Sex Differences in 5-Year Outcomes After Deferral of Revascularization Following Physiological Coronary Assessment.

Background: The relationship between sex differences and long-term outcomes after fractional flow reserve (FFR)- and instantaneous wave-free ratio (iFR)-guided deferral of revascularization has yet to be elucidated. Methods and Results: From the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on FFR in a multicenter registry), this study included 432 lesions from 385 patients (men, 323 lesions in 286 patients; women, 109 lesions in 99 patients) with paired data of FFR and iFR. The primary endpoint was the cumulative 5-year incidence of target vessel failure (TVF), including cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization. The median FFR value was lower in men than in women (0.85 [0.81, 0.88] vs. 0.87 [0.83, 0.91], P=0.002), but the iFR value was comparable between men and women (0.94 [0.90, 0.98] vs. 0.93 [0.89, 0.98], P=0.26). The frequency of discordance between FFR and iFR was comparable between men and women (19.5% vs. 23.9%, P=0.34), although with different discordance patterns (P=0.036). The cumulative incidence of 5-year TVF did not differ between men and women after adjustment for baseline characteristics (13.9% vs. 6.9%, adjusted hazard ratio 1.82 [95% confidence interval: 0.44-7.56]; P=0.41). Conclusions: Despite sex differences in the results for physiological indexes, the 5-year TVF in deferred lesions did not differ between men and women after adjustment for baseline characteristics.

Prognostic Impact of Renal Function on 5-Year Outcomes After Fractional Flow Reserve-Guided Deferral of Revascularization.

Background Chronic kidney disease (CKD) might influence fractional flow reserve (FFR) value, potentially attenuating its prognostic utility. However, few large-scale data are available regarding clinical outcomes after FFR-guided deferral of revascularization in patients with CKD. Methods and Results From the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), 1218 patients were divided into 3 groups according to renal function: (1) non-CKD (estimated glomerular filtration rate ≥60 mL/min per 1.73 m2), n=385; (2) CKD (estimated glomerular filtration rate 15-59 mL/min per 1.73 m2, n=763); and (3) end-stage renal disease (ESRD) (eGFR <15 mL/min per 1.73 m2, n=70). The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel myocardial infarction, and clinical driven target vessel revascularization. Cumulative 5-year incidence of TVF was significantly higher in the ESRD group than in the CKD and non-CKD group, whereas it did not differ between the CKD and non-CKD groups (26.3% versus 11.9% versus 9.5%, P<0.001). Although the 5-year TVF risk increased as the FFR value decreased regardless of renal function, patients with ESRD had a remarkably higher risk of TVF at every FFR value than those with CKD and non-CKD. Conclusions At 5 years, patients with ESRD showed a higher incidence of TVF than patients with CKD and non-CKD, although with similar outcomes between patients with CKD and non-CKD. Patients with ESRD had an excess risk of 5-year TVF at every FFR value compared with those with CKD and non-CKD. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000014473.

Long-Term Outcomes in Elderly Patients After Deferral of Coronary Revascularization Guided by Fractional Flow Reserve.

BACKGROUND: Little evidence is available regarding the long-term outcome in elderly patients after deferral of revascularization based on fractional flow reserve (FFR).Methods and Results: From the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on fractional flow reserve in multicenter registry), 1,262 patients were divided into 2 groups according to age: elderly and younger patients (aged ≥75 or <75 years, respectively). The primary endpoint was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction (TVMI), and clinically driven target vessel revascularization (CDTVR). Cumulative 5-year incidence of TVF was not significantly different between elderly and younger patients (14.3% vs. 10.8%, P=0.12). Cardiac death occurred more frequently in elderly patients than younger patients (4.4% vs. 0.8%, P<0.001), whereas TVMI and CDTVR did not differ between groups (1.3% vs. 0.9%, P=0.80; 10.7% vs. 10.1%, P=0.80, respectively). FFR values in lesions with diameter stenosis <50% were significantly higher in elderly patients than in younger patients (0.88±0.07 vs. 0.85±0.07, P=0.01), whereas this relationship was not observed in those with diameter stenosis ≥50%. CONCLUSIONS: Elderly patients had no excess risk of ischemic events related to the deferred coronary lesions by FFR, although FFR values in mild coronary artery stenosis were modestly different between elderly and younger patients.

