Glucagon-like Peptide-1 analogues and delipidation of coronary atheroma in statin-treated type 2 diabetic patients with coronary artery disease: The prespecified sub-analysis of the OPTIMAL randomized clinical trial.

Background and aims: Randomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. Methods: The OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). Results: All patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to -0.5) vs. -0.4 (-0.6 to -0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to -0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to -1.3) vs. -0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (-0.9 ± 0.25 vs. -0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19-16.30, p = 0.02). Conclusions: In statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.

The effect of continuous glucose monitoring-guided glycemic control on progression of coronary atherosclerosis in type 2 diabetic patients with coronary artery disease: The OPTIMAL randomized clinical trial.

BACKGROUND: Continuous glucose monitoring (CGM) improves glycemic fluctuation and reduces hypoglycemic risk. Whether CGM-guided glycemic control favorably modulates coronary atherosclerosis in patients with type 2 diabetes (T2DM) remains unknown. METHODS: The OPTIMAL trial was a prospective, randomized, single-center trial in which 94 T2DM patients with CAD were randomized to CGM- or HbA1c-guided glycemic control for 48 weeks (jRCT1052180152). The primary endpoint was the nominal change in total atheroma volume (TAV) measured by serial IVUS. The secondary efficacy measure was the nominal change in maxLCBI4mm on near-infrared spectroscopy imaging. RESULTS: Among the 94 randomized patients, 82 had evaluable images at 48 weeks. Compared to HbA1c-guided glycemic control, CGM-guided control achieved a greater reduction in %coefficient of variation [-0.1 % (-1.8 to 1.6) vs. -3.3 % (-5.1 to -1.5), p = 0.01] and a greater increase in the duration with glucose between 70 and 180 mg/dL [-1.5 % (-6.0 to 2.9) vs. 6.7 % (1.9 to 11.5), p = 0.02]. TAV increased by 0.11 ± 1.9 mm3 in the HbA1c-guided group and decreased by -3.29 ± 2.00 mm3 in the CGM-guided group [difference = -3.4 mm3 (95%CI: -8.9 to 2.0 mm3), p = 0.22]. MaxLCBI4mm, increased by 90.1 ± 25.6 in the HbA1c-guided group and by 50.6 ± 25.6 in the CGM-guided group (difference = -45.6 (95%CI: -118.1 to 26.7) p = 0.21]. A post-hoc exploratory analysis showed a greater regression of maxLCBI4mm in the CGM-guided group [difference = 20.4 % (95%CI:1.3 to 39.5 %), p = 0.03]. CONCLUSIONS: CGM-guided control for 48 weeks did not slow disease progression in T2DM patients with CAD. A greater regression of lipidic plaque under CGM-guided glycemic control in the post-hoc analysis requires further investigation.

Incessant non-sustained ventricular tachycardia immediately after MitraClip placement: a case report.

Background: MitraClip therapy has become an alternative therapy for primary and secondary mitral regurgitation (MR) in patients at high surgical risk. However, this procedure is associated with several complications. Case summary: The patient was a 93-year-old male with severe MR caused by prolapse of the mid-posterior mitral leaflet (P2) and atrial enlargement. His heart failure (HF) continued to worsen, requiring hospitalization. Considering his high surgical risk, the heart team chose MitraClip treatment. After one clip was placed in the centre of the mitral valve (P2 lateral side), MR severity was reduced from severe to trivial. However, immediately after grasping, incessant non-sustained ventricular tachycardia (VT) with a heart rate of 150 beats/min occurred. Since there were no significant ST-T changes on electrocardiogram and no left ventricular (LV) wall motion abnormalities on echocardiography, ischaemic heart disease was ruled out, and pacing with a temporary pacemaker, potassium level correction, and intravenous amiodarone administration were performed. The frequency of VT decreased but it did not disappear. Diuretics were administered for HF, and VT disappeared within a few hours, with no recurrence, probably due to a decrease in the LV chamber size after diuresis. Discussion: The VT waveform showed a right bundle branch block pattern with a superior axis. Furthermore, a negative lead I and a transition zone with an abrupt change from V4 to V5 indicated that PVC/VT arose from the posterior papillary muscle area. The probable cause was mechanical extension of the posterior medial papillary muscle as a result of leaflet grasping, with resolution following appropriate volume management.

Characterization of Polyvascular Disease in Heterozygous Familial Hypercholesterolemia: Its Association With Circulating Lipoprotein(a) Levels.

