Diabetes, heart failure, and renal dysfunction:The vicious circles

Type 2 diabetes mellitus (T2DM), heart failure(HF), and diabetic kidney disease (DKD) are major pandemics of the twenty first century. T2DM affects more than 400 million persons worldwide. These three conditions often coexist,and each worsens the prognosis of the other two, setting up a series of vicious circles.(Fig. 1) For example, T2DM is a powerful risk factor for the development of HF(Fig.1a);it is associated with a 2 to 4 times greater risk of the development of cardiovascular disease (CVD), which is responsible for about two-thirds of all deaths in patients with T2DM.

The combination of T2DM and left ventricular dysfunction is particularly dangerous, with high incidence of chronic disability and mortality.In addition to the increase in HF attributed to T2DM, there is also evidence for the reverse, i.e. it is a "two-way street."1(Fig. 1b) Thus, HF can play a causal role in the development of T2DM, with advanced HF being associated with the development of marked insulin resistance. Conversely, treatment of advanced HF with implantation of a left ventricular assist device has been shown to result in improved diabetic control.

By definition, diabetes is the cause of DKD(Fig.1c). There is "crosstalk" between the failing heart and the failing kidney. The combination of a lower cardiac output and an elevated renal venous pressure reduces renal blood flow. The upregulation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) in HF causes constriction of afferent glomerular arterioles,reducing glomerular filtration.The failing kidney in DKD may contribute to secondary hypertension and to anemia, thereby placing extra burdens on the failing heart. This bidirectional interaction between the heart and kidneys sets up an important vicious circle.(Fig.1c and d).Both HF(Fig.1f)and DKD (Fig.1g)result in sodium retention which can be responsible for pulmonary congestion, dyspnea, and edema.

Disease mechanisms

The vicious circle between HF and T2DM is shown in Fig. 2, modified from Maack et al. Central to the development of T2DM is insulin resistance (Fig. 2a),which is responsible for insulin hypersecretion(Fig. 2b).With progression, insulin secretion by the pancreas,while greater than normal, is insufficient to prevent hyperglycemia, signifying the presence of T2DM(Fig.2c). Fig. 3 shows the relations between HbA1c and arterial pressure with adverse outcomes in patients with T2DM.These include vascular complications,which can be divided into two major categories:The macrovascular complications include epicardial coronary artery disease, cerebrovascular disease, aortic and peripheral arterial disease (Fig. 2d); the microvascular complications include DKD, neuropathy, retinopathy, and small vessel coronary disease. Many patients, especially those with longstanding T2DM, may have multiple vascular complications. Patients with microvascular complications are at increased risk of developing macrovascular complications,as well.

Increased insulin resistance of cardiomyocytes reduces their glucose utilization and contributes to hyperglycemia. It also increases the uptake and metabolism of free fatty acids, which impairs the efficiency of cardiac contraction. When excessive, this uptake can lead to triglyceride storage in cardiomyocytes, causing lipotoxicity, a contributor to impairment of cardiac contractility.

Figure 1 The vicious circle:an overview.Type 2 diabetes mellitus (T2DM), heart failure (HF), and diabetic kidney disease (DKD). T2DM is a major risk factor forHF(a)and for DKD(c).HF can cause or intensify the severity of T2DM(b).Both T2DM(c)and HF(d)can cause DKD.DKD can intensify HF(e). Both HF(f) and DKD(g) can cause sodium retention(Na+ret),pulmonary congestion,dyspnea and edema.

Figure 2 The vicious circle between T2DM and Heart Failure.AGEs,advanced glycation end products;HFrEF,heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; RAAS, reninangiotensin-aldosterone system;LV,left ventricle.

An important mechanism by which hyperglycemia is responsible for adverse clinical outcomes in T2DM is through the production of advanced glycation end products(AGE) (Fig. 2e), which act upon and activate a specific receptor, RAGE. This causes an accumulation of reactive O2 species (ROS) which, in turn, trigger inflammation (Fig. 2f) in both the myocardium and the microcirculation. Oxidative stress and myocardial inflammation can lead to myocyte apoptosis as well as mitochondrial dysfunction; the latter can reduce myocardial production of ATP, which may reduce the uptake of Ca2+by the sarcoplasmic reticulum of cardiomyocytes and thereby interfere with contraction.AGEs can also lead to cardiac fibrosis, which causes myocardial stiffness and HF with preserved ejection fraction(HFpEF)(Fig.2g).AGEs may also be responsible for endothelial dysfunction and microangiopathy.

