Left ventricular hypertrophy (LVH) is the major risk factor associated with myocardial failure. An explanation for why a presumptive adaptation such as LVH would prove pathological has been elusive. Insights into the impairment in contractility of the hypertrophied myocardium have been sought in the biochemistry of cardiac myocyte contraction. Equally compelling is a consideration of abnormalities in myocardial structure that impair organ contractile function while preserving myocyte contractility. For example, in the LVH that accompanies hypertension, the extracellular space is frequently the site of an abnormal accumulation of fibrillar collagen. This reactive and progressive interstitial and perivascular fibrosis accounts for abnormal myocardial stiffness and ultimately ventricular dysfunction and is likely a result of cardiac fibroblast growth and enhanced collagen synthesis. The disproportionate involvement of this nonmyocyte cell, however, is not a uniform accompaniment to myocyte hypertrophy and LVH, suggesting that the growth of myocyte and nonmyocyte cells is independent of each other. This has now been demonstrated in in vivo studies of experimental hypertension in which the abnormal fibrous tissue response was found in the hypertensive, hypertrophied left ventricle as well as in the normotensive, nonhypertrophied right ventricle. These findings further suggest that a circulating substance that gained access to the common coronary circulation of the ventricles was involved. This hypothesis has been tested in various animal models in which plasma concentrations of angiotensin II and aldosterone were varied. Based on morphometric and morphological findings, it can be concluded that arterial hypertension (i.e., an elevation in coronary perfusion pressure) together with elevated circulating aldosterone are associated with cardiac fibroblast involvement and the resultant heterogeneity in tissue structure. Nonmyocyte cells of the cardiac interstitium represent an important determinant of pathological LVH. The mechanisms that invoke short- (e.g., collagen metabolism) and long-term (e.g., mitosis) responses of cardiac fibroblasts require further investigation and integration of in vitro with in vivo studies. The stage is set, however, to prevent pathological LVH resulting from myocardial fibrosis as well as to reverse it.

Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system.

Swynghedauw, Bernard. Molecular Mechanisms of Myocardial Remodeling. Physiol. Rev. 79: 215–262, 1999. — “Remodeling” implies changes that result in rearrangement of normally existing structures. Th...

Molecular Mechanisms of Myocardial Remodeling

Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation.

Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes.

/pdf/dietary-metabolism-the-gut-microbiome-and-heart-failure-31qeh6leiq.pdf

Dietary metabolism, the gut microbiome, and heart failure

When considering the pathological steps in the progression from cardiac overload towards the full clinical syndrome of heart failure, it is becoming increasingly clear that the extracellular matrix (ECM) is an important determinant in this process. Chronic pressure overload induces a number of structural alterations, not only hypertrophy of cardiomyocytes but also an increase in ECM proteins in the interstitium and perivascular regions of the myocardium. When this culminates in excessive fibrosis, myocardial compliance decreases and electrical conduction is affected. Altogether, fibrosis is associated with an increased risk of ventricular dysfunction and arrhythmias. Consequently, anti-fibrotic strategies are increasingly recognized as a promising approach in the prevention and treatment of heart failure. Thus, dissecting the molecular mechanisms underlying the development of cardiac fibrosis is of great scientific and therapeutic interest. In this review, we provide an overview of the available evidence supporting the general idea that fibrosis plays a causal role in deteriorating cardiac function. Next, we will delineate the signalling pathways importantly governed by transforming growth factor β (TGFβ) in the control of cardiac fibrosis. Finally, we will discuss the recent discovery that miRNAs importantly regulate cardiac fibrosis.

Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart

Study objective – The aim was to compare the temporal sequence and structural relationship between perivascular and interstitial fibrosis and microscopic scarring seen in the left ventricle in response to either a transient or sustained stimulus to fibrosis.

Design – In 72 male Wistar rats (250 – 350 g) the transient stimulus model was based on the administration of isoprenaline (500 μg·kg−1) while the sustained stimulus model was produced by abdominal aortic banding with right renal artery constriction. Serial sections of myocardium were examined and compared at 4 and 12 weeks in each model and to corresponding controls.

Experimental material – The collagen specific stain, Sirius Red F3BA, was used to determine collagen volume fraction and the fibrillar nature of the fibrous tissue response seen by light microscopy.

