Natriuretic peptides (NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure (CHF), countering renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system ...(SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial (ANP) or brain (BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system (NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter‐regulatory hormones of the RAAS and SNS, and endothelin‐1 become over‐activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF.
Hypertensive heart disease (HHD) is currently the second leading cause of heart failure. The prevalence of HHD and its associated risk of heart failure have increased despite substantial improvement ...in arterial hypertension treatment and control in the recent decades. Therefore, the prevention of heart failure in patients with HHD represents an unmet medical need, due to its clinical, economic, and social impact. In this conceptual framework, we call to action because the time has come for diagnosis and treatment of patients with HHD not to be limited to assessment of morphological and functional left ventricular changes, blood pressure control, and left ventricular hypertrophy regression. We propose a further perspective incorporating also the detection and reversal of the histological changes that develop in the hypertensive heart and that lead to the structural remodeling of the myocardium. In particular, we focus on the diagnosis and treatment of myocardial interstitial fibrosis, likely the lesion most critically involved in the transition from subclinical HHD to clinically overt heart failure. In this context, it is worth considering whether the use of imaging and circulating biomarkers for the noninvasive diagnosis of myocardial interstitial fibrosis should be incorporated in the medical study of hypertensive patients, especially of those with HHD.
Myocardial interstitial fibrosis contributes to left ventricular dysfunction leading to the development of heart failure. Basic research has provided abundant evidence for the cellular and molecular ...mechanisms behind this lesion and the pathways by which it imparts a detrimental impact on cardiac function. Translation of this knowledge, however, to improved diagnostics and therapeutics for patients with heart failure has not been as robust. This is partly related to the paucity of biomarkers to accurately identify myocardial interstitial fibrosis and to the lack of personalized antifibrotic strategies to treat it in an effective manner. This paper summarizes current knowledge of the mechanisms and detrimental consequences of myocardial interstitial fibrosis, discusses the potential of circulating and imaging biomarkers available to recognize different phenotypes of this lesion and track their clinical evolution, and reviews the currently available and potential future therapies that allow its individualized management in heart failure patients.
Changes in the composition of cardiac tissue develop in hypertensive patients with left ventricular hypertrophy (ie, hypertensive heart disease) and lead to structural remodeling of the myocardium. ...One of these changes is related to the disruption of the equilibrium between the synthesis and degradation of collagen types I and III molecules, which results in an excessive accumulation of collagen types I and III fibers within the myocardium. Myocardial fibrosis is the consequence of a number of pathologic processes mediated by mechanical, neurohormonal, and cytokine routes. The clinical relevance of fibrosis is that it may contribute to heart failure and other cardiac complications in patients with hypertensive heart disease. This brief review focuses on the mechanisms of hypertensive myocardial fibrosis.
The cardiac lymphatic network plays a key role in regulation of myocardial extracellular volume and immune cell homeostasis. In different pathological conditions cardiac lymphatics undergo ...significant remodeling, with insufficient lymphatic function and/or lymphangiogenesis leading to fluid accumulation and development of edema. Additionally, by modulating the reuptake of tissue-infiltrating immune cells, lymphatics regulate immune responses. Available evidence suggests that both edema and inadequate immune response resolution may contribute to extracellular matrix remodeling and interstitial myocardial fibrosis. Interestingly, stimulation of lymphangiogenesis has been shown to improve cardiac function and reduce the progression of myocardial fibrosis during heart failure development after myocardial infarction. This review goes through the available clinical and experimental data supporting a role for cardiac lymphatics in cardiac disease, focusing on the current evidence linking poor cardiac lymphatic transport to the fibrogenic process and discussing potential avenues for novel biomarkers and therapeutic targets to limit cardiac fibrosis and dysfunction.