Thrombotic Risk and Cardiovascular Events in Patients With Revascularization Deferral After Fractional Flow Reserve Assessment.

OBJECTIVES: The aim of this study was to evaluate the impact of thrombotic risk on the occurrence of cardiovascular events in patients with coronary artery disease with deferred revascularization after fractional flow reserve (FFR) measurements. BACKGROUND: Deferral of revascularization on the basis of FFR is generally considered to be safe, but after deferral, some patients have cardiovascular events over time. METHODS: From J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), 1,263 patients with deferral of revascularization on the basis of FFR were evaluated. The association between thrombotic risk as assessed by CREDO-Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) thrombotic score and 5-year target vessel failure (TVF) and major adverse cardiac and cerebrovascular events (MACCE) was investigated. RESULTS: FFR and high thrombotic risk (HTR) were associated with increased risk for 5-year TVF (FFR per 0.01-unit decrease: HR: 1.08; 95% CI: 1.05-1.11; P < 0.001; HTR: HR: 2.16; 95% CI: 1.37-3.39; P < 0.001) and MACCE (FFR per 0.01-unit decrease: HR: 1.05; 95% CI: 1.02-1.06; P < 0.001; HTR: HR: 2.11; 95% CI: 1.56-2.84; P = 0.001). Patients with HTR had higher risk for 5-year TVF (HR: 2.30; 95% CI: 1.45-3.66; P < 0.001) and MACCE (HR: 2.34; 95% CI: 1.75-3.13; P < 0.001) than those without HTR, even when they had negative FFR. CONCLUSIONS: Assessment of thrombotic risk provides additional prognostic value to FFR in predicting 5-year TVF and MACCE in patients with deferral of revascularization after FFR measurements. (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry; UMIN000014473).

Five-Year Outcomes After Fractional Flow Reserve-Based Deferral of Revascularization in Chronic Coronary Syndrome: Final Results From the J-CONFIRM Registry.

BACKGROUND: Little large-scale data is available about the long-term (beyond 3 years) clinical outcomes after fractional flow reserve (FFR)-based deferral of revascularization in clinical practice. We sought to assess the 5-year outcomes after deferral of revascularization based on FFR. METHODS: The J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry) prospectively enrolled 1263 patients with 1447 lesions in whom revascularization was deferred based on FFR from 28 Japanese centers. The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), including cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization. RESULTS: Five-year follow-up was completed in 92.2% of patients. The 5-year TVF rate was 11.6% in deferred lesions, mainly driven by clinically driven target vessel revascularization (9.8%). Cardiac death and target vessel-related myocardial infarction were 1.9% and 0.95%, respectively. Cumulative 5-year incidence of TVF was similar between the FFR 0.75 to 0.80 and 0.81 to 0.85 groups even after adjustment for baseline characteristics (12.2% versus 13.0%, inverse probability-weighted hazard ratio, 0.86 [95% CI, 0.46-1.60]; P=0.63). Compared with the almost normal FFR (0.86-1.00) group, the significant (<0.75) and borderline (0.75-0.85) FFR groups showed a higher incidence of TVF at 5 years (29.9% versus 12.8% versus 8.6%, P<0.001). Independent predictors of the 5-year TVF were hemodialysis, FFR value, left main coronary artery lesion, prior percutaneous coronary intervention, and male sex. CONCLUSIONS: The 5-year TVF rate was 11.6% in deferred lesions, mainly driven by clinically driven target vessel revascularization. Notably, cardiac death and target vessel-related myocardial infarction rarely occurred during the follow-up. Our findings highlight the long-term safety of FFR-based deferral of revascularization in patients with chronic coronary syndrome. Registration: URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000014473.

Association of guideline-directed medical therapy adherence with outcomes after fractional flow reserve-based deferral of revascularization.