Measurements and main results – Following isoprenaline a stable reparative fibrosis of the endomyocardium and increase in collagen volume fraction was seen without an interstitial or perivascular fibrosis of the non-involved myocardium. In unilateral renal ischaemia, on the other hand, a progressive perivascular fibrosis was evident throughout the myocardium and from which fibrillar collagen extended into the extracellular space between muscle bundles creating an interstitial fibrosis; microscopic scarring of the endomyocardium became evident at 12 weeks.

Conclusions – The reactive perivascular fibrosis of intramyocardial coronary arteries seen in renovascular hypertension is a progressive process that leads to an interstitial fibrosis and eventual microscopic scarring. In contrast, the endomyocardial scarring that follows isoprenaline induced myocyte necrosis is stable and intramural vessels in remote regions are not involved.

Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis

Myocardial fibrosis constitutes a nonspecific common pathway of myocardial response to injury. There is increasing evidence for the unfavorable effect of myocardial fibrosis on the outcome of patients with myocardial disease.1 Adverse functional effects of myocardial collagen have been shown in systemic hypertension,2 aortic valve stenosis,3 idiopathic dilated cardiomyopathy4 and other myocardial diseases.5 However, initial and serial assessment of the severity of myocardial fibrosis is difficult in the absence of a practical and noninvasive method. Endomyocardial biopsy allows direct visualization and quantitation of the structural components of the myocardium. Using data obtained from endomyocardial biopsies in 24 patients, we sought to develop a noninvasive method of estimation of the degree of myocardial fibrosis.

Usefulness of the electrocardiogram and echocardiogram in predicting the amount of interstitial myocardial collagen in endomyocardial biopsy specimens of patients with chronic heart failure

Between 1976 and 1986, approximately 83,000 patients had heart valve replacement with the Bjork-Shiley 60 ° CC prosthesis. A recognized complication of this prosthesis is strut fracture with embolization of the occluder disk. 1 This linearized frequency of this complication has been related to prosthetic size and date of manufacture. Whereas this complication is recognized for prostheses used in the mitral and aortic positions it has not yet been described in a prosthesis in the tricuspid position. The case described highlights such an occurrence.

Strut fracture and embolization of a Björk-Shiley valve from the tricuspid valve position.

Endothelial dysfunction has been recognized as a pathophysiologic mechanism in the progression of heart failure (HF). However, little attention has been given to the ability of dietary approaches to improve endothelial function. This study examined the effects of the Dietary Approaches to Stop Hypertension (DASH) diet on endothelial function, exercise capacity, and quality of life in patients with chronic symptomatic (stage C) HF. Forty-eight patients were randomized to follow the DASH diet (n = 24) or the general HF dietary recommendations (n = 24). Endothelial function was assessed by measuring large and small arterial elasticity (LAE and SAE) at rest. Exercise capacity (measured with the 6-minute walk test) and quality of life (measured with the Minnesota Living with Heart Failure Questionnaire) at baseline and 3 months were also evaluated. Patients were older adults with an average HF duration of 5 years. LAE at 1 month improved significantly in the DASH diet group (P < 0.01). Overall LAE and SAE scores at 3 months also improved; however, the net changes were not statistically significant. The DASH group had better exercise capacity (292 m vs 197 m; P = 0.018) and quality of life scores (21 vs 39; P = 0.006) over time, while sodium intake levels at 1, 2, and 3 months were comparable between the groups. Adhering to the DASH diet improved arterial compliance initially and improved exercise capacity and quality of life scores at 3 months. The DASH diet may be an important adjunctive therapy for patients with symptomatic HF.

/pdf/impact-of-the-dash-diet-on-endothelial-function-exercise-xa60ftp1kb.pdf

Impact of the DASH diet on endothelial function, exercise capacity, and quality of life in patients with heart failure.

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Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis

Usefulness of the electrocardiogram and echocardiogram in predicting the amount of interstitial myocardial collagen in endomyocardial biopsy specimens of patients with chronic heart failure

Strut fracture and embolization of a Björk-Shiley valve from the tricuspid valve position.

Impact of the DASH diet on endothelial function, exercise capacity, and quality of life in patients with heart failure.