ObjectiveTo explore the value of the Model for End-Stage Liver Disease （MELD） 3.0 in predicting survival outcomes for patients with alcoholic cirrhosis and to establish an effective mortality prediction model. MethodsClinical data of 788 hospitalized patients who were first diagnosed with alcoholic cirrhosis at the Third Affiliated Hospital of Sun Yat-sen University between January 1， 2011 and December 31， 2019 were analyzed. Patients were followed up until December 31， 2023 and divided into survival and mortality groups based on the survival outcomes at 30 days， 90 days， 1 year， and 3 years after admission. The prognostic values of the MELD 3.0， MELD， MELD-Sodium （MELD-Na） for survival in alcoholic cirrhosis patients were assessed and compared by using the receiver operating characteristic （ROC） curve and the area under the curve （AUC）. Additional risk factors associated with mortality in alcoholic cirrhosis patients were identified， and a novel mortality prediction model based on MELD 3.0 was developed. ResultsThe AUC of the MELD 3.0 score in predicting 30-day， 90-day， 1-year， and 3-year survival was 0.823， 0.730， 0.686， and 0.658， respectively， which were superior to those of the MELD-Na （0.802， 0.708， 0.666， and 0.645， respectively） and MELD scores （0.698， 0.668， 0.654， and 0.633， respectively） （all P < 0.05）. MELD 3.0 demonstrated better performance at 30 and 90 days （AVC=0.823，0.730； both P < 0.05） than at 1 year and 3 years （AVC=0.686，0.658； both P < 0.05）. Binary logistic regression combined with LASSO regression indicated that the independent risk factors associated with the 1-year outcome included MELD 3.0， baseline ascites and hepatocellular carcinoma. A survival prediction model was then established with AUC of 0.748， sensitivity of 0.695， and specificity of 0.775. ConclusionsMELD 3.0 has a superior predictive ability for 30-day， 90-day， 1-year， and 3-year survival in patients with alcoholic cirrhosis than MELD-Na and MELD. The prediction model incorporating MELD 3.0， ascites and hepatocellular carcinoma improves the prediction of 1-year survival outcomes for alcoholic cirrhosis patients.

Objective:To investigate the influences and mechanism of extracellular vesicles from dermal papilla cells (DPC-EVs) of mice on human hypertrophic scar fibroblasts (HSFs).Methods:The study was an experimental research. The primary dermal papilla cells (DPCs) of whiskers were extracted from 10 6-week-old male C57BL/6J mice and identified successfully. The DPC-EVs were extracted from the 3 rd to 5 th passage DPCs by ultracentrifugation, and the morphology was observed through transmission electron microscope and the particle diameter was detected by nanoparticle tracking analyzer ( n=3) at 24 h after culture. The 3 rd passage of HSFs were divided into DPC-EV group and phosphate buffer solution (PBS) group, which were cultured with DPC-EVs and PBS, respectively. The cell scratch test was performed and cell migration rate at 24 h after scratching was calculated ( n=5). The cell proliferation levels at 0 (after 12 h of starvation treatment and before adding DPC-EVs or PBS), 24, 48, 72, and 96 h after culture were detected by using cell counting kit 8 ( n=4). The protein expressions of α-smooth muscle actin (α-SMA) and collagen typeⅠ (ColⅠ) in cells at 24 h after culture were detected by immunofluorescence method and Western blotting, and the protein expression of Krüppel-like factor 4 (KLF4) in cells at 24 h after culture was detected by Western blotting. After the 3 rd passage of HSFs were cultured with DPC-EVs for 24 h, the cells were divided into blank control group, KLF4 knockdown group, and KLF4 overexpression group according to the random number table. The cells in blank control group were only routinely cultured for 48 h. The cells in KLF4 knockdown group and KLF4 overexpression group were incubated with KLF4 knockdown virus for 24 h, then the cells in KLF4 knockdown group were routinely cultured for 24 h while the cells in KLF4 overexpression group were incubated with KLF4 overexpression virus for 24 h. The protein expressions of KLF4, α-SMA, and ColⅠ in cells were detected by Western blotting at 48 h after culture. Results:At 24 h after culture, the extracted DPC-EVs showed vesicular structure with an average particle diameter of 108.8 nm. At 24 h after scratching, the migration rate of HSFs in PBS group was (54±10)%, which was significantly higher than (29±8)% in DPC-EV group ( t=4.37, P<0.05). At 48, 72, and 96 h after culture, the proliferation levels of HSFs in DPC-EV group were significantly lower than those in PBS group (with t values of 4.06, 5.76, and 6.41, respectively, P<0.05). At 24 h after culture, the protein expressions of α-SMA and ColⅠ of HSFs in DPC-EV group were significantly lower than those in PBS group, while the protein expression of KLF4 was significantly higher than that in PBS group. At 48 h after culture, compared with those in blank control group, the protein expression of KLF4 of HSFs in KLF4 knockdown group was down-regulated, while the protein expressions of α-SMA and ColⅠ were both up-regulated; compared with those in KLF4 knockdown group, the protein expression of KLF4 of HSFs in KLF4 overexpression group was up-regulated, while the protein expressions of ColⅠ and α-SMA were down-regulated. Conclusions:The DPC-EVs of mice can inhibit the proliferation and migration of human HSFs and significantly inhibit the expressions of fibrosis markers α-SMA and ColⅠ in human HSFs by activating KLF4.