Diffuse myocardial fibrosis resulting from the excessive deposition of collagen fibres through the entire myocardium is encountered in a number of chronic cardiac diseases. This lesion results from ...alterations in the regulation of fibrillary collagen turnover by fibroblasts, facilitating the excessive deposition of type I and type III collagen fibres within the myocardial interstitium and around intramyocardial vessels. The available evidence suggests that, beyond the extent of fibrous deposits, collagen composition and the physicochemical properties of the fibres are also relevant in the detrimental effects of diffuse myocardial fibrosis on cardiac function and clinical outcomes in patients with heart failure. In this regard, findings from the past 20 years suggest that various clinicopathological phenotypes of diffuse myocardial fibrosis exist in patients with heart failure. In this Review, we summarize the current knowledge on the mechanisms and detrimental consequences of diffuse myocardial fibrosis in heart failure. Furthermore, we discuss the validity and usefulness of available imaging techniques and circulating biomarkers to assess the clinicopathological variation in this lesion and to track its clinical evolution. Finally, we highlight the currently available and potential future therapeutic strategies aimed at personalizing the prevention and reversal of diffuse myocardial fibrosis in patients with heart failure.
The estimated glomerular filtration rate (eGFR) provides insight into cardiovascular disease (CVD) risk stratification and proactive management. Accumulating evidence suggests that combining eGFR ...calculated from serum cystatin C (eGFRcys) and from serum creatinine (eGFRcrea) improves CVD risk stratification over eGFRcrea alone. The term selective glomerular hypofiltration syndrome (SGHS) or shrunken pore syndrome has been proposed to define an eGFRcys:eGFRcrea ratio <1, which is hypothesized to result from a reduced glomerular filtration of 5- to 30-kDa molecules as compared with smaller molecules. SGHS may be identified in people with normal or reduced measured GFR, but the prevalence depends on the cut-off value of the eGFRcys:eGFRcrea ratio used, which is not yet standardized. SGHS is strongly associated with increased CVD and mortality risks and it may offer an opportunity to expand our understanding of the mechanisms linking GFR disorders with CVD risk (e.g. an altered plasma proteome), which may guide treatment decisions. However, muscle wasting may also contribute to a reduced eGFRcys:eGFRcrea ratio and there are open questions regarding the pathophysiology of a reduced eGFRcys:eGFRcrea ratio, the reference cut-off values of the ratio to define the syndrome and its clinical implications. We now critically review the SGHS concept, its pathophysiological basis and links to CVD and the potential consequences for clinical practice and propose a research agenda.
Myocardial interstitial fibrosis (MIF) is a histological hallmark of several cardiac diseases that alter myocardial architecture and function and are associated with progression to heart failure. MIF ...is a diffuse and patchy process, appearing as a combination of interstitial microscars, perivascular collagen fiber deposition, and increased thickness of mysial collagen strands. Although MIF arises mainly because of alterations in fibrillar collagen turnover leading to collagen fiber accumulation, there are also alterations in other nonfibrillar extracellular matrix components, such as fibronectin and matricellular proteins. Furthermore, in addition to an excess of collagen, qualitative changes in collagen fibers also contribute to the detrimental impact of MIF. In this part 3 of a 4-part JACC Focus Seminar, we review the evidence on the complex mechanisms leading to MIF, as well as its contribution to systolic and diastolic cardiac dysfunction and impaired clinical outcomes in patients with nonischemic heart disease.
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•MIF is a histological hallmark of several cardiac diseases that alter myocardial architecture and function.•MIF is a diffuse and patchy process, appearing as a combination of interstitial microscars, perivascular collagen fiber deposition, and increased thickness of mysial collagen strands.•MIF plays an important role in systolic and diastolic cardiac dysfunction, as well as impaired clinical outcomes in patients with nonischemic heart disease.•Ongoing preclinical research for reversing nonischemic MIF is aiming to prevent excessive fibrous tissue deposition; however, although many new therapies targeting MIF appear promising in the preclinical setting, their translation to the clinical arena remains challenging.
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