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.

A case report on intravascular lithotripsy to facilitate retrograde wire passage from the subintimal to the luminal space in a calcified chronic total occlusion.

Background: Severe calcifications are a major reason for failures in chronic total coronary occlusions, as they can obstruct the wire passage both in the antegrade and retrograde technique. Case summary: The proximal occlusion of the left anterior descending artery in a 75-year-old man presented with a completely concentric calcified ring all along the segment proximal to the occlusion. The antegrade wire could not pass the calcified occlusion, and in a retrograde approach via the right posterior descending artery the retrograde wire was not able to enter the lumen from a subintimal position outside of the calcified ring. Intravascular lithoplasty in the proximal segment led to a crack in this ring to enable the same retrograde wire now to pass into the true lumen with then successful conclusion of the case. Intravascular ultrasound demonstrated the modification of the calcified ring and the passage of the wire with only a very short subintimal pathway. Discussion: Intravascular lithoplasty is a new option to modify severely calcified vessel segments to facilitate the reverse controlled antegrade and retrograde tracking approach. In the present case, this helped to avoid a long subintimal pathway and preserved the vessel anatomy.

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.

Objective Evaluation With Noncontrast Computed Tomography Can Reveal Calcified Plaque Solidity in Peripheral Artery Diseases.

PURPOSE: The presence of severely calcified plaque remains problematic in endovascular therapy, and no specific endovascular treatment strategy has been established. Estimating plaque solidity before the procedure may help operators penetrate calcified plaque with a guide wire. The aim of this study was to establish a method of measuring plaque solidity with noncontrast computed tomography (CT). METHODS: This retrospective, single-center study included consecutive patients who, between October 2020 and July 2022, underwent noncontrast 5 mm and 1 mm CTs before endovascular therapy to penetrate calcified plaque with a wire in the common femoral, superficial femoral, and popliteal arteries. Three cross-sectional CT slices were selected. To target a calcified plaque lesion, the operator identified a region of interest, which corresponded to 24×24 pixels, and Hounsfield unit (HU) values of each pixel were displayed on the CT image. The average HU values and the ratio of number of pixels of lower values (130-599 HU) represented plaque solidity. We used the Mann-Whitney-Wilcoxon rank-sum test and the chi-square test to compare the solidity of plaques penetrated and not penetrated by the wire. RESULTS: We evaluated 108 images of 36 calcified plaque lesions (in 19 patients). The wire penetrated 28 lesions (77.8%) successfully. The average HU value was significantly lower in the lesions that the wire penetrated than in the others, in both the 5 mm CT slices (434.7±86.8 HU vs 554.3±112.7 HU, p=0.0174) and 1 mm slices (497.8±103.1 HU vs 593.5±114.5 HU, p=0.0381). The receiver operating curve revealed that 529.9 and 533.9 HU in the 5 and 1 mm slices, respectively, were the highest values at which wires could penetrate. Moreover, at the lesions that were penetrates successfully, the ratio of number of lower HU value pixels was significantly higher both in 5 mm slice CTs (74.7±13.4 vs 61.7±13.1%, p=0.0347) and 1 mm (68.7±11.8 vs 57.1±11.4%, p=0.0174). CONCLUSION: The use of noncontrast CT to evaluate plaque solidity was associated with successful wire penetration of calcified lesions in peripheral arteries. CLINICAL IMPACT: This study revealed an association between the wire penetration inside calcified plaque and plaque solidity estimated using non-contrasted computed tomography. The mean Hounsfield unit values of three cross-sections in calcified plaques were associated with the successful wire penetration. This wire penetration difficulty is associated with extended procedure time, excessive radiation exposure, usage of extra contrast agents, and increased medical costs. Therefore, estimating calcified plaque solidity before procedure enables us to choose effective and lean procedures. In addition, to predict the success of dilating calcified plaque from the inside is also beneficial when the operator wants to avoid extra scaffold implantation for target lesions.

Impact of bystander cardiopulmonary resuscitation on neurological outcomes in patients undergoing veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) requires a large amount of economic and human resources. The presence of bystander cardiopulmonary resuscitation (CPR) was focused on selecting appropriate V-A ECMO candidates. RESULT: This study retrospectively enrolled 39 patients with V-A ECMO due to out-of-hospital cardiac arrest (CA) between January 2010 and March 2019. The introduction criteria of V-A ECMO included the following: (1) < 75 years old, (2) CA on arrival, (3) < 40 min from CA to hospital arrival, (4) shockable rhythm, and (5) good activity of daily living (ADL). The prescribed introduction criteria were not met by 14 patients, but they were introduced to V-A ECMO at the discretion of their attending physicians and were also included in the analysis. Neurological prognosis at discharge was defined using The Glasgow-Pittsburgh Cerebral Performance and Overall Performance Categories of Brain Function (CPC). Patients were divided into good or poor neurological prognosis (CPC ≤ 2 or ≥ 3) groups (8 vs. 31 patients). The good prognosis group had a significantly larger number of patients who received bystander CPR (p = 0.04). The mean CPC at discharge was compared based on the combination with the presence of bystander CPR and all five original criteria. Patients who received bystander CPR and met all original five criteria showed significantly better CPC than patients who did not receive bystander CPR and did not meet some of the original five criteria (p = 0.046). CONCLUSION: Considering the presence of bystander CPR help in selecting the appropriate candidate of V-A ECMO among out-of-hospital CA cases.