Objective:To evaluate the predictive value of anthropometric indicators in predicting cardiovascular risk in the population with metabolic syndrome(MS).Methods:A cross-sectional study was used to analyze the correlation between anthropometric measures and cardiovascular risk in subjects with MS. Cardiometabolic risk was assessed with cardiometabolic risk index(CMRI). Receiver operating characteristic(ROC) curve analysis was used to assess the predictive power of anthropometric measures for cardiometabolic risk.Results:(1) The anthropometric measures [body mass index(BMI), waist-hip ratio(WHR), waist-to-height ratio(WtHR), body fat percentage(BFP), visceral fat index(VFI), conicity index(CI), a body shape index(ABSI), body roundness index(BRI), abdominal volume index(AVI)] in the MS group were significantly higher than those in the non-MS group( P<0.05). Moreover, there were significant differences in CMRI score and vascular risk between the two groups( P<0.05). (2) Logistic regression analysis showed that the cardiovascular risk was increased with the increases of BMI, VFI, WHR, WtHR, CI, BRI, and AVI after adjusting for confounding factors in the overall population, the non-MS population, and the MS population( P<0.05). (3) In the ROC analysis, the AUC values of BMI, VFI, and AVI were 0.767, 0.734, and 0.770 in the overall population; 0.844, 0.816, and 0.795 in the non-MS population; 0.701, 0.666, and 0.702 in the MS population, respectively. For the overall population and non-MS population, the optimal cut points of BMI to diagnose high cardiovascular risk were 26.04 kg/m 2 and 24.36 kg/m 2; the optimal cut points of VFI were 10.25 and 9.75; the optimal cut points of AVI were 17.3 cm 2 and 15.53 cm 2, respectively. In the MS population, the optimal cut point as a predictor of high cardiovascular risk in young and middle-aged men with MS was 27.63 kg/m 2, and the optimal cut point of AVI in women was 18.08 cm 2. Conclusion:BMI, VFI, and AVI can be used as predictors of cardiovascular risk in the general population. BMI can be used as a predicator of high cardiovascular risk in young and middle-age men with MS. AVI can be used as a predicator of high cardiovascular risk in women with MS.

