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We aimed to investigate the characteristics and outcomes of HTx recipients with a history of pretransplant malignancy (PTM). Among 1062 HTx recipients between 1997 and 2013, 73 (7.1%) patients had PTMs (77 cancer cases). We analyzed post-HTx outcome, recurrence of PTM, and development of de novo malignancies. Post-HTx outcome included overall survival, 10-year survival, 10-year freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). Four most common PTMs were lymphoproliferative disorders (18.2%), prostate cancers (18.2%), non-melanoma skin cancers (18.2%), and breast cancers (13.0%). Median time from PTM and HTx was 9.0 years. During a median follow-up of 8.6 years after HTx, patients with PTM, compared to those without, showed significantly higher incidence of posttransplant malignancies (43.8% vs. 20.8%, p< .001) including 9.6% (n= 7) of PTM recurrences. However, patients with PTM, compared to those without, showed comparable overall survival, 10-year survival, 10-year freedom from CAV, NF-MACE, ATR, ACR, and AMR. Therefore, a history of PTM should not disqualify patients from HTx listing, while further research is necessary for early detection of posttransplant malignancies in these patients.

Familial transthyretin amyloidosis may manifest with several ocular findings. No ocular involvement has yet been identified for all patients with familial transthyretin amyloidosis. Patients with familial transthyretin amyloidosis having Asp38Ala and Thr59Lys mutations may manifest with ocular findings such as anterior lens capsule opacity and retinal deposits.

The mass spectrometry-based analysis of protein post-translational modifications requires large amounts of sample, complicating the analysis of samples with limited amounts of proteins such as clinical biopsies. Here, we present a tip-based N-terminal analysis method, tipNrich. The entire procedure is processed in a single pipette tip to minimize sample loss, which is so highly optimized to analyze small amounts of proteins, even femtomole-scale of a single protein. With tipNrich, we investigated various single proteins purified from different organisms using a low-resolution mass spectrometer and identified several N-terminal peptides with different Nt-modifications such as ragged N-termini. Furthermore, we applied matrix-assisted laser desorption ionization time-of-flight mass spectrometry to our method for shortening the analysis time. Moreover, we showed that our method could be utilized in disease diagnosis as exemplified by the characterization of wild-type transthyretin amyloidosis patients compared to the healthy individuals based on N-terminome profiling. In summary, tipNrich will satisfy the need of identifying N-terminal peptides even with highly scarce amounts of proteins and of having faster processing time to check the quality of protein products or to characterize N-terminal proteoform-related diseases.

Aesthetically appealing photovoltaic (PV) panels with colorful layers are used in numerous applications involving color matching with the surroundings. To develop a colored film for a PV system, appropriate optical properties such as high transparency and low angle sensitivity are necessary because the colored layers can reduce the efficiency of the PV system by causing variations in the transmittance and angle of incidence. Herein, we propose a facile fabrication method for bioinspired three-dimensional (3D) photonic crystal (PC) films that exhibit broad angle-insensitive transmission and reflection, for application in colorful PV. This structure, patterned on a sequentially stacked 11-layer film of SiO2and TiO2, is fabricated via nanoimprint lithography and a one-step dry-etching process, without using a metal mask. The changes in transmission and reflection are observed via ultraviolet–visible spectroscopy and from the reflected images obtained under various angles. The transmittance dips of the 3D PC film shift by less than 10 nm in wavelength, for angles from 0 to 45°, indicating low angle dependency. In addition, the change in the observed color, with respect to the viewing position, is less in the fabricated film. Once the 3D PC film was added to a commercial PV cell, it exhibited a higher efficiency (approximately 6% upper) when compared to a cell with a one-dimensional PC film, during the duration of the experiment, from 0 to 30°. Thus, the proposed method demonstrates excellent potential for developing structural color films for achieving aesthetically appealing PV cells.