Background Heterozygous familial hypercholesterolemia (HeFH) more likely exhibits extensive atherosclerotic disease at multiple vascular beds. Lipoprotein(a) (Lp(a)) is an atherogenic lipoprotein that elevates HeFH-related atherosclerotic cardiovascular disease risks. Whether circulating Lp(a) level associates with polyvascular propagation of atherosclerosis in subjects with HeFH remains uncertain. Methods and Results The current study analyzed 370 subjects with clinically diagnosed HeFH who received evaluation of systemic arteries. Polyvascular disease (polyVD) was defined as more than 2 coexisting atherosclerosis conditions including coronary artery disease, carotid stenosis, or peripheral artery disease. Clinical characteristics and lipid features were analyzed in subjects with HeFH and polyVD; 5.7% of patients with HeFH (21/370) had polyVD. They were more likely to have a clustering of risk factors, tendon (P<0.001) and skin xanthomas (P=0.004), and corneal arcus (P=0.026). Furthermore, an elevated Lp(a) level (P=0.006) and a greater frequency of Lp(a) level ≥50 mg/dL (P<0.001) were observed in subjects with HeFH and polyVD. On multivariable analysis adjusting risk factors and lipid-lowering agents, Lp(a) ≥50 mg/dL (odds ratio [OR], 5.66 [95% CI, 1.68-19.0], P=0.005), age, and family history of premature coronary artery disease independently predicted polyVD in subjects with HeFH. Of note, the prevalence of polyVD rose to 33.3% in patients with HeFH and age >58 years old, family history of premature coronary artery disease, and Lp(a) ≥50 mg/dL (OR, 10.3 [95% CI, 3.12-33.4], P<0.001). Conclusions An increased level of circulating Lp(a) levels predicted concomitance of polyVD in patients with HeFH. The current findings suggest subjects with HeFH and Lp(a) ≥50 mg/dL as a high-risk category who require meticulous screening of systemic vascular beds.

How Can We Identify Very High-Risk Heterozygous Familial Hypercholesterolemia?

Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder that elevates low-density lipoprotein cholesterol and increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). However, despite their atherogenic lipid profiles, the cardiovascular risk of HeFH varies in each individual. Their variety of phenotypic features suggests the need for better risk stratification to optimize their therapeutic management. The current review summarizes three potential approaches, including (1) definition of familial hypercholesterolemia (FH)-related risk scores, (2) genetic analysis, and (3) biomarkers. The International Atherosclerosis Society has recently proposed a definition of severe FH to identify very high-risk HeFH subjects according to their clinical characteristics. Furthermore, published studies have shown the association of FH-related genetic phenotypes with ASCVD, which indicates the genetic analysis's potential to evaluate individual cardiovascular risks. Biomarkers reflecting disease activity have been considered to predict the formation of atherosclerosis and the occurrence of ASCVD in HeFH subjects. Incorporating these risk stratifications will be expected to allocate adequate intensity of lipid-lowering therapies in HeFH subjects, which ultimately improves cardiovascular outcomes.

Repeated loss of consciousness as the first symptom of recurrence of head and neck malignancy: a case report.

BACKGROUND: Head and neck malignancies rarely cause reflex syncope. Three mechanistic patterns of reflex syncope are known in such patients: carotid sinus syndrome, glossopharyngeal neuralgia syndrome, and parapharyngeal space lesions syncope syndrome. There are few reports describing parapharyngeal space lesions syncope syndrome. CASE SUMMARY: A 61-year-old man with a history of head and neck cancer underwent left lingual resection and left anterior cervical lymph node dissection followed by chemoradiotherapy. Two months later, he experienced his first syncope and was admitted to our hospital for further investigation. During the first few days in the hospital, he experienced loss of consciousness. Carotid artery massage and cervical rotation-extension examinations revealed no abnormalities, and glossopharyngeal neuralgia was not observed. Cervical computed tomography showed recurrence of tongue cancer infiltrating the para-nasopharyngeal space. Consequently, the patient had sinus pause during the loss of consciousness; hence, we suspected parapharyngeal space lesions syncope syndrome. Pacemaker implantation was considered but could not be performed as the patient passed away because of the original malignancy. DISCUSSION: Parapharyngeal space tumours are often characterized by the absence of subjective symptoms, although symptoms such as neck swelling and discomfort in the throat have been reported. Parapharyngeal space lesions syncope syndrome is caused by tumour invasion into the parapharyngeal space, and there is no known trigger for syncope. Our case is unique because the patient's first symptom of recurrence of tongue cancer infiltrating the para-nasopharyngeal space was repeated loss of consciousness.