Objective:To observe the effect of pressure therapy on the formation of hypertrophic scars(HTS) and transforming growth factor beta 1 (TGF-β1) / Sma and Mad homolog proteins (Smad) signaling pathway.Methods:Twelve adult healthy New Zealand white rabbits(provided by the Animal Experiment Center of the Air Force Military Medical University) were wounded with 1 cm round punch on 4 sites of the ventral side of each ear. Round scalpels were used to make incisions along the marked lines, dissect the skin and perichondrium. The remaining tissue was scraped off to expose the wound surface. Scar formation was observed on the 28th day after surgery. After the establishment of rabbit ear HTS models, the right ears were used as self-controls, while the left ears were set as the experimental group. Two hypertrophic scars were randomly selected from each rabbit ear, 24 per group. Experimental group: 4-0 nylon silk thread was used to sew the pressure pad on the circular NdFeB magnets pad with a diameter of 1.5 cm to the rabbit ear cartilage. Flexiforce pressure sensor was used to measure the pressure, and the pads were adjusted to maintain a pressure of 20-25 mmHg (1 mmHg=0.133 kPa) for more than 23 h per day. Control group: no treatment. On the 40th day of pressure therapy, the general morphology of rabbit ear scars were observed, and the tissues were harvested for hematoxylin and eosin (HE) staining and Masson’s Trichrome staining for histological study. The scar elevation index (SEI), the number of fibroblasts, and the thickness of the stratum corneum were calculated. The relative mRNA expression levels of TGF-β1, Smad3, collagen type (Collagen )Ⅰ, Collagen Ⅲ, α-smooth muscle actin (α-SMA) were measured with qPCR; Western blotting was used to detect the relative protein expression levels of TGF-β1, Collagen Ⅰ, Collagen Ⅲ, α-SMA and the phosphorylation level of Smad3 (the ratio of p-Smad3 and Smad3 proteins). Statistical analysis was performed with Excel 2019 and GraphPad Prism 8.0. The measurement data conformed to normal distribution and was expressed as Mean±SD. Student’s t-test was used for the comparison between two groups. P<0.05 was considered statistically significant. Results:A total of 96 wounds were formed in 12 rabbits, 27 wounds had no obvious hyperplasia, and the remaining 69 wounds formed hypertrophic scar tissue blocks with a prominent skin surface, firm texture, and dark red appearance. The scars formation rate was 71.9% (69/96). On the 40th day after the application of pressure, the scars in the experimental group were significantly reduced, softer, and the color was slightly lighter compared with the control group. The results of HE staining and Masson’s Trichrome staining showed that the thickness of the stratum corneum, SEI, and the number of fibroblasts were (69.33±6.03) μm, 1.30±0.08, and (236.30±14.64) cells/field, respectively, which were significantly lower than those in the control group [(114.00±10.15) μm, 1.72±0.05, (320.30±14.57) cells/field] (all P<0.01). Abundance in capillaries, inflammatory cells, and fibroblasts were not observed in the dermal layer. The collagen fibers were orderly arranged and sparse. The results of fluorescence quantitative PCR showed that the relative expression levels of TGF-β1, Smad3, Collagen Ⅰ, Collagen Ⅲ, and α-SMA mRNA in the experimental group were 0.48±0.08, 0.58±0.05, 0.04±0.01, 0.15±0.02, 0.31±0.03, respectively, lower than those of the control group(1.00±0.07, 1.00±0.05, 1.00±0.08, 1.00±0.10, 1.00±0.06) (all P<0.01). The results of Western blotting showed that the relative protein expression of TGF-β1, Collagen Ⅰ, Collagen Ⅲ, α-SMA and the phosphorylation level of Smad3 in the experimental group were 0.65±0.03, 0.07±0.01, 0.43±0.03, 0.53±0.03, 0.54±0.03, all lower than the control group’s 1.02±0.06, 0.93±0.05, 0.92±0.03, 0.82±0.03, 0.92±0.03 (all P<0.01). Conclusions:Pressure therapy can significantly inhibit the hyperplasia of scars, improve the structure of HTS tissue, facilitate the normal arrangement of collagen fiber, and reduce the excessive deposition of collagen. Pressure therapy may inhibit scar proliferation by regulating the TGF-β1/Smad signaling pathway.