The development of HF causes activation of two systems:1)the RAAS(Fig.2h),which causes retention of Na+and H2O; and 2) the sympathetic nervous system(Fig. 2i), causing lipolysis (Fig. 2j), which when combined with a typical Western diet and obesity(Fig.2k), can lead to insulin resistance (Fig. 2a), thereby completing the"vicious circle."

Heart failure

T2DM increases the risk of hospitalization or death secondary to HF both with reduced and with preserved ejection fraction. Hypertension (Fig.3a) and dyslipidemias (Fig. 3b) occur earlier, more frequently,and more severely in patients with T2DM, and play an important role in accelerating atherosclerosis (Fig. 3c),which is characterized by earlier and more extensive development of coronary artery plaques. Moreno et al.compared coronary atherectomy specimens obtained from patients with and without T2DM. The former showed greater contents of lipid,with larger infiltrates of macrophages. Such plaques are at high risk of rupture and have been referred to as"vulnerable"plaques.

T2DM can also produce a prothrombotic state(Fig.3e), with hyperactive platelets, and increases in coagulation factors including thrombin, and impaired fibrinolysis. The combination of vulnerable plaques and the prothrombotic state enhance the risk of development of coronary thrombosis, acute myocardial infarction(Fig.3d and f)and HF with reduced ejection fraction(HFrEF).Other important outcomes of accelerated atherosclerosis include chronic coronary artery disease, peripheral vascular disease,cerebrovascular disease,and stroke.

Figure 3 Mechanism of heart failure development in T2DM,which is frequently associated with hypertension(HT,a)and dyslipidemia (DL,b). These and other risk factors are responsible for accelerated atherosclerosis (AA,c),which in turn is responsible for coronary artery disease.The latter interacts with the prothrombotic state(PTS,e)of T2DM to cause myocardial infarction (MI, d and f),which is responsible for HF with reduced ejection fraction. T2DM can cause diabetic cardiomyopathy(DCM, h), in which microvascular coronary artery disease (MVD, i), contributes to the development of heart failure with preserved ejection fraction.

Diabetic cardiomyopathy(DCM)

T2DM is also responsible for molecular changes in myocardial structure and function that can cause DCM(Fig. 3h), a condition characterized by ventricular dysfunction in patients with T2DM in the absence of hypertension and coronary artery disease. Several mechanisms are believed to play important roles in the genesis of DCM. Seferovic and Paulus have described two phenotypes of HF resulting from DCM. The first,myocyte death, causes left ventricular systolic dysfunction and HFrEF. The second, caused by coronary microvascular disease (Fig. 3i), is a restrictive phenotype characterized by concentric left ventricular remodeling and diastolic dysfunction leading to HFpEF.More recently, depressed function of cardiomyocytes related to impaired mitochondrial Ca2+has been implicated. As pointed out above, the presence of HF intensifies the severity of T2DM(Fig.3j).

Diabetic kidney disease

In 1972, Rubler et al. described a "new type of cardiomyopathy associated with diabetic glomerulosclerosis." This condition, DKD, is a microvascular complication which frequently progresses to the need for dialysis or renal transplantation. Next to CVD, DKD is the most common cause of death in patients with T2DM. Mortality is increased about fourfold in patients with albuminuria and preserved glomerular function, about fivefold in patients with impaired glomerular function without albuminuria, but about ten-fold in patients with the combination of impaired glomerular filtration rate R and albuminuria.

T2DM and arterial hypertension play important roles in the development of DKD by causing glomerular hyperfiltration, glomerular hypertrophy, followed by expansion of the mesangium, and accumulation of extracellular matrix. The latter can lead to a loss of podocytes, disruption of the mesangium(mesangiolysis),and glomerular fibrosis. Thus, another vicious circle is created whereby the combination of T2DM and essential hypertension leads to DKD, which may cause secondary hypertension and further impairment of renal function.

As is the case with other microvascular complications of T2DM, early and effective glycemic control reduces the likelihood of developing DKD.Hyperuricemia,which in some instances is secondary to renal dysfunction, can "feed" into this circle. Uric acid is pro-inflammatory, induces oxidative stress, and activates the RAAS. Hyperuricemia is believed to increase the incidence and severity of DKD,which may,in part,be responsive to uric acid lowering.