Substantially Elevated Atherosclerotic Risks in Japanese Severe Familial Hypercholesterolemia Defined by the International Atherosclerosis Society.

Background: The International Atherosclerosis Society (IAS) has proposed "severe familial hypercholesterolemia" (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown. Objectives: This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH. Methods: This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n = 135) and non-severe (n = 227) FH. Results: Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol (P < 0.001) and lipoprotein(a) (P = 0.03) levels. Moreover, they more frequently received high-intensity statin (P < 0.001), PCSK9 inhibitor (P < 0.001), and lipoprotein apheresis (P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9 mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite (P < 0.001), cardiac (P < 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first (P < 0.001) and of subsequent (P < 0.001) composite outcomes in subjects with severe FH. Conclusions: Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management.

Novel Evaluation Method for Lower Extremity Peripheral Artery Disease With Duplex Ultrasound　- Usefulness of Acceleration Time.

BACKGROUND: Duplex ultrasound scanning (DUS) plays a major role in less invasive diagnosis and assessment of lesion severity in lower extremity peripheral artery disease (PAD). In this study, we evaluated the efficacy of each DUS parameter measured in patients with PAD and established a simple method for PAD evaluation.Methods and Results:We retrospectively investigated 211 patients (270 limbs) who underwent assessment with both angiography and DUS. During DUS of the common femoral artery (CFA) and popliteal artery, we measured 3 parameters: acceleration time (AcT), peak systolic velocity (PSV), and waveform contour. We compared these parameters with the degree of angiographic stenosis. AcT at the CFA had a significantly higher value in prediction of aortoiliac artery lesions with >50% stenosis (c-index, 0.85; 95% confidence interval (CI), 0.79-0.91), with a sensitivity of 0.82 and specificity of 0.76 at the best cutoff point, compared with PSV and waveform contour (P<0.001, respectively). For femoropopliteal lesions, the ratio of AcT at the popliteal artery to AcT at the CFA is the most predictive parameter, with sensitivity of 0.86 and specificity of 0.92 at the best cutoff point (c-index, 0.93; 95% CI, 0.90-0.97), compared with others (P<0.001, respectively). CONCLUSIONS: For the assessment of PAD with DUS, AcT and AcT ratio are simple and reliable parameters for evaluating aortoiliac and femoropopliteal artery disease.

Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients.

BACKGROUND: In the field of palliative care, morphine is known to be effective for alleviating dyspnea in cancer patients. However, little is known regarding the safety and efficacy of morphine therapy for refractory dyspnea as palliative care in advanced heart failure (HF) patients. METHODS: We retrospectively reviewed consecutive advanced HF patients who were referred to the Palliative Care Team at our institution and administered morphine for refractory dyspnea during hospitalization between September 2013 and December 2018. We investigated the details of morphine usage, vital signs, an 11-point quantitative symptom scale, and adverse events at baseline, 24 h, and 72 h after the start of treatment. RESULTS: Morphine was administered for refractory dyspnea in 43 advanced HF patients [mean age: 73.5 years, male: 28 (65%), New York Heart Association functional class IV: 43 (100%), median left ventricular ejection fraction: 25%, median B-type natriuretic peptide level: 927 pg/ml, concurrent intravenous inotrope: 33 (77%)]. Median initial dose of morphine was 5 mg/day in both oral and intravenous administration and median duration of administration was 5 days. Significant decreases in an 11-point quantitative symptom scale [7 (5, 9) vs. 2 (1, 6); p < 0.01, (data available in 8 patients)] and respiratory rate (22.2 ± 6.1 vs. 19.7 ± 5.2 breaths per minute; p < 0.01) were observed 24 h after the start of morphine administration. Meanwhile, oxygen saturation, blood pressure, and heart rate were not significantly altered after treatment (NS). Common adverse events were delirium (18%) and constipation (8%); however, no lethal adverse event definitely related to morphine therapy occurred during treatment. CONCLUSIONS: This single-center retrospective study revealed the clinical practice of morphine therapy and suggested that morphine therapy might be feasible for refractory dyspnea as palliative care in advanced HF patients.

Elevated admission urinary N-acetyl-ß-D-glucosamidase level is associated with worse long-term clinical outcomes in patients with acute heart failure.

