Type 2 diabetes mellitus(T2DM or T2D)is a devastating metabolic abnormality featured by insulin resistance,hyperglycemia,and hyperlipidemia.T2D provokes unique metabolic changes and compromises cardiovascular geometry...Type 2 diabetes mellitus(T2DM or T2D)is a devastating metabolic abnormality featured by insulin resistance,hyperglycemia,and hyperlipidemia.T2D provokes unique metabolic changes and compromises cardiovascular geometry and function.Meanwhile,T2D increases the overall risk for heart failure(HF)and acts independent of classical risk factors including coronary artery disease,hypertension,and valvular heart diseases.The incidence of HF is extremely high in patients with T2D and is manifested as HF with preserved,reduced,and midrange ejection fraction(HFpEF,HFrEF,and HFmrEF,respectively),all of which significantly worsen the prognosis for T2D.HFpEFis seen in approximately half of the HF cases and is defined as a heterogenous syndrome with discrete phenotypes,particularly in close association with metabolic syndrome.Nonetheless,management of HFpEF in T2D remains unclear,largely due to the poorly defined pathophysiology behind HFpEF.Here,in this review,we will summarize findings from multiple preclinical and clinical studies as well as recent clinical trials,mainly focusing on the pathophysiology,potential mechanisms,and therapies of HFpEF in T2D.展开更多
Heart failure with preserved ejection fraction(HFpEF)displays normal or near-normal left ventricular ejection fraction,diastolic dysfunction,cardiac hypertrophy,and poor exercise capacity.Berberine,an isoquinoline alk...Heart failure with preserved ejection fraction(HFpEF)displays normal or near-normal left ventricular ejection fraction,diastolic dysfunction,cardiac hypertrophy,and poor exercise capacity.Berberine,an isoquinoline alkaloid,possesses cardiovascular benefits.Adult male mice were assigned to chow or high-fat diet with L-NAME(“two-hit”model)for 15 weeks.Diastolic function was assessed using echocardiography and noninvasive Doppler technique.Myocardial morphology,mitochondrial ultrastructure,and cardiomyocyte mechanical properties were evaluated.Proteomics analysis,autophagic flux,and intracellular Ca^(2+)were also assessed in chow and HFpEF mice.The results show exercise intolerance and cardiac diastolic dysfunction in“two-hit”-induced HFpEF model,in which unfavorable geometric changes such as increased cell size,interstitial fibrosis,and mitochondrial swelling occurred in the myocardium.Diastolic dysfunction was indicated by the elevated E value,mitral E/A ratio,and E/e’ratio,decreased e’value and maximal velocity of re-lengthening(-dL/dt),and prolonged re-lengthening in HFpEF mice.The effects of these processes were alleviated by berberine.Moreover,berberine ameliorated autophagic flux,alleviated Drp1 mitochondrial localization,mitochondrial Ca^(2+)overload and fragmentation,and promoted intracellular Ca^(2+)reuptake into sarcoplasmic reticulum by regulating phospholamban and SERCA2a.Finally,berberine alleviated diastolic dysfunction in“two-hit”diet-induced HFpEF model possibly because of the promotion of autophagic flux,inhibition of mitochondrial fragmentation,and cytosolic Ca^(2+)overload.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(81770261 and 82130011)Science and Technology Innovation Project of the Chinese Academy of Medical Sciences(Health and Longevity Pilot Special Project 2019-RC-HL-021).
文摘Type 2 diabetes mellitus(T2DM or T2D)is a devastating metabolic abnormality featured by insulin resistance,hyperglycemia,and hyperlipidemia.T2D provokes unique metabolic changes and compromises cardiovascular geometry and function.Meanwhile,T2D increases the overall risk for heart failure(HF)and acts independent of classical risk factors including coronary artery disease,hypertension,and valvular heart diseases.The incidence of HF is extremely high in patients with T2D and is manifested as HF with preserved,reduced,and midrange ejection fraction(HFpEF,HFrEF,and HFmrEF,respectively),all of which significantly worsen the prognosis for T2D.HFpEFis seen in approximately half of the HF cases and is defined as a heterogenous syndrome with discrete phenotypes,particularly in close association with metabolic syndrome.Nonetheless,management of HFpEF in T2D remains unclear,largely due to the poorly defined pathophysiology behind HFpEF.Here,in this review,we will summarize findings from multiple preclinical and clinical studies as well as recent clinical trials,mainly focusing on the pathophysiology,potential mechanisms,and therapies of HFpEF in T2D.
基金supported in part by the National Natural Science Foundation of China(Nos.82272184 and 82130011)Shanghai Xuhui District Scientific Research Project(Nos.202104 and 202105).
文摘Heart failure with preserved ejection fraction(HFpEF)displays normal or near-normal left ventricular ejection fraction,diastolic dysfunction,cardiac hypertrophy,and poor exercise capacity.Berberine,an isoquinoline alkaloid,possesses cardiovascular benefits.Adult male mice were assigned to chow or high-fat diet with L-NAME(“two-hit”model)for 15 weeks.Diastolic function was assessed using echocardiography and noninvasive Doppler technique.Myocardial morphology,mitochondrial ultrastructure,and cardiomyocyte mechanical properties were evaluated.Proteomics analysis,autophagic flux,and intracellular Ca^(2+)were also assessed in chow and HFpEF mice.The results show exercise intolerance and cardiac diastolic dysfunction in“two-hit”-induced HFpEF model,in which unfavorable geometric changes such as increased cell size,interstitial fibrosis,and mitochondrial swelling occurred in the myocardium.Diastolic dysfunction was indicated by the elevated E value,mitral E/A ratio,and E/e’ratio,decreased e’value and maximal velocity of re-lengthening(-dL/dt),and prolonged re-lengthening in HFpEF mice.The effects of these processes were alleviated by berberine.Moreover,berberine ameliorated autophagic flux,alleviated Drp1 mitochondrial localization,mitochondrial Ca^(2+)overload and fragmentation,and promoted intracellular Ca^(2+)reuptake into sarcoplasmic reticulum by regulating phospholamban and SERCA2a.Finally,berberine alleviated diastolic dysfunction in“two-hit”diet-induced HFpEF model possibly because of the promotion of autophagic flux,inhibition of mitochondrial fragmentation,and cytosolic Ca^(2+)overload.