ObjectiveMyocardial ischaemia is a leading cause of acute heart failure (AHF). However, optimal revascularisation strategies in AHF are unclear. We aimed to compare two revascularisation strategies, coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI), in patients with AHF.MethodsAmong 5625 consecutive patients enrolled prospectively in the Korean Acute Heart Failure registry from March 2011 to February 2014, 717 patients who received CABG or PCI during the index hospitalisation for AHF were included in this analysis. We compared adverse outcomes (death, rehospitalisation for HF aggravation or cardiovascular causes, ischaemic stroke and a composite outcome of death and rehospitalisation for HF aggravation or cardiovascular causes) with the use of propensity score matching.ResultsFor the propensity score-matched cohort with 190 patients, CABG had a lower risk of all-cause mortality than PCI (83 vs 147 deaths per 1000 patient-years; HR 0.57, 95% CI 0.34 to 0.96, p=0.033) during the median follow-up of 4 years. There was also a trend towards lower rates of rehospitalisation due to cardiovascular events or HF aggravation. Subgroup analysis revealed that the adverse outcomes were significantly lower in the CABG group than in PCI group, especially in patients with old age, three-vessel diseases, significant proximal left anterior descending artery disease and those without left main vessel disease or chronic total occlusion.ConclusionsCompared with PCI, CABG is associated with significant lower all-cause mortality in patients with AHF. Further studies should evaluate proper revascularisation strategies in AHF.Clinical trial registrationNCT01389843; Results.

ObjectivesThis study evaluated the relationship between guideline adherence for recommended therapy on discharge and relevant 60-day and 1-year clinical outcomes in patients with acute heart failure (HF) with reduced ejection fraction and atrial fibrillation (AF).MethodsOf 5625 acute patients with HF in the Korean Acute Heart Failure registry, 986 patients with HF and documented AF were analysed. Guideline adherence scores were calculated for the prescription of ACE inhibitors, angiotensin receptor blockers, β-blockers, mineralocorticoid receptor antagonists and anticoagulants.ResultsIn patients with HF with AF, there was a significant trend of reduced 60-day and 1-year mortality rates and the composite end point with guideline adherence. According to the Cox proportion hazard model, poor adherence was associated with a significantly higher risk of 60-day mortality (HR 4.75; 95% CI 1.77 to 12.74) and the composite end point (HR 2.36; 95% CI 1.33 to 4.18) compared with good adherence. Furthermore, poor adherence was associated with a significantly higher risk of 1-year mortality compared with moderate (HR 1.64; 95% CI 1.15 to 2.33) and good adherence (HR 2.34; 95% CI 1.39 to 3.97) and with a higher risk of the 1-year composite end point compared with good adherence (HR 1.58; 95% CI 1.07 to 2.33).ConclusionBetter adherence to guidelines was associated with better 60-day and 1-year prognoses in patients with HF with AF.

The optimal time for initiating β-blocker (BB) treatment in patients with severe acute decompensated heart failure requiring inotropic therapy has not been well defined. We evaluated the effect of predischarge initiation of BB treatment on clinical outcomes.

In SPR structure panel, GIP circuit which is different from normal RGB should be applied, and GIP circuit should be designed by referring to the concept applied in the algorithm. In SPR applying 2x2 pixel algorithm, interlace driving can be applied by changing the design so that GIP driving is driven in 2 line units, which can save power by 20% or more.

This study sought to examine the impact of door-to-diuretic (D2D) time on mortality in patients with acute heart failure (AHF) who were presenting to an emergency department (ED).

ObjectivesHyponatraemia is a well-known predictor of clinical outcomes in heart failure (HF). However, the mechanism remains poorly understood. Previous reports suggest that hyponatraemia is related to right HF. We sought to evaluate the association between right ventricular (RV) dysfunction and hyponatraemia, and the impact of this relationship on the prognosis of patients with acute heart failure (AHF).MethodsThis is a nested case–control study of the Korean Acute Heart Failure registry. Among 2935 AHF patients enrolled prospectively and consecutively at four tertiary hospitals in Korea from 2011 to 2014, 116 patients with severe persistent hyponatraemia, defined as serum sodium level <130 mmol/L at admission and <135 mmol/L before discharge, were matched with 232 controls, based on propensity scores for hyponatraemia. RV function was assessed with fractional area change (FAC) by echocardiography.ResultsRV dysfunction (FAC <35%) was more prevalent in patients with severe persistent hyponatraemia than in those without (81.0% vs 33.6%, p<0.001). Hyponatraemia was strongly associated with RV dysfunction (adjusted OR 8.00, 95% CI 4.50 to 14.22, p<0.001), but not with left ventricular dysfunction (adjusted OR 1.21, 95% CI 0.74 to 1.50, p=0.308). RV dysfunction was an independent predictor of all-cause mortality, after adjustment for hyponatraemia (adjusted HR 2.20, 95% CI 1.53 to 3.15, p<0.001), while hyponatraemia was not (adjusted HR 1.33, 95% CI 0.94 to 1.87, p=0.108).ConclusionsIn patients with AHF, hyponatraemia was more common with RV dysfunction. RV dysfunction, rather than hyponatraemia, was more significantly related with patients’ prognosis. Thus, the utility of RV dysfunction instead of hyponatraemia per se should be considered in HF risk models.Trial registration numberKorean Acute Heart Failure registry NCT01389843; Results.