Objective:To observe the effect of pressure therapy on the formation of hypertrophic scars(HTS) and transforming growth factor beta 1 (TGF-β1) / Sma and Mad homolog proteins (Smad) signaling pathway.Methods:Twelve adult healthy New Zealand white rabbits(provided by the Animal Experiment Center of the Air Force Military Medical University) were wounded with 1 cm round punch on 4 sites of the ventral side of each ear. Round scalpels were used to make incisions along the marked lines, dissect the skin and perichondrium. The remaining tissue was scraped off to expose the wound surface. Scar formation was observed on the 28th day after surgery. After the establishment of rabbit ear HTS models, the right ears were used as self-controls, while the left ears were set as the experimental group. Two hypertrophic scars were randomly selected from each rabbit ear, 24 per group. Experimental group: 4-0 nylon silk thread was used to sew the pressure pad on the circular NdFeB magnets pad with a diameter of 1.5 cm to the rabbit ear cartilage. Flexiforce pressure sensor was used to measure the pressure, and the pads were adjusted to maintain a pressure of 20-25 mmHg (1 mmHg=0.133 kPa) for more than 23 h per day. Control group: no treatment. On the 40th day of pressure therapy, the general morphology of rabbit ear scars were observed, and the tissues were harvested for hematoxylin and eosin (HE) staining and Masson’s Trichrome staining for histological study. The scar elevation index (SEI), the number of fibroblasts, and the thickness of the stratum corneum were calculated. The relative mRNA expression levels of TGF-β1, Smad3, collagen type (Collagen )Ⅰ, Collagen Ⅲ, α-smooth muscle actin (α-SMA) were measured with qPCR; Western blotting was used to detect the relative protein expression levels of TGF-β1, Collagen Ⅰ, Collagen Ⅲ, α-SMA and the phosphorylation level of Smad3 (the ratio of p-Smad3 and Smad3 proteins). Statistical analysis was performed with Excel 2019 and GraphPad Prism 8.0. The measurement data conformed to normal distribution and was expressed as Mean±SD. Student’s t-test was used for the comparison between two groups. P<0.05 was considered statistically significant. Results:A total of 96 wounds were formed in 12 rabbits, 27 wounds had no obvious hyperplasia, and the remaining 69 wounds formed hypertrophic scar tissue blocks with a prominent skin surface, firm texture, and dark red appearance. The scars formation rate was 71.9% (69/96). On the 40th day after the application of pressure, the scars in the experimental group were significantly reduced, softer, and the color was slightly lighter compared with the control group. The results of HE staining and Masson’s Trichrome staining showed that the thickness of the stratum corneum, SEI, and the number of fibroblasts were (69.33±6.03) μm, 1.30±0.08, and (236.30±14.64) cells/field, respectively, which were significantly lower than those in the control group [(114.00±10.15) μm, 1.72±0.05, (320.30±14.57) cells/field] (all P<0.01). Abundance in capillaries, inflammatory cells, and fibroblasts were not observed in the dermal layer. The collagen fibers were orderly arranged and sparse. The results of fluorescence quantitative PCR showed that the relative expression levels of TGF-β1, Smad3, Collagen Ⅰ, Collagen Ⅲ, and α-SMA mRNA in the experimental group were 0.48±0.08, 0.58±0.05, 0.04±0.01, 0.15±0.02, 0.31±0.03, respectively, lower than those of the control group(1.00±0.07, 1.00±0.05, 1.00±0.08, 1.00±0.10, 1.00±0.06) (all P<0.01). The results of Western blotting showed that the relative protein expression of TGF-β1, Collagen Ⅰ, Collagen Ⅲ, α-SMA and the phosphorylation level of Smad3 in the experimental group were 0.65±0.03, 0.07±0.01, 0.43±0.03, 0.53±0.03, 0.54±0.03, all lower than the control group’s 1.02±0.06, 0.93±0.05, 0.92±0.03, 0.82±0.03, 0.92±0.03 (all P<0.01). Conclusions:Pressure therapy can significantly inhibit the hyperplasia of scars, improve the structure of HTS tissue, facilitate the normal arrangement of collagen fiber, and reduce the excessive deposition of collagen. Pressure therapy may inhibit scar proliferation by regulating the TGF-β1/Smad signaling pathway.