AIMS: Guideline-directed medical therapy (GDMT) is essential to prevent future cardiovascular events in chronic coronary syndrome (CCS) patients. However, whether achieving optimal GDMT could improve clinical outcomes in CCS patients with deferred lesions based on fraction flow reserve (FFR) remains thoroughly investigated. We sought to evaluate the association of GDMT adherence with long-term outcomes after FFR-based deferral of revascularization in a real-world registry. METHODS AND RESULTS: This is a post-hoc analysis of the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on fractional flow reserve in multicentre registry). Optimal GDMT was defined as combining four types of medications: antiplatelet drug, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, beta-blocker, and statin. After stratifying patients by the number of individual GDMT agents at 2 years, landmark analysis was conducted to assess the relationship between GDMT adherence at 2 years and 5-year major adverse cardiac events (MACEs), defined as a composite of all-cause death, target vessel-related myocardial infarction, clinically driven target vessel revascularization. Compared with the suboptimal GDMT group (continuing ≤3 types of medications, n = 974), the optimal GDMT group (n = 139) showed a lower 5-year incidence of MACE (5.2% vs. 12.4%, P = 0.02). The optimal GDMT was associated with a lower risk of MACE (hazard ratio: 0.41; 95% confidence interval: 0.18 to 0.92; P = 0.03). CONCLUSION: Patients with optimal GDMT were associated with better outcomes, suggesting the importance of achieving optimal GDMT on long-term prognosis in CCS patients after FFR-guided deferral of revascularization.

Two-Year Outcomes of Asymptomatic vs. Symptomatic Patients After Deferral of Revascularization Based on Fractional Flow Reserve　- Insights From the J-CONFIRM Registry.

Background: The effect of symptoms on clinical outcomes after deferral of revascularization based on fractional flow reserve (FFR) remains poorly understood. Methods and Results: From the J-CONFIRM (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter) Registry, this study evaluated 1,215 patients with stable coronary artery disease, including symptomatic and asymptomatic patients (n=571 and 644, respectively). The primary endpoint was the cumulative 2-year incidence of target vessel failure (TVF), including cardiac death, target vessel-related myocardial infarction (TVMI), and clinically driven target vessel revascularization (CDTVR). An inverse probability weighted analysis was performed to adjust for the differences in baseline clinical characteristics between the 2 groups. At 2 years, the TVF rate did not differ significantly between symptomatic and asymptomatic patients (6.5% vs. 4.9%, respectively; P=0.15) or between symptomatic and asymptomatic patients with lesions with an FFR ≤0.80 (8.0% vs. 12.3%, respectively; P=0.20). Conversely, symptomatic patients showed significantly higher rates of TVF (6.2% vs. 3.3%; P=0.01) and CDTVR (6.2% vs. 3.1%; P=0.009) than asymptomatic patients, regardless of negative FFR values (>0.80). Conclusions: Despite negative FFR values, symptomatic patients were at higher risk of TVF than asymptomatic patients, driven primarily by a higher rate of CDTVR. Conversely, those with a positive FFR were likely to develop TVF regardless of their symptoms.

Two-Year Outcomes After Deferral of Revascularization Based on Fractional Flow Reserve: The J-CONFIRM Registry.

BACKGROUND: The safety of fractional flow reserve (FFR)-based deferral of revascularization remains to be fully established in real-world practice. We sought to assess clinical outcomes after deferral of revascularization based on FFR. METHODS: The J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry) prospectively enrolled 1263 patients with 1447 lesions in whom revascularization was deferred based on FFR at 28 Japanese centers. The primary study end point was the cumulative 2-year incidence of target vessel failure, including cardiac death, target-vessel related myocardial infarction, and clinically driven target vessel revascularization. RESULTS: The mean FFR was 0.86±0.06. At 2 years, the target vessel failure rate was 5.5% in deferred lesions, mainly driven by a high rate of clinically driven target vessel revascularization (5.2%), and significantly increased with decreasing FFR, especially in the proximal location. Cardiac death and target-vessel related myocardial infarction rarely occurred during the 2-year follow-up (0.41% and 0.41%, respectively). Independent predictors of 2-year target vessel failure were FFR value (per 0.01 decrease; hazard ratio [HR] 1.07 [95% CI, 1.04-1.11], P<0.001), left main coronary artery lesion (HR, 5.89 [95% CI, 2.72-12.8], P<0.001), moderately to severely calcified lesion (HR, 2.49 [95% CI, 1.36-4.58]; P=0.003), hemodialysis (HR, 2.90 [95% CI, 1.11-7.58]; P=0.03), and right coronary artery lesion (HR, 1.78 [95% CI, 1.02-3.11], P=0.042). CONCLUSIONS: The J-CONFIRM registry demonstrated the 2-year target vessel failure rate was 5.5% in deferred lesions, highlighting the safety of FFR-based deferral of revascularization in daily practice. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp. Unique identifier: UMIN000014473.

