of congestive heart failure due to acute viral myocarditis.

OBJECTIVES: This study, performed in a murine model of encephalomyocarditis virus myocarditis, used a new Millar 1.4F conductance-micromanometer system for the in vivo determination of the left ventricular (LV) pressure-volume relationship (PVR). BACKGROUND: Viral myocarditis is an important cause of congestive heart failure and may lead to dilated cardiomyopathy. However, the hemodynamic changes associated with its acute phase have not been analyzed in detail. METHODS: Four-week-old DBA/2 mice were inoculated with EMCV (day 0). Serial hemodynamic measurements, compared with uninfected control mice were made on days 0, 1, 3, 4, 5, 7, 9, 12, and 14. RESULTS: On day 1, the hearts of infected mice manifested enhanced contractile function, decreased LV compliance, and abnormal diastolic function with increased LV end-diastolic pressure (EDP). Mean stroke index, ejection fraction (EF), and cardiac index (CI) were significantly higher than in uninfected control mice (p < 0.05). Contractile function decreased from days 4 to 14. On day 7, when hemodynamic abnormalities consistent with heart failure culminated, end-diastolic volume (EDV), EDP, and EDPVR were significantly higher, and CI, EF, end-systolic pressure (ESP), and ESPVR significantly lower in the infected than in control mice. Heart rate remained comparable in both groups. Although heart failure receded between day 9 and day 14, ESPVR, ESP, and EF remained significantly depressed up to day 14, and EDV and EDP remained significantly higher. CONCLUSIONS: These hemodynamic data provide new insights into the pathophysiology of acute viral myocarditis and may be useful in the development of therapeutic interventions.

Carvedilol increases the production of interleukin-12 and interferon-gamma and improves the survival of mice infected with the encephalomyocarditis virus.

OBJECTIVES: This study was designed to examine the effects of carvedilol in a murine model of viral myocarditis induced by encephalomyocarditis virus (EMCV) infection. BACKGROUND: Cytokines play an important role in the pathophysiology of viral myocarditis. Catecholamines influence the production of cytokines via beta-adrenergic receptors, suggesting that beta-adrenergic blockers could modulate the production of cytokines and exert a therapeutic effect in viral myocarditis by blocking the beta-stimulating action of endogenous catecholamines. In clinical trials, the third-generation, nonselective beta-blocker carvedilol was the first among several beta-blockers to reduce mortality in heart failure. However, the effects of carvedilol in acute viral myocarditis and on cytokine production are unknown. METHODS: This study compared the effects of carvedilol, the selective beta(1)-blocker metoprolol, and the nonselective beta-blocker propranolol in a murine model of viral myocarditis induced by EMCV. RESULTS: Carvedilol improved the 14-day survival of the animals, attenuated myocardial lesions on day 7, and increased myocardial levels of interleukin (IL)-12 and interferon (IFN)-gamma, whereas reducing myocardial virus replication. Propranolol also attenuated myocardial lesions, but to a lesser extent, and increased IL-12 and IFN-gamma levels. Metoprolol had no effect in this model. Encephalomyocarditis virus infection increased plasma catecholamine levels. CONCLUSIONS: These results suggest that by blocking the beta(2)-stimulating effects of catecholamines, carvedilol exerts some of its beneficial effects by increasing the production of IL-12 and IFN-gamma. Carvedilol may be effective in patients with viral myocarditis by boosting IL-12 and IFN-gamma production.

Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice.

OBJECTIVES: This study examined the role of angiotensin II (Ang-II) in a murine model of viral myocarditis. BACKGROUND: Ang-II plays an important role in the pathophysiology of various cardiovascular disorders. However, the role of Ang-II in inflammatory heart diseases is not known. METHODS: Four-week-old wild-type (WT) and Ang-II type 1 receptor (AT(1)R) knockout (KO) mice were inoculated with the encephalomyocarditis virus (EMCV). Survival, histopathology, expression of proinflammatory cytokines, and activity of nuclear factor-kappa B (NF-kB) in the heart were examined. RESULTS: The 14-day survival was significantly increased in KO compared with WT mice. Histopathologic scores for myocardial necrosis (0.86 +/- 0.69 vs. 2.44 +/- 0.88, p < 0.01) and cellular infiltration (0.86 +/- 0.38 vs. 2.33 +/- 0.50, p < 0.01) were lower in KO than in WT mice. The expression of tumor necrosis factor-alpha (TNF-alpha) was increased 43.2-fold, that of interleukin-1-beta (IL-1-beta) 45.8-fold, and the activity of NF-kB 2.24-fold by EMCV inoculation in WT mice (each p < 0.01), but not in KO mice (5.9-fold, 6.3-fold, and 1.12-fold, respectively, each p = NS). The AT(1)R blocker also significantly attenuated the expression of proinflammatory cytokines and the activation of NF-kB in virus-inoculated WT mice. Intravenous Ang-II injection enhanced the activation of NF-kB (2.28-fold, p < 0.01) and increased the expression of TNF-alpha (2.31-fold, p < 0.01) and IL-1-beta (2.45-fold, p < 0.01) in heart tissue of WT but not KO mice. CONCLUSIONS: These results indicate that the AT(1)R signal is obligatory for the development of virus-induced myocardial injury through the proinflammatory action of Ang-II via the NF-kB/cytokine pathway.

Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats.

OBJECTIVES: We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling. BACKGROUND: Although it is known that the extracellular matrix (ECM) must be altered during LV remodeling, its local regulation has not been fully elucidated. METHODS: In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks, we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities. RESULTS: No changes were found at the LVH stage. However, during the transition to CHF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased. At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.763) and to systolic wall stress (r = 0.858) in vivo. CONCLUSIONS: Both TIMPs and MMP-2 remained inactive during hypertrophy, per se; they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of LV enlargement.