Five-Year Outcomes After Fractional Flow Reserve-Guided Deferral of Revascularization in Infarct-Related Artery Lesions.

Background: Little evidence is available about the long-term safety of fractional flow reserve (FFR)-guided deferral of revascularization in infarct-related artery (IRA) lesions, especially when measuring FFR in the late setting after myocardial infarction (MI). This study aimed to assess the long-term outcomes after deferral of revascularization in IRA lesions based on FFR assessed in the late phase of post-MI. Methods: From the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), data on 1447 lesions (1263 patients) were divided into 2 groups: the IRA and non-IRA groups. The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), such as cardiac death, target vessel-related MI, and clinically driven target vessel revascularization. Results: Of the 1447 lesions, 138 (9.5%) were classified into the IRA group. The median duration of FFR measurement was 716 days after MI. The frequency of visual-functional mismatches (ie, FFR >0.80 and percent diameter stenosis ≥50% or FFR ≤0.80 and percent diameter stenosis <50%) was comparable between the IRA and non-IRA groups (31.9% vs 36.3%). The cumulative 5-year incidence of TVF did not differ between the groups (9.2% vs 11.8%; inverse probability-weighted hazard ratio, 1.18, 95% confidence intervals, 0.48-2.91, P = .71). Similar results were observed irrespective of regional wall motion assessed by ultrasonic cardiography and acute MI type. Conclusions: The 5-year TVF rate did not differ between the IRA and non-IRA lesions when deferring revascularization guided by FFR in the late setting of post-MI.

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.

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.

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).

Reducing Fluoroscopic and Cineangiographic Contribution to Radiation Exposure for Chronic Total Coronary Occlusion Interventions.

BACKGROUND: The treatment of chronic total coronary occlusions (CTO) carries the highest radiation exposure among percutaneous coronary interventions (PCI). In order to minimize radiation damage, we need to understand and optimize the contribution of all components of radiation exposure. METHODS: A total of 1000 CTO procedures performed between 2011 and 2020 were compared according to implemented radiation modifications. Group 1 used the original set-up of the X-ray equipment (Artis Zee, Siemens). In group 2 a modified protocol aimed at reducing the fluoroscopy exposure, in group 3 further modifications aimed at reducing cineangiographic exposure. RESULTS: Despite an increased lesion complexity, Air Kerma (AK) was reduced from 2619 mGy (1653-4574) in group 1 to 2178 mGy (1332-3500; p < 0.001) in group 2 by mainly reducing fluoroscopic contribution by 54.1%, the cineangiographic contribution was lowered by only 6.6%. In group 3 AK dropped drastically to 746 mGy (480-1225; p < 0.001) mainly by reducing the cineangiographic contribution by 53.4%, still there was a further reduction of fluoroscopy contribution of 8.2%. This also led to a reduction of the skin entry dose from 1038 mGy (690-1589) in group 2 to 359 mGy (204-591; p < 0.001) in group 3. This was achieved both in normal weight and obese patients, and both in antegrade and retrograde procedures. CONCLUSIONS: The present study demonstrates that by modifying both the fluoroscopic and cineangiographic contribution to radiation exposure a drastic reduction of radiation risk can be achieved, even in obese patients. Currently accepted radiation thresholds may no longer be a limit for CTO PCI.

A Case of ST-Elevation Acute Myocardial Infarction in a Nonhospitalized Patient with SARS-CoV-2 Pneumonia: Treatment with Primary Percutaneous Coronary Intervention.

We experienced a case of primary percutaneous coronary intervention for ST-elevation myocardial infarction (STEMI) with coronavirus disease 2019 (COVID-19) using appropriate infection prevention protocol. However, recanalization was difficult due to severe coagulopathy. Further researches are needed to clarify optimal treatment for STEMI in patients with COVID-19.

A prospective study on the incidence of contrast-associated acute kidney injury after recanalization of chronic total coronary occlusions with contemporary interventional techniques.