Objective:To explore the effects of mechanical tension on the formation of hypertrophic scars in rabbit ears and transforming growth factor-β 1 (TGF-β 1)/Smad signaling pathway. Methods:The experimental research method was adopted. Six New Zealand white rabbits, male or female, aged 3-5 months were used and 5 full-thickness skin defect wounds were made on the ventral surface of each rabbit ear. The appearance of all rabbit ear wounds was observed on post surgery day (PSD) 0 (immediately), 7, 14, 21, and 28. On PSD 28, the scar formation rate was calculated. Three mature scars in the left ear of each rabbit were included in tension group and the arch was continuously expanded with a spiral expander. Three mature scars in the right ear of each rabbit were included in sham tension group and only the spiral expander was sutured without expansion. There were 18 scars in each group. After mechanical tension treatment (hereinafter referred to as treatment) for 40 days, the color and texture of scar tissue in the two groups were observed. On treatment day 40, the scar elevation index (SEI) was observed and calculated; the histology was observed after hematoxylin eosin staining, and the collagen morphology was observed after Masson staining; mRNA expressions of TGF-β 1, Smad3, collagen Ⅰ, collagen Ⅲ, and α-smooth muscle actin (α-SMA) in scar tissue were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction; and the protein expressions of TGF-β 1, collagen Ⅰ, collagen Ⅲ, and α-SMA, and phosphorylation level of Smad3 in scar tissue were detected by Western blotting. The number of samples of each group in the experiments was 3. Data were statistically analyzed with independent sample t test. Results:On PSD 0, 5 fresh wounds were formed on all the rabbit ears; on PSD 7, the wounds were scabbed; on PSD 14, most of the wounds were epithelialized; on PSD 21, all the wounds were epithelialized; on PSD 28, obvious hypertrophic scars were formed. The scar formation rate was 75% (45/60) on PSD 28. On treatment day 40, the scar tissue of rabbit ears in tension group was more prominent than that in sham tension group, the scar tissue was harder and the color was more ruddy; the SEI of the scar tissue of rabbit ears in tension group (2.02±0.08) was significantly higher than 1.70±0.08 in sham tension group ( t=5.07, P<0.01). On treatment day 40, compared with those in sham tension group, the stratum corneum of scar tissue became thicker, and a large number of new capillaries, inflammatory cells, and fibroblasts were observed in the dermis, and collagen was more disordered, with nodular or swirling distribution in the scar tissue of rabbit ears in tension group. On treatment day 40, the mRNA expressions of TGF-β 1, Smad3, collagen Ⅰ, collagen Ⅲ, and α-SMA in the scar tissue of rabbit ears in tension group were respectively 1.81±0.25, 5.71±0.82, 7.86±0.56, 4.35±0.28, and 5.89±0.47, which were significantly higher than 1.00±0.08, 1.00±0.12, 1.00±0.13, 1.00±0.14, and 1.00±0.14 in sham tension group (with t values of 5.36, 9.82, 20.60, 18.26, and 17.13, respectively, all P<0.01); the protein expressions of TGF-β 1, collagen Ⅰ, collagen Ⅲ, and α-SMA, and phosphorylation level of Smad3 in the scar tissue of rabbit ears in tension group were respectively 0.865±0.050, 0.895±0.042, 0.972±0.027, 1.012±0.057, and 0.968±0.087, which were significantly higher than 0.657±0.050, 0.271±0.029, 0.631±0.027, 0.418±0.023, and 0.511±0.035 in sham tension group (with t values of 5.08, 21.27, 15.55, 16.70, and 8.40, respectively, all P<0.01). Conclusions:Mechanical tension can inhibit the regression of hypertrophic scars in rabbit ears through stimulating the hyperplasia of scars, inhibiting the normal arrangement of dermal collagen fibers, and intensifying the deposition of collagen fibers, and the mechanism may be related to the activation of TGF-β 1/Smad signaling pathway by mechanical tension.

Immune checkpoint inhibitors (ICIs) is a negative regulatory factor antibody, which activates T cells to play an anti-tumor effect in immunotherapy, and can also cause immune-related adverse responses, thereby inducing a series of immune related adverse events (irAEs). Among these irAEs, although the incidence of ICIs-related myocarditis is very low, the fatality rate is significantly higher than other adverse reactions, close to 50%. Clinicians should be vigilant when applying ICIs, but the pathogenesis of ICIs-related myocarditis is still unclear. This article combines the recent research results of ICIs to summarize the mechanism and clinical manifestations of ICIs-related myocarditis, so as to improve clinicians' understanding of the adverse reactions.
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Biomedical Research/trends* ; Cardiotoxicity/physiopathology* ; Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Immunotherapy/adverse effects* ; Myocarditis/physiopathology* ; Neoplasms/drug therapy*

Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and represent the major cause of postsurgical morbidity. Enterolysis at repeat surgeries induces adhesion reformation that is more difficult to prevent than primary adhesion. Here we studied the preventive effects of different approaches of berberine treatment for primary adhesion, and its effects on adhesion reformation compared to Interceed. We found the primary adhesion was remarkably prevented by berberine through intraperitoneal injection 30 min before abrasive surgery (pre-berberine) or direct addition into injured cecum immediately after the surgery (inter-berberine). Rats with adhesion reformation had a more deteriorative collagen accumulation and tissue injury in abrasive sites than rats with primary adhesion. The dysregulated TIMP-1/MMP balance was observed in patients after surgery, as well as adhesion tissues from primary adhesion or adhesion reformation rats. Inter-berberine treatment had a better effect for adhesion reformation prevention than Interceed. Berberine promoted the activation of MMP-3 and MMP-8 by directly blocking TIMP-1 activation core, which was reversed by TIMP-1 overexpression in fibroblasts. In conclusion, this study suggests berberine as a reasonable approach for preventing primary adhesion formation and adhesion reformation.