ObjectiveThere are conflicting results among previous studies regarding the prognosis of heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF). This study aimed to compare the outcomes of patients with de novo acute heart failure (AHF) or acute decompensated HF (ADHF) according to HFpEF (EF≥50%), or HFrEF (EF<40%) and to define the prognosis of patients with HF with mid-range EF (HFmrEF, 40≤EF<50%).MethodsBetween March 2011 and February 2014, 5625 consecutive patients with AHF were recruited from 10 university hospitals. A total of 5414 (96.2%) patients with EF data were enrolled, which consisted of 2867 (53.0%) patients with de novo and 2547 (47.0%) with ADHF. Each of the enrolled group was stratified by EF.ResultsIn de novo, all-cause death rates were not significantly different between HFpEF and HFrEF (HFpEF vs HFrEF, 206/744 (27.7%) vs 438/1631 (26.9%), HRadj1.15, 95% CI 0.96 to 1.38, p=0.14). However, among patients with ADHF, HFrEF had a significantly higher mortality rate compared with HFpEF (HFpEF vs HFrEF, 245/613 (40.0%) vs 694/1551 (44.7%), HRadj1.25, 95% CI 1.06 to 1.47, p=0.007). Also, in ADHF, HFmrEF was associated with a significantly lower mortality rate within 1 year compared with HFrEF (HFmrEF vs HFrEF, 88/383 (23.0%) vs 430/1551 (27.7%), HRadj1.31, 95% CI 1.03 to 1.65, p=0.03), but a significantly higher mortality rate after 1 year compared with HFpEF (HFmrEF vs HFpEF, 83/295 (28.1%) vs 101/469 (21.5%), HRadj0.70, 95% CI 0.52 to 0.96, p=0.02).ConclusionsHFpEF may indicate a better prognosis compared with HFrEF in ADHF, but not in de novo AHF. For patients with ADHF, the prognosis associated with HFmrEF was similar to that of HFpEF within the first year following hospitalisation and similar to HFrEF 1  year after hospitalisation.

This study aimed to assess the relationship between on-treatment blood pressure (BP) and clinical outcomes of patients with heart failure (HF).

Although several case reports and case series have described 18F-FDG PET/CT in amyloidosis, the value of 18F-FDG PET/CT for diagnosing amyloidosis has not been clarified. We investigated the imaging findings of 18F-FDG PET/CT in patients with primary systemic AL amyloidosis. Subjects were 15 patients (M:F = 12:3; age, 61.5 ± 7.4 years) with histologically confirmed primary systemic AL amyloidosis who underwent pretreatment 18F-FDG PET/CT to rule out the possibility of malignancy or for initial workup of alleged cancer. For involved organs, visual and semiquantitative analyses were performed on 18F-FDG PET/CT images. In total, 22 organs (10 hearts, 5 kidneys, 2 stomachs, 2 colons, 1 ileum, 1 pancreas, and 1 liver) were histologically confirmed to have primary systemic AL amyloidosis. F-FDG uptake was significantly increased in 15 of the 22 organs (68.2 %; 10 hearts, 2 kidneys, 1 colon, 1 ileum, and 1 liver; SUVmax = 7.0 ± 3.2, range 2.1–14.1). However, in 11 of 15 PET-positive organs (78.6 %; 10 hearts and the ileum), it was difficult to differentiate pathological uptake from physiological uptake. Definitely abnormal 18F-FDG uptake was found in only 4 of the 22 organs (18.2 %; 2 kidneys, 1 colon, and the liver). 18F-FDG uptake was negative for pancreas and gastric lesions. Although 18F-FDG PET/CT showed high uptake in two-thirds of the organs involving primary systemic AL amyloidosis, its sensitivity appeared to be low to make differentiation of pathological uptake from physiological uptake. However, due to the small number of cases, further study for the role of 18F-FDG PET/CT in amyloidosis will be warranted.

