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Kinin-kallikrein system: New perspectives in heart failure
Keivan Mohammadi1, Davood Shafie2, Newsha Ghomashi3
1Shahid Chamran Heart Center, Isfahan University of Medical Sciences, Isfahan, Iran.
Insights
The kinin-kallikrein system (KSS) plays a dual role in heart failure (HF). Blocking KSS may offer a promising strategy to reduce cardiac remodeling and improve HF symptoms.
Area of Science:
- Cardiovascular Medicine
- Physiology
- Pharmacology
Background:
- Heart failure (HF) is a major clinical issue impacting cardiac function and quality of life.
- The kinin-kallikrein system (KSS), a complex peptide cascade, is increasingly recognized for its involvement in HF.
- Aberrations in KSS components are associated with increased HF risk.
Purpose of the Study:
- To investigate the multifaceted role of the kinin-kallikrein system (KSS) in the pathophysiology of heart failure (HF).
- To explore the potential of KSS blockade as a therapeutic strategy for managing HF progression and symptoms.
Main Methods:
- Review of existing literature on the kinin-kallikrein system (KSS) and its components, including bradykinin (BK), B1 and B2 receptors, and kallikreins.
- Analysis of the physiological effects of KSS activation on cardiac function, inflammation, coagulation, blood pressure, and vascular permeability.
- Examination of the interplay between KSS and the renin-angiotensin-aldosterone system (RAAS) in the context of HF.
Main Results:
- Kinin-kallikrein system (KSS) activation exhibits dual effects: beneficial in acute cardiac damage (e.g., vasodilation via bradykinin) but detrimental in chronic HF (e.g., inflammation, collagen loss).
- Kallikrein activity can lead to both beneficial bradykinin effects and detrimental angiotensin II upregulation, promoting vasoconstriction and fluid retention.
- Prolonged KSS activation contributes to cardiac collagen loss and remodeling, exacerbated by conventional renin-angiotensin-aldosterone system (RAAS) inhibitors.
Conclusions:
- Kinin-kallikrein system (KSS) blockade is a potential therapeutic strategy to mitigate cardiac remodeling and improve heart failure (HF) outcomes.
- Inhibiting KSS may attenuate the detrimental effects of immune system activation and tissue damage in HF.
- Further research is needed to understand the long-term benefits of kallikrein inhibitors in chronic HF, considering the complex roles of bradykinin.
Abstract:
Heart failure (HF) is a pervasive clinical challenge characterized by compromised cardiac function and reduced quality of life. The kinin-kallikrein system (KSS), a multifaceted peptide cascade, has garnered substantial attention due to its potential role in HF. Through activation of B1 and/or B2 receptors and downstream signaling, kinins modulate various physiological processes, including inflammation, coagulation, pain, blood pressure control, and vascular permeability. Notably, aberrations in KKS components have been linked to HF risk. The elevation of vasodilatory bradykinin (BK) due to kallikrein activity reduces preload and afterload, while concurrently fostering sodium reabsorption inhibition. However, kallikrein's conversion of prorenin to renin leads to angiotensinsII upregulation, resulting in vasoconstriction and fluid retention, alongside increased immune cell activity that fuels inflammation and cardiac remodeling. Importantly, prolonged KKS activation resulting from volume overload and tissue stretch contributes to cardiac collagen loss. The conventional renin-angiotensin-aldosterone system (RAAS) inhibitors used in HF management may inadvertently intensify KKS activity, exacerbating collagen depletion and cardiac remodeling. It is crucial to balance the KKS's role in acute cardiac damage, which may temporarily enhance function and metabolic parameters against its detrimental long-term effects. Thus, KKS blockade emerges as a promising strategy to impede HF progression. By attenuating the link between immune system function and tissue damage, KKS inhibition can potentially reduce cardiac remodeling and alleviate HF symptoms. However, the nuanced roles of BK in various acute conditions necessitate further investigation into the sustained benefits of kallikrein inhibitors in patients with chronic HF.
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