Mineralocorticoid receptor is overexpressed in cardiomyocytes of patients with congestive heart failure.

Mineralocorticoid receptors (MRs) have been identified in the human cardiovascular tissues. We determined MR expression in the failing heart to clarify the mechanism of action of aldosterone antagonist in the treatment of congestive heart failure. MR protein and MR mRNA content were detected by immunohistochemical staining and in situ hybridization in the cardiac tissues. Immunohistochemical staining of the receptor, as well as in situ hybridization of MR mRNA, was dense in cardiomyocytes of the failing left ventricle as compared with the controls. The staining ratio of the cytoplasm to the interstitium showed that MRs were located mainly in the cytoplasm. The cytoplasm to the interstitium in the failing left ventricle was 1.53+/-0.13, which was significantly higher than that of the controls 1.25+/-0.19 (p<0.05). These findings suggest that the efficacy of aldosterone antagonists in treating congestive heart failure may be in part through blocking the MRs, which are upregulated in the failing heart.

Diagnostic use of serum deoxyribonuclease I activity as a novel early-phase marker in acute myocardial infarction.

BACKGROUND: The delayed release of serum cardiac markers such as creatine kinase isoenzyme MB and equivocal early electrocardiographic changes have hampered a diagnosis of acute myocardial infarction (AMI) in the early phase after its onset. Therefore, a reliable serum biochemical marker for the diagnosis of AMI in the very early phase is desirable. METHODS AND RESULTS: Serum samples were collected from the patients with AMI, unstable angina pectoris, stable angina pectoris, and other diseases. Levels of serum deoxyribonuclease I (DNase I) activity in the patients were determined. An abrupt elevation of serum DNase I activity was observed within approximately 3 hours of the onset of symptoms in patients with AMI, with significantly higher activity levels (21.7+/-5.10 U/L) in this group compared with the other groups with unstable angina pectoris (10.4+/-4.41 U/L), angina pectoris (10.8+/-3.70 U/L), and other diseases (9.22+/-4.16 U/L). Levels of the DNase I activity in serum then exhibited a marked time-dependent decline within 12 hours and had returned to basal levels within 24 hours. CONCLUSIONS: We suggest that serum DNase I activity could be used as a new diagnostic marker for the early detection of AMI.

Pitavastatin-induced thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family.

OBJECTIVE: 3-hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. The main feature of the antithrombotic properties of endothelial cells is an increase in the expression of thrombomodulin (TM) without induction of tissue factor (TF) expression. We investigated the effect of statins on the expression of TM and TF by endothelial cells. METHODS AND RESULTS: The incubation of endothelial cells with pitavastatin led to a concentration- and time-dependent increase in cellular TM antigen and mRNA levels. In contrast, the expression of TF mRNA was not induced under the same conditions. A nuclear run-on study revealed that pitavastatin accelerates TM transcription rate. The stimulation of TM expression by pitavastatin was prevented by either mevalonate or geranylgeranylpyrophosphate. Specific inhibition of geranylgeranyltransferase-I and Rac/Cdc42 by GGTI-286 and Clostridium sordellii lethal toxin, respectively, enhanced TM expression, whereas inactivation of Rho by Clostridium botulinum C3 exoenzyme was ineffective. CONCLUSIONS: Statins regulate TM expression via inhibition of small G proteins of the Rho family; Rac/Cdc42. A statin-mediated increase in TM expression by endothelial cells may contribute to the beneficial effects of statins on endothelial function.

Amphiregulin is a potent mitogen for the vascular smooth muscle cell line, A7r5.

The regulation of amphiregulin, an epidermal growth factor (EGF) family member, and its effect on vascular smooth muscle cells (VSMC) were examined. Amphiregulin mRNA was upregulated by amphiregulin itself as well as alpha-thrombin. Amphiregulin caused an approximate 3-fold increase in DNA synthesis. Its effect on growth was compared with those of other mitogens, and was found to be approximately 3.5-, 2.4-, and 1.0-fold greater than those of endothelin-I (ET-I), alpha-thrombin, and platelet-derived growth factor-AB (PDGF-AB), respectively. As evidenced by Western blot analysis, amphiregulin stimulated the phosphorylation of p42/p44-mitogen-activated protein kinase (MAPK), p38-MAPK, c-Jun NH2-terminal protein kinase (JNK), and Akt/protein kinase B (PKB), respectively. By statistical analysis, the amphiregulin-induced growth effect was significantly decreased by the MAP kinase/ extracellular regulated kinase kinase-1 (MEK-1) inhibitor PD98059, p38-MAPK inhibitor SB203580, and phosphatidylinositol 3-kinase (PI-3 kinase) inhibitor wortmannin, respectively, but was not decreased by JNK inhibitor SP600125. These results suggest that amphiregulin is the most potent mitogen of the mitogens tested, and its growth effect is mediated at least in part through the p42/p44-MAPK, p38-MAPK, and PI-3 kinase-Akt/PKB pathways in VSMC.