To evaluate the role of systemic anticoagulation using warfarin in patients with post–myocardial infarction left ventricular (LV) aneurysm formation with or without definite LV thrombus formation.

We investigated the utility of comprehensive scoring systems for organ failure compared with the duration of extracorporeal life support (ECLS) in predicting survival after heart transplantation. From November 2004 to August 2013, 25 adult patients ultimately underwent heart transplantation while on ECLS. We did not include patients who were younger than 18 years old or patients with extracorporeal ventricular assist devices. Seven patients (28) died within 1 year after transplantation. The areas under the curve (receiver operating characteristics (ROC), optimal cut-off value) of the sequential organ-failure assessment and the model for end-stage liver disease score modified by the United Network for Organ Sharing scores were 0.794 (13) and 0.825 (24), respectively. In multivariate analysis, the model for end-stage liver disease score modified by the United Network for Organ Sharing score was independently prognostic regardless of the duration of ECLS and sequential organ-failure assessment score.

To determine how often left ventricular wall thickness (LVWT) is normal and to assess the effect of LVWT on clinical outcomes of patients with immunoglobulin light chain (AL) cardiac amyloidosis.

We generated a cardiotropic replication-competent chimeric coxsackievirus B3 (CVB3) to express alcohol dehydrogenase (ADH). Although exogenously expressed ADH was found by Western blot analysis, its enzyme function was repressed. To define the factor that inhibits the enzymatic function of ADH, we introduced a site-directed mutation at the second amino acid (MGAQEF···) of the CVB3 VP0 capsid protein, effectively changing glycine to alanine. This glycine is known to be a myristoylation site during viral capsid protein maturation in infected cells. In contrast to the unmodified virus, ADH expression and enzymatic function were readily detectable in the mutated rCVB3-ADH (G2A) virus. While expression of ADH required mutation of the CVB3 VP0 myristoylation site for proper function, another chimeric virus that expresses green fluorescent protein (rCVB3-GFP (G or A)) worked independently of the myristoylation site. Indeed, infected HeLa cells displayed GFP under a fluorescent microscope. These results indicate that the myristoylation site in the VP0 capsid protein inhibited the expression of enzymatically active ADH but not GFP. VP0 myristoylation is dispensable for chimeric CVB3 virus replication.

ABSTRACTAntiviral therapeutics are currently unavailable for treatment of coxsackievirus B3, which can cause life-threatening myocarditis. A modified small interfering RNA (siRNA) containing 5′-triphosphate, 3p-siRNA, was shown to induce RNA interference and interferon activation. We aimed to develop a potent antiviral treatment using CVB3-specific 3p-siRNA and to understand its underlying mechanisms. Virus-specific 3p-siRNA was superior to both conventional virus-specific siRNA with an empty hydroxyl group at the 5′ end (OH-siRNA) and nonspecific 3p-siRNA in decreasing viral replication and subsequent cytotoxicity. A single administration of 3p-siRNA dramatically attenuated virus-associated pathological symptoms in mice with no signs of toxicity, and their body weights eventually reached the normal range. Myocardial inflammation and fibrosis were rare, and virus production was greatly reduced. A nonspecific 3p-siRNA showed relatively less protective effect under identical conditions, and a virus-specific OH-siRNA showed no protective effects. We confirmed that virus-specific 3p-siRNA simultaneously activated target-specific gene silencing and type I interferon signaling. We provide a clear proof of concept that coxsackievirus B3-specific 3p-siRNA has 2 distinct modes of action, which significantly enhance antiviral activities with minimal organ damage. This is the first direct demonstration of improved antiviral effects with an immunostimulatory virus-specific siRNA in coxsackievirus myocarditis, and this method could be applied to many virus-related diseases.