This article briefly introduces the strategic framework of genetic technology of Chinese government and Chinese Academy of Sciences, and the remarkable progress of genetic technology under this guidance. Using bibliometric and patent analysis methods, we reveal the current status of genetic technology research and development in China. China has made great achievements, both in terms of quantity and quality of academic publications, and quantity of patent applications. However, there are still something need to be improved, such as international cooperation and combination the efforts of enterprises, universities and research institutes. In the future, China will improve top-level planning and government guidance and supervision. In addition, it is also crucial to encourage investment from enterprise and communities, and to broadcast the science and technology to the whole society. Moreover, actions have to be taken to reduce the risks of bio-safety and bio-security. The innovation and breakthrough of genetic technology is a key to sustainable development in the bio-industry and bio-economy in China.

Objective To investigate the association between bicuspid aortic valve ( BAV ) morphologic findings ( raphe vs nonraphe) ,the degree of valve dysfunction and prognosis . Methods Clinical and echocardiographic data in 317 BAV patients were analyzed retrospectively . According to the Sievers classification ,the morphologic BAV findings were categorized into no raphe ( type 0) ,one raphe ( type 1) and two raphes ( type 2 ) . T he patients with type 1 were further divided into three subtypes ,including R‐L subtype ( fusion of the left and right coronary cusps ) ,R‐N subtype ( fusion of the right and noncoronary cusps) and L‐N subtype ( fusion of the left and noncoronary cusps ) . Results Of the 317 patients ,there were 83 ( 26 .2% ) of type 0 ,232 ( 73 .2% ) of type 1 and 2 ( 0 .6% ) of type 2 .Among the 232 patients of type 1 ,there were 126 ( 54 .3% ) of R‐L subtype ,88 ( 37 .9% ) of R‐N subtype and 18 ( 7 .8% ) of L‐N subtype . BAV with raphe had a significantly higher prevalence of aortic valve calcification [ 120 ( 51 .3% ) vs 19 ( 22 .9% ) , P ＜ 0 .001 ] ,with significantly higher frequencies of aortic stenosis [ 164 ( 70 .1% ) vs 6 ( 7 .2% ) , P＜ 0 .001 ] ,aortic regurgitation [ 168 ( 71 .8% ) vs 40 ( 48 .2% ) , P ＝ 0 .001 ] ,increased left ventricular mass[ ( 253 .4 ± 113 .7) g vs ( 176 .4 ± 69 .3) g , P ＜0 .001] and left heart failure [ 34 ( 14 .5% ) vs 3 ( 3 .6% ) , P ＝0 .009] . Furthermore ,the dilation of aortic root and ascending aorta in BAV patients with raphe were significantly higher than those without raphe ( P ＜0 .01 ) ,however ,ascending aortic aneurysm rates were not significant between BAV with and without raphe[ 23( 9 .8% ) vs 4( 4 .8% ) , P ＝0 .251] . T he patients in R‐N subtype had a significantly higher proportion of aortic valve calcification than those in R‐L and L‐N subtype [ 55 ( 62 .5% ) vs 57 ( 45 .2% ) vs 6 ( 33 .3% ) , P ＝ 0 .01 ] ,with a significantly higher frequency of severe aortic stenosis [ 50 ( 56 .8% ) vs 21 ( 16 .7% ) vs 3 ( 16 .7% ) , P ＜0 .001 ] . However , there was no significant difference among different subtypes in other complications( P ＞0 .05).Conclusions T he presence of raphe is associated with a higher frequency of significant aortic valve calcification ,aortic valve dysfunction ,and increases left ventricular mass and left heart failure .T he R‐N type is also associated with aortic valve calcification and severe aortic stenosis .