Myocardial metabolic regulation through peroxisome proliferator-activated receptor alpha after myocardial infarction.

Although peroxisome proliferator-activated receptor alpha (PPARalpha) is closely associated with myocardial fatty acid metabolism, the pathophysiological role of PPARalpha in myocardial infarction (MI) is not yet known. The aim of the present study was to clarify the relationship between cardiac energy metabolism and PPARalpha expression in the remodelling of myocardium after MI. We assayed the expression of PPARalpha and several metabolic genes in cultured cardiac cells (myocytes and nonmyocytes) and in MI hearts. PPARalpha was strongly expressed in cardiac myocytes but not in nonmyocytes (mainly fibroblasts). In MI rats, PPARalpha and PPARalpha-regulated genes (lipoprotein lipase, heart-type fatty acid binding protein, long-chain acyl-CoA dehydrogenase and uncoupling protein-3) were decreased concomitantly, whereas uncoupling protein-2 was not decreased in severely ischemic regions. Immunohistochemical staining for PPARalpha was less decreased in borderline myocardium than in sham-operated hearts. Furthermore, in electron microscopic study, there were no lipid droplet accumulations in surviving myocardium after MI. Our results suggest that the reduced expression of PPARalpha is closely related to that of fatty acid metabolism genes in infarcted myocardium, and PPARalpha may play an important role in cardiac energy metabolism during remodelling after MI.

A role of heparin-binding epidermal growth factor-like growth factor in cardiac remodeling after myocardial infarction.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is known to induce cell growth in various cell types via transactivation of epidermal growth factor receptor (EGFR). To investigate the involvement of HB-EGF and EGFR in cardiac remodeling after myocardial infarction (MI), we examined the expressions of mRNA and protein in rat hearts 6 weeks after MI-induction. Where increased expressions of HB-EGF mRNA and protein were observed, infarcted myocardium was replaced by extracellular matrix and interstitial fibroblasts. EGFR mRNA and protein expression did not show significant changes in sham-operated heart tissues, non-infarcted region, and infarcted region. In vitro study demonstrated that HB-EGF mRNA was expressed mainly in cultured fibroblasts rather than in myocytes. We suggest that the interaction between HB-EGF and EGFR transactivation is closely related to the proliferation of cardiac fibroblasts and cardiac remodeling after MI in an autocrine, paracrine, and juxtacrine manner.

Remnant lipoprotein particles are taken up into myocardium through VLDL receptor--a possible mechanism for cardiac fatty acid metabolism.

The VLDL (very low-density lipoprotein) receptor is a peripheral lipoprotein receptor expressing in fatty acid active tissues abundantly. In the Balb/c fasting mice, VLDL receptor as well as LPL (lipoprotein lipase), FAT (fatty acid translocase)/CD36, H-FABP (heart-type fatty acid-binding protein), ACS (acyl-CoA synthetase) and LCAD (long-chain acyl-CoA dehydrogenase) expressions increased. An electron microscopic examination indicated the lipid droplets that accumulated in the hearts of fasting Balb/c mice. During the development of SD (Sprague-Dawley) rats, VLDL receptor, LPL, FAT/CD36, H-FABP, ACS, and LCAD mRNAs concomitantly increased with growth. However, PK (pyruvate kinase) mRNA expression was negligible. In cultured neonatal rat cardiomyocytes, VLDL receptor expression increased with days in culture. Oil red-O staining showed that cardiomyocytes after 7 days in culture (when the VLDL receptor protein is present) accumulated beta-migrating VLDL. Thereby, we showed that the cardiac VLDL receptor pathway for delivery of remnant lipoprotein particles might be part of a cardiac fatty acid metabolism.