Pulmonary hypertension (PH) is characterized by structural and functional changes in the lung including proliferation of vascular smooth muscle cells (VSMCs) and excessive collagen synthesis. Although connective tissue growth factor (CTGF) is known to promote cell proliferation, migration, adhesion, and extracellular matrix production in various tissues, studies on the role of CTGF in pulmonary hypertension have been limited. Here, we examined CTGF expression in the lung tissues of male Sprague Dawley rats treated with monocrotaline (MCT, 60 µgram/kg), a pneumotoxic agent known to induce PH in animals. Establishment of PH was verified by the significantly increased right ventricular systolic pressure and right ventricle/left ventricle weight ratio in the MCT-treated rats. Histological examination of the lung revealed profound muscular hypertrophy in the media of pulmonary artery and arterioles in MCT-treated group. Lung parenchyma, vein, and bronchiole did not appear to be affected. RT-PCR analysis of the lung tissue at 5 weeks indicated significantly increased expression of CTGF in the MCT-treated group. In situ hybridization studies also confirmed abundant CTGF mRNA expression in VSMCs of the arteries and arterioles, clustered pneumocytes, and infiltrated macrophages. Interestingly, CTGF mRNA was not detected in VSMCs of vein or bronchiole. In saline-injected control, basal expression of CTGF was seen in bronchial epithelial cells, alveolar lining cells, and endothelial cells. Taken together, our results suggest that CTGF upregulation in arterial VSMC of the lung might be important in the pathogenesis of pulmonary hypertension. Antagonizing the role of CTGF could thus be one of the potential approaches for the treatment of PH.

Endomyocardial biopsy often fails to show myocardial inflammation for patients with clinically suspected myocarditis. The serum isoforms of troponin T (cTnT) level is a very sensitive marker of myocardial injury and it is elevated even in the absence of myocardial inflammation. We investigated the correlations for myocardial injury, virus titers and inflammation in acute viral infection. Using the murine coxsackievirus group B3 (CVB3) myocarditis model, the histopathologic findings and virus titers in mouse hearts were compared with the serum cTnT levels measured by ELISA at various time points. Viable virus titers in the hearts peaked at 3 days after infection (8.22±0.13 log10 PFU/100 mg of heart); they decreased at day 7 and no viable virus was detected from day 14. Myocardial inflammation was minimal at day 3, peaked at day 7 and markedly decreased at day 14. The individual serum TnT levels were significantly increased at day 3 (7.37±1.46 ng/ml), persisted to day 7 (0.73±0.08 ng/ml), and normalized at day 14. Serum cTnT levels were correlatable with virus titers in the heart (r=0.744, P <0.01), but the serum cTnT levels were not correlated with the degrees of inflammation. Using the less myocarditic strain of CVB3, similar relationships were observed between the changes for the serum cTnT levels and the heart virus titers. During the course of viral infection, myocardial injury precedes the pathologic evidence of inflammation, and the elevated cTnT levels provide evidence of myocardial injury even in the absence of any histologic findings of myocarditis.

Direct injection of the vascular endothelial growth factor (VEGF) gene plasmid DNA into the myocardium was shown to induce development of new blood vessels to increase the circulation in the heart of patients with coronary artery diseases. However, such angiogenic gene therapy (via naked DNA) was limited by low level of gene expression. Furthermore, the temporal and spatial characteristics of VEGF gene transfer in the heart are not known. In this study, we demonstrated that a plasmid vector, containing the human cytomegalovirus immediate early (HCMV IE) promoter and enhancer, induces greater expression of gene in the rat heart monitored by gene fused to the chloramphenicol acetyl transferase (CAT) reporter, than four different viral and cellular promoters. Interestingly, expression of VEGF121 protein showed an earlier peak, a shorter duration, and a wider distribution than that of CAT only. Therefore, a plasmid vector with an HCMV IE promoter/enhancer provides clear advantages over other previously developed plasmids. Furthermore, expression profile of VEGF121 gene may provide useful information in the design of angiogenic gene therapy in the heart

Limited data are available regarding echocardiographic predictors for successful weaning from venoarterial (VA) extracorporeal membrane oxygenation (ECMO). We sought to determine whether echocardiographic parameters during ECMO flow study could predict successful weaning from ECMO.