詞 匯

crosstalk n.串話干擾，交談，巧妙的回答（或反駁），相聲

afferent adj.傳入的，向心的

signify v.表示，說明，預示，表達

lipotoxicity n.脂毒性

glycation n.糖化

species n.種，物種，基團，（物）核素

apoptosis n.程序性細胞死亡，細胞凋亡

sarcoplasmic adj. 肌質的，肌漿的

implicate n.&v. 包含的東西；牽涉，涉及（某人），表明（或意指）…是起因

glomerulosclerosis n.腎小球硬化癥，小動脈性腎硬化

mesangium n.腎小球環(huán)毛細血管膜，腎小球膜

mesangiolysis n.腎小球膜基質溶解，腎小球膜細胞退化

atherectomy n.斑塊切除術

注 釋1.two-way street 有兩種譯義，一指“雙行道路”，二指“互諒互讓”。In most instances the route is a two-way street, as his condition improves or worsens.多數(shù)情況下隨著他的病情改善或惡化而呈雙向途徑。Marriage is a two-way street.夫妻之道在于夫妻互諒互讓。

參考譯文

第100 課 糖尿病、心力衰竭和腎功能不全：惡性循環(huán)

2 型糖尿病（T2DM），心力衰竭（HF）和糖尿病性腎病（DKD）是21 世紀的主要流行疾病。全球有4 億T2DM 患者。這三種疾病經常共存，每一種可以使另外兩種進展惡化，形成一系列的惡性循環(huán)（圖1）。例如，T2DM 是發(fā)生HF 的強力危險因素（圖1a）；伴發(fā)心血管疾?。–VD）的風險2～4 倍，后者約占T2DM 所有死因的2/3。

T2DM 合并左心室功能不全特別危險，伴發(fā)的慢性失能和死亡率高。除HF 的增加歸因于T2DM 外，也有依據(jù)表明可倒過來，即為“雙向車道”（圖1b）。因此，HF 在T2DM 的發(fā)生過程中起因果作用，重度HF 伴隨著明顯的胰島素抵抗形成。相反，已表明通過植入左心室輔助裝置治療重度HF 后糖尿病控制得以改善。

基于定義，糖尿病是DKD 的病因（圖1c）。衰竭心臟與衰竭腎臟之間存在交叉影響。低心排合并腎靜脈壓的增高導致腎血流減少。HF 時的交感神經和腎素-血管緊張素-醛固酮系統(tǒng)上調引起入球小動脈收縮，減少腎小球濾過。DKD時的衰竭腎臟導致繼發(fā)性高血壓和貧血，以致衰竭心臟增加額外負擔。心臟與腎臟之間的這種雙向作用形成重要的惡性循環(huán)（圖1c-d）。HF（圖1f）和DKD（圖1g）均導致鈉滯留，從而引起肺淤血、呼吸困難和水腫。

發(fā)病機制

HF 與T2DM 之間的惡性循環(huán)見圖2，修改自Maack 等。T2DM 的發(fā)生以胰島素抵抗為中心（圖2a），胰島素抵抗導致胰島素高分泌（圖2b）。隨著疾病進展，胰腺分泌的胰島素雖然仍然高于正常，但不足以防止高血糖，預示發(fā)生T2DM（圖2c）。圖3 顯示T2DM 患者HbA1c 與動脈壓之間的關系及不良預后。這些包括血管并發(fā)癥，可分為兩大類：包括心外膜冠狀動脈疾病、腦血管疾病、主動脈和周圍血管疾病在內的大血管并發(fā)癥（圖2d）；包括DKD、神經病變、視網膜病變和小血管冠狀動脈病變在內的微血管并發(fā)癥。許多患者，特別是那些患有長期T2DM 者，可有多種血管并發(fā)癥。同樣，患有微血管并發(fā)癥者發(fā)生大血管并發(fā)癥的風險增高。心肌細胞胰島素抵抗的增加減少了葡萄糖的利用而促進高血糖。這也促進游離脂肪酸的攝取和代謝，這會損害心臟收縮的效能。如攝取過量，可導致甘油三酯儲存于心肌細胞，引起脂毒性，這是心臟收縮性損害的加劇因素。

T2DM 患者高血糖導致不良臨床預后的重要機制是通過產生晚期糖化終末產物（AGE）（圖2e），AGE 作用于特殊受體RAGE 并激活它。引起反應性O2基團（ROS）積聚，隨之促發(fā)心肌和微循環(huán)炎癥（圖2f）。氧化應激和心肌炎癥可導致心肌細胞凋亡以及線粒體功能障礙，后者使得心肌ATP 產生減少，從而使得心肌細胞肌漿網Ca2+攝取減少而影響收縮。AGEs 也可引起心肌纖維化，導致心肌僵硬而發(fā)生收縮功能保留的HF（HFpEF）（圖2g）。AGEs 也與內皮功能障礙和微血管病有關。

HF 的發(fā)展引起兩個系統(tǒng)的激活：1）RAAS（圖2h），這可引起Na+和水滯留；2）交感神經系統(tǒng)（圖2i），引起脂肪分解（圖2j），當結合典型的西方飲食和肥胖（圖2k），可導致胰島素抵抗（圖2a），因此而形成“惡性循環(huán)”。