BACKGROUND: Contrast-associated acute kidney injury (CA-AKI) is a potential risk associated with the percutaneous coronary interventions (PCI) for chronic total coronary occlusions (CTO). This study should evaluate the incidence of CA-AKI in an era of advanced strategies of recanalization techniques and identify modifiable determinants. METHODS: We analysed 1924 consecutive CTO procedures in 1815 patients between 2012 and 2019. All patients were carefully monitored at least up to 48 h after a CTO procedure for changes in renal function. RESULTS: The incidence of CA-AKI was 5.6%, but there was no relation to the technical approach such as frequency of the retrograde technique, intravascular ultrasound or radial access. Procedures with CA-AKI had longer fluoroscopy times (37.6 vs 46.1 min; p = 0.005). The major determinants of CA-AKI were age, presence of diabetes and reduced ejection fraction, as well as chronic kidney disease stage ≥2, serum haemoglobin, and fluoroscopy time. Contrast volume or contrast volume/GFR ratio were not independent determinants of CA-AKI. Periprocedural perforations were more frequent in CA-AKI patients (11.3 vs 2.3%; p < 0.001), and in-hospital mortality was higher (2.8 vs 0.4%; p < 0.001). CONCLUSIONS: CA-AKI was associated with the risk of in-hospital adverse events. Established patient-related risk factors for CA-AKI (age, diabetes, preexisting chronic kidney disease, low ejection fraction) were confirmed in this study. In addition, the length of the procedure, coronary perforations and low preprocedural serum haemoglobin were risk factors that might be preventable in patients at high risk for CA-AKI.

Resolving chronic stent under-expansion in calcified lesions by intravascular lithoplasty.

Severe coronary calcification is a common cause for stent under-expansion, which is associated with an increased risk of stent thrombosis and restenosis. Presently the devices for treatment of under-expanded stent due to severe calcification are rotational atherectomy and high-pressure non-compliant balloons with the limitation of potential balloon rupture and perforation risk. We report on a series of seven successful treatments of chronically under-expanded stents due to severe calcification using shockwave coronary intravascular lithoplasty (IVL). Our report suggests that IVL is a feasible and safe tool for such chronically under-expanded stents. .

Modulated radiation protocol achieves marked reduction of radiation exposure for chronic total coronary occlusion intervention.

OBJECTIVE: To evaluate the feasibility of a new acquisition protocol to reduce radiation exposure. BACKGROUND: Percutaneous coronary interventions (PCI) for chronic total coronary occlusions (CTO) are characterized by the highest radiation exposure among PCI procedures. METHODS: We analyzed 552 consecutive CTO procedures between January 2018 and October 2019. After 366 procedures (Group 1) a modified radiation acquisition protocol was implemented for the subsequent 186 procedures (Group 2). Besides a low fluoroscopy frame rate of 6/s and cine frame rate of 7.5/s for both groups, additional modifications consisted of increased copper filtering with lower entry dose in combination with a modified image postprocessing. Radiation exposure was assessed as air kerma (AK; mGy), and dose-area product (DAP; cGy*cm2 ). RESULTS: There was no significant difference in lesion or procedural complexity between the study groups with 46 and 43% of the procedures done via the retrograde approach. While fluoroscopy time remained similar (median: 32.7 vs. 34.3 min), the protocol modifications resulted in a drastic reduction of AK by 68% from 2,040 (1,321-3,339) mGy to 655 (415-1,113) mGy (p < .001) without affecting the procedural success rate. DAP was equally decreased by 71%. These considerable reductions were observed even in obese patients of BMI > 30. In Group 2, not a single procedure exceeded the 5 Gy threshold as compared to 10.4% in Group 1. CONCLUSIONS: Radiation exposure decreased considerably with a new acquisition protocol without affecting procedure duration and success. These modifications were applicable also to patients with a high BMI.

Association between cognitive impairment patient with solid cancer and insulin resistance.

OBJECTIVES: In an aging population, an increase in the number of elderly cancer patients with cognitive impairment is expected. The possible association between cancer and cognitive impairment is important to elucidate, because it can have a serious impact on quality of life. Here, we focused on glucose metabolism as a factor that links cancer and cognitive impairment. RESULTS: Thirteen subjects with solid cancers and cognitive impairment were recruited. As a control group, 14 subjects with cognitive impairment alone and 8 subjects with cancer alone were recruited. A Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and that of ß-cell function (HOMA-B) were used. In comparison with patients with solid cancer alone, those with cognitive impairment alone and those with both cancer and cognitive impairment had increased HOMA-IR values. Insulin resistance was increased in patients with cognitive impairment alone and those with both cognitive impairment and solid cancer than in patients without cognitive impairment; however, ß-cell function was not affected. The present data indicated that elderly cancer patients with high HOMA-IR score may be at a relatively high risk for developing cognitive impairment. Furthermore, early treatment to reduce insulin sensitivity may prevent cognitive impairment.