Introduction:The effect of beta blockers is neutral in patients with heart failure with preserved ejection fraction (HFpEF).Hypothesis:B-type natriuretic peptide (BNP) can be used to risk-stratify patients with HF. We investigated the effect of beta blockers according to BNP levels.Methods:The Korean Acute Heart Failure (KorAHF) registry enrolled 5,625 consecutive patients hospitalized for AHF. HF phenotypes were defined as HFrEF (LVEF < 40%), HFmrEF (40% ? LVEF < 50%), and HFpEF (LVEF ? 50%). Patients were further stratified according to the tertiles of natriuretic peptide (NP) levels. The threshold for 2ndand 3rdtertiles were 596 pg/ml and 1371 pg/ml for BNP, and 2969 pg/ml and 8394 pg/ml for NT-proBNP, respectively. Primary outcome was all-cause post-discharge mortality according to beta blocker use.Results:After excluding patients without LVEF, 3088 (60.5%), 730 (14.3%), and 1285 (25.2%) had HFpEF, HFmrEF, and HFpEF, respectively. There was a negative correlation between NP level and LVEF (r=-0284, P <0.001), so that in HFpEF proportion of patients in 1stNP-tertile was high. During a median follow-up duration of 966 days (interquartile range, 333 to 1354 days), 1927 (36%) patients died. Overall, BB use was associated with a 26% reduced risk for all-cause mortality in HFrEF (HR, 0.41: 95% CI 0.65-0.84, P <0.001), but not in HFmrEF (HR, 0.85; 95% CI: 0.66-1.11, P=0.236) or in HFpEF (HR, 0.84; 95% 0.69-1.03; P=0.090). Interestingly, when stratifying the patients with HFpEF according to natriuretic peptide levels, BB use was associated with a 42% reduced risk in patients in 3rdNP tertile (HR, 0.58, 95% CI: 0.37-0.93, P = 0.023).Conclusions:Beta-blockers are associated with improved prognosis for patients with HFrEF. Furthermore, beta blockers may be also beneficial in patients with HFpEF and high NP levels.

Background:Promoting adequate self-care behaviors is important to improve heart failure (HF) outcomes. In the process of self-care, symptom perception is critical for patients to respond to altered symptoms in a timely manner. The awareness of body sensation and physical cues may be essential for HF patients to quickly recognize worsening symptoms of HF, which may result in timely symptom management and prevention of unnecessary use of health services.Purpose:To determine whether levels of body awareness are associated with self-care in HF patientsMethods:HF patients (N=135, 60 years, 28% female, 89% NYHA II) were asked to complete the Body Awareness Questionnaire and the two subscales of Self-Care of HF Index: the self-care maintenance subscale comprised with items capturing recommended everyday practices (e.g., low sodium diet, regular symptom monitoring), and the self-care management subscale comprised with items capturing symptom recognition, implementation of treatment strategies, and the treatment strategy evaluation (e.g., fluid intake restriction if symptoms occur). Multivariable regression was used to determine the associations of body awareness with self-care maintenance and management after adjusting for relevant covariates (age, gender, living arrangement, education level, comorbidity burden, NYHA functional class, social support, HF knowledge, and cognitive function)Results:Higher levels of body awareness independently predicted better self-care maintenance after adjusting for covariates (?=0.23, p-value=0.008). However, self-care management was not predicted by levels of body awareness.Conclusion:Our study indicates that awareness of body sensations was associated with activities to maintain physiological stability (self-care maintenance), but not patients? symptom recognition and responses to altered symptoms (self-care management). This unexpected finding suggests that a greater awareness of general body sensations and physical cues alone did not enhance self-care management in HF. More efforts are needed to identify factors that can contribute to better recognition of worsening symptoms of HF and adequate management of the symptoms.

Early regression of left ventricular (LV) hypertrophy (LVH) after aortic valve replacement (AVR) for severe aortic stenosis (AS) was associated with less fibrosis before AVR and better long-term survival after AVR. However, predicting factors for early LVH regression after AVR has not been fully elucidated.

In Korea, acute decompensated heart failure (ADHF) becomes more prevalent and require large amount of public health resources. But very little information is available on the clinical characteristics and prognosis of patients with ADHF, especially on the patients with severe LV dysfunction.

Using structure‐based drug design based on computer‐aided molecular docking, an isophthalamide moiety in a known BACE‐1 inhibitor is replaced by the 1,4‐dihydropyridine (DHP) skeleton with assumed enhanced permeability through the blood‐brain barrier.