心力衰竭

T2DM 增加收縮功能降低和保留HF 患者的住院和死亡風險。T2DM 患者高血壓（圖3a）和血脂異常（圖3b）發(fā)生較早、更為頻發(fā)和較為嚴重，在加重動脈粥樣硬化方面起重要作用（圖3c），特征表現(xiàn)為較早和較為廣泛的冠狀動脈斑塊形成。Moreno 等對有無T2DM 患者的冠狀動脈旋切斑塊進行了比較。前者脂質成分多，且有較多巨噬細胞。這種斑塊的破裂風險高，稱為“易損”斑塊。

T2DM 也可產生高凝狀態(tài)（圖3e），伴隨血小板高反應性、包括凝血酶在內的凝血因子增加和纖溶受損。易損斑塊合并高凝狀態(tài)增加冠狀動脈血栓形成、急性心肌梗死以及收縮功能降低HF(HFrEF)的風險（圖3d-f）。加速動脈粥樣硬化的其他明顯結果包括慢性冠狀動脈疾病、周圍血管病、腦血管病和中風。

糖尿病性心肌?。―CM）

T2DM 也引起心肌結構和功能分子變化而導致DCM（圖3h），這特征表現(xiàn)為無高血壓和冠狀動脈病變情況下的T2DM 患者心室功能不全。有認為多種機制在DCM 的發(fā)生上起重要作用。Seferovic 和Paulus 描述過兩種DCM 引起的HF表型。第一種是心肌細胞死亡，引起左心室收縮功能不全和HFrEF。第二種是由冠狀動脈微血管病所致（圖3i）的限制性表型，特征為左心室向心性重構和舒張功能不全導致HFpEF。最近認為心肌細胞功能抑制與線粒體Ca2+受損有關。正如上面指出的，HF 使得T2DM 嚴重性增加（圖3j）。

糖尿病性腎病

1972 年Rubler 等描述了與糖尿病腎小球硬化相關的新型心肌病。DKD，一種微血管并發(fā)癥，常常進展而需血透或腎移植。繼CVD 后，DKD 是引起T2DM 患者死亡的最常見病因。有蛋白尿而保留腎小球功能者死亡率增加4 倍，腎小球功能受損而無蛋白尿者死亡率增加5 倍，同時有腎小球濾過率受損和蛋白尿者死亡率增加約10 倍。

T2DM 和高血壓通過引起腎小球超濾、腎小球肥大，隨之腎小球膜擴張和細胞外基質積聚，在DKD 的發(fā)展中起重要作用。細胞外基質積聚可導致足細胞喪失、腎小球膜斷裂（腎小球膜基質溶解）和腎小球纖維化。這樣，另一惡性循環(huán)形成，T2DM 和高血壓的結合導致DKD，這又可引起繼發(fā)性高血壓而進一步損害腎功能。

如同T2DM 的其他微血管并發(fā)癥一樣，早期和積極的血糖控制減少DKD 發(fā)生的可能性。高尿酸血癥，某些情況下，繼發(fā)于腎功能不全，可加入這一循環(huán)。尿酸促進炎癥，引發(fā)氧化應激和激活RAAS。高尿酸血癥增加DKD 的發(fā)病率和嚴重性，DKD 對尿酸的降低有部分反應。

圖1惡性循環(huán)一覽圖。2 型糖尿?。═2DM），心力衰竭（HF），和糖尿病性慢性腎?。―KD）。T2DM 是HF（a)）和DKD（c）的主要危險因素。HF 可引起或加重T2DM（b）。T2DM（c）和HF（d）均可引起DKD。DKD 可加重HF（e）。HF（f）和DKD（g）均可引起鈉滯留（Na+ ret），肺淤血，呼吸困難和水腫。

圖2T2DM 與心力衰竭之間的惡性循環(huán)。AGEs，晚期糖化終末產物；HFrEF，收縮功能降低心力衰竭；HFpEF，收縮功能保留心力衰竭；RAAS，腎素-血管緊張素-醛固酮系統(tǒng)；LV，左心室。

圖3T2DM 患者心力衰竭發(fā)生機制，常常合并高血壓（HT，a）和血脂異常（DL，b）。這些和其他因素加速動脈粥樣硬化（AA，c），引起冠狀動脈疾病。后者與T2DM 的致血栓狀態(tài)（PTS，e）相互作用而導致心肌梗死（MI，d 和f），引起收縮功能降低HF。T2DM 可引起糖尿病性心肌?。―CM，h），微血管性冠狀動脈病變（MVD，i），促進收縮功能保留心力衰竭的發(fā)生。