Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease

Abstract

Purpose of the review: Drugs targeting the renin-angiotensin system (RAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious angiotensin II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF).

Recent findings: Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from Ang-(1-12). The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. Ang-(1-12) expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the Ang-(1-12)/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.

Keywords: Angiotensin receptor blockers; Angiotensin-(1-12); Angiotensin-converting enzyme inhibitor; Cardiomyocyte; Chymase; Intracrine.

Figure 1

Ang II as an intracrine hormone. Schematic diagram of tissue-delimited RAS depicting the enzymatic action of a yet to be determined enzyme and chymase to form Ang-(1-12) and Ang II, respectively, in a cardiac cell. This intracrine system is independent from circulating RAS, as shown in the presence of ACE inhibition and AT₁R blockade, and is capable of cell-contained production of Ang II, which can then interact with intracellular AT₁R to exert biological actions. AGT: angiotensinogen; Ang I: angiotensin I; Ang II: Ang II; Ang-(1-12): angiotensin-(1-12); AT₁R: Ang II type 1 receptor.

Figure 2

Relative risk and 95 % confidence intervals of the effect of angiotensin converting enzyme inhibitors (open diamonds) or Ang II receptor blockers (closed diamonds) on primary cardiac end points of large randomized clinical trials. Overall, the reduction in the primary end-point across all the trials documented here averaged 0.87 (CI, 0.83 – 0.92). Acronyms are: ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension [96]; AIRE, Acute Infarction Ramipril Efficacy [97]; ANBP-2, Second Australian National Blood Pressure Study Group [98]; ASCOT BPLA, Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm [99]; ATLAS (high dose), Assessment of Treatment with Lisinopril And Survival [100]; CAPPP, Captopril Prevention Project [101]; CHARM-Alternative, Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity [77]; CHARM-Added, Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity [79]; ELITE, Evaluation of Losartan in the Elderly Study [102]; ELITE II, the Losartan Heart Failure Survival Study (Evaluation of Losartan in the Elderly Study) [103]; EUROPA, European trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease [104]; GISSI-3, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico [105]; HYVET, Hypertension in the Very Elderly Trial [106]; HEAAL, Heart failure Endpoint evaluation of Ang II Antagonist Losartan [107]; HOPE, Heart Outcomes Prevention Evaluation Study [108]; I-PRESERVE, Irbesartan in Heart Failure with Preserved Ejection Fraction Study [109]; LIFE, Losartan Intervention For Endpoint reduction Study [78]; ONTARGET, The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial [110]; OPTIMAAL, Optimal Trial in Myocardial Infarction with the Ang II Antagonist Losartan [111]; PEACE, Prevention of Events with Angiotensin Converting Enzyme Inhibition [112]; SAVE, Survival and Ventricular Enlargement trial [113]; SMILE, Survival of Myocardial Infarction Long-Term Evaluation trial [114]; SOLVD, Studies of Left Ventricular Dysfunction [76]; SOLVD 2, Studies of Left Ventricular Dysfunction [115]; STOP-Hypertension 2, Swedish Trial in Old Patients with Hypertension-2 study [116]; TRACE, Trandolapril Cardiac Evaluation [117]; TRASCEND, Telmisartan Randomised Assessmen Study in ACE Intolerant subjects with cardiovascular Disease [118]; TROPHY, Trial Preventing Hypertension [119]; VAL-HEFT, Valsartan Heart Failure Trial [120]; VALIANT, Valsartan in Acute Myocardial Infarction trial [121]; VALUE, Valsartan Antihypertensive Long-term Use Evaluation study [122].