BACKGROUND: The prognostic significance of urinary N-acetyl-ß-D-glucosamidase in acute heart failure has not been fully elucidated. Accordingly, this study investigated whether urinary N-acetyl-ß-D-glucosamidase could be associated with subsequent adverse events in acute heart failure patients. METHODS: We studied 708 consecutive acute heart failure patients who had accessible N-acetyl-ß-D-glucosamidase data on admission from the National Cerebral and Cardiovascular Center Acute Decompensated Heart Failure registry. We assessed the relationship between the admission N-acetyl-ß-D-glucosamidase level and the combined endpoint of all-cause death and worsening heart failure. Worsening heart failure was defined as worsening symptoms and signs of heart failure requiring intensification of intravenous therapy such as diuretics, vasodilators and inotropes or initiation of mechanical support after stabilisation with initial treatment during hospitalisation, or readmission due to heart failure after discharge. RESULTS: During a median follow-up period of 763 (interquartile range 431-1028) days, higher urinary N-acetyl-ß-D-glucosamidase was significantly related to increased events of all-cause death and worsening heart failure. In addition, patients with higher urinary N-acetyl-ß-D-glucosamidase and lower estimated glomerular filtration rate on admission had the worst clinical outcomes. In multivariable Cox regression, urinary N-acetyl-ß-D-glucosamidase on admission was independently associated with adverse events (hazard ratio 1.19, 95% confidence interval 1.04-1.35) even after adjustment by covariates including the baseline estimated glomerular filtration rate. CONCLUSIONS: Higher urinary N-acetyl-ß-D-glucosamidase level on admission was independently associated with worse clinical outcomes. Our findings indicate the potential value of assessing urinary N-acetyl-ß-D-glucosamidase on admission for further risk stratification in patients with acute heart failure.

Rationale and Design of a Prospective, Multicenter, Single-Arm Clinical Trial to Investigate the Safety and Effectiveness of Rotablator Atherectomy System as an Adjunctive Device for Endovascular Treatment of Occlusive Atherosclerotic Lesions in Below-the-Knee Arteries With Critical Limb Ischemia (RESCUE-BTK).

Background: Endovascular treatment with balloon angioplasty plays a major role in revascularization of below-the-knee (BTK) arteries in patients with critical limb ischemia (CLI). However, with severely calcified lesions, achieving optimal revascularization with balloon angioplasty alone is difficult. Therefore, we are evaluating the safety and effectiveness of the Rotablator atherectomy system as an adjunctive device in the treatment of severely calcified lesions in BTK arteries in the RESCUE-BTK trial, a multicenter, single-arm, open-label, exploratory investigator-initiated clinical study of medical devices. In this paper we describe the design of the trial. Methods and Results: Seventeen patients with CLI in whom balloon angioplasty has failed are enrolled in the study. The primary endpoint is the procedural success rate of balloon angioplasty after rotational atherectomy. Success is defined as the fulfillment of 3 requirements upon assessment by the core laboratory: (1) final residual diameter stenosis <50%; (2) the absence of a delay in flow or vessel perforation in the target artery, or both; and (3) brisk antegrade flow to the foot. Key secondary endpoints are the number of complications associated with the trial procedures and the limb salvage rate. Participants are followed-up for 6 months after the trial procedures. Conclusions: The RESCUE-BTK trial will clarify the safety and effectiveness of the adjunctive use of the Rotablator system in severely calcified lesions of BTK arteries in patients with CLI.

Survey of Palliative Sedation at End of Life in Terminally Ill Heart Failure Patients　- A Single-Center Experience of 5-Year Follow-up.

BACKGROUND: Little is known about palliative sedation in terminally ill heart failure (HF) patients.Methods and Results:We retrospectively reviewed terminally ill HF patients who received palliative sedation from September 2013 to August 2018. Among 95 terminally ill HF patients, 25 were prescribed dexmedetomidine and 12 were prescribed midazolam at the end of life. Richmond Agitation-Sedation Scale was significantly reduced (P<0.01), but blood pressure and heart rate were unaltered after treatment in both the dexmedetomidine and midazolam groups. CONCLUSIONS: Prescription of dexmedetomidine and/or midazolam might be feasible in selected terminally ill HF patients.

Depressive Status in Patients With Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: The present comparative study with healthy volunteers was conducted to investigate the depressive status and temperament in patients with chronic thromboembolic pulmonary hypertension (CTEPH).Methods and Results:The results of the temperament and personality scale test, and the Quick Inventory of Depressive Symptomatology-Self Report revealed that CTEPH patients have a significantly higher depressive status than healthy volunteers. CONCLUSIONS: It may be that CTEPH patients are more likely to have a depressive temperament in origin. It is expected that the relationship between the biological traits of CTEPH (e.g., genetics) and patients' depressive temperament will be elucidated in the future.