Pure Volume Overload Research Articles

Isolated tricuspid regurgitation: a new entity to face. Prevalence, prognosis and treatment of isolated tricuspid regurgitation.

In recent years the tricuspid is no longer considered the "forgotten valve," but nowadays, specialists focused the treatment of tricuspid regurgitation (TR) especially at the time of left heart valve (LHV) surgery, overlooking the emerging entity of isolated TR. Its incidence appears to be rising along with the higher prevalence of atrial fibrillation (AF), intracardiac devices and intravenous drug users. Hence, the aim of the present review is to summarize the available evidences in terms of natural history, clinical presentation and treatment of isolated TR. Tricuspid regurgitation is commonly classified into primary and secondary etiology. Primary or organic TR is relatively uncommon (10%) and may be due to either acquired or congenital diseases. Conversely, secondary or functional TR, caused by dilatation and flattening of the tricuspid annulus along with increase of leaflet tethering due to the remodeling of the right ventricle (RV) has become in last decade an emerging entity. Secondary TR may be due grade progression after left heart valve surgery, to previous TV surgery failure, RV remodeling or permanent AF. Primary TR causes pure volume overload on initially normal right-sided cardiac chambers. Conversely, RV enlargement is the major finding of secondary TR; RV systolic area, RV spherical index and right atrial area were identified as independent factors correlated with TV tethering height. The RV has less muscle mass than the left ventricle, and RV systolic function is therefore more load sensitive. Thus, pulmonary hypertension results in an early fall in RV ejection fraction and associated RV enlargement. An interesting entity is isolated TR related to AF, whose prevalence is estimated to be 14% in recent studies. It is known to cause dilation of the mitral and tricuspid annulus, together with changes in the dynamic mechanisms that govern the variation in area size during the cardiac cycle; as a matter of fact the relative change in TA area was significantly lower in AF (13.5%) than in sinus rhythm (SR) (33.1%). In isolated TR, medical therapy (MT) is indicated only in patients with secondary TR having also severe RV/LV dysfunction or severe pulmonary hypertension. Diuretics are the main MT in case of isolated TR in the presence of right HF in carefully selected candidates, surgery can be performed safely with good long-term survival and it should be considered early at first stages. In the treatment of isolated TR we had two diametrically opposed approaches so far, such as medical therapy, based almost exclusively on diuretics, and surgical therapy. In this scenario, trans-catheter approach is gaining momentum, including repair or replacement treatment. The former sees the use of devices for direct or indirect annuloplasty, or leaflet approximation. The second consists of orthotopic or heterotopic replacement devices (transcatheter tricuspid valve replacement devices). Evidences from randomized studies and longer follow-up will help clarify the best patient selection and treatment strategies.

Increased fibroblast chymase production mediates procollagen autophagic digestion in volume overload

BackgroundPrevious work has identified mast cells as the major source of chymase largely associated with a profibrotic phenotype. We recently reported increased fibroblast autophagic procollagen degradation in a rat model of pure volume overload (VO). Here we demonstrate a connection between increased fibroblast chymase production and autophagic digestion of procollagen in the pure VO of aortocaval fistula (ACF) in the rat. Methods and resultsIsolated LV fibroblasts taken from 4 and 12week ACF Sprague–Dawley rats have significant increases in chymase mRNA and chymase activity. Increased intracellular chymase protein is documented by immunocytochemistry in the ACF fibroblasts compared to cells obtained from age-matched sham rats. To implicate VO as a stimulus for chymase production, we show that isolated adult rat LV fibroblasts subjected to 24h of 20% cyclical stretch induces chymase mRNA and protein production. Exogenous chymase treatment of control isolated adult cardiac fibroblasts demonstrates that chymase is internalized through a dynamin-dependent mechanism. Chymase treatment leads to an increased formation of autophagic vacuoles, LC3-II production, autophagic flux, resulting in increased procollagen degradation. Chymase inhibitor treatment reduces cyclical stretch-induced autophagy in isolated cardiac fibroblasts, demonstrating chymase's role in autophagy induction. ConclusionIn a pure VO model, chymase produced in adult cardiac fibroblasts leads to autophagic degradation of newly synthesized intracellular procollagen I, suggesting a new role of chymase in extracellular matrix degradation.

Increased myocardial stiffness due to cardiac titin isoform switching in a mouse model of volume overload limits eccentric remodeling

We investigated the cellular and molecular mechanisms of diastolic dysfunction in pure volume overload induced by aortocaval fistula (ACF) surgery in the mouse. Four weeks of volume overload resulted in significant biventricular hypertrophy; protein expression analysis in left ventricular (LV) tissue showed a marked decrease in titin's N2BA/N2B ratio with no change in phosphorylation of titin's spring region. Titin-based passive tensions were significantly increased; a result of the decreased N2BA/N2B ratio. Conscious echocardiography in ACF mice revealed eccentric remodeling and pressure volume analysis revealed systolic dysfunction: reductions in ejection fraction (EF), +dP/dt, and the slope of the end-systolic pressure volume relationships (ESPVR). ACF mice also had diastolic dysfunction: increased LV end-diastolic pressure and reduced relaxation rates. Additionally, a decrease in the slope of the end diastolic pressure volume relationship (EDPVR) was found. However, correcting for altered geometry of the LV normalized the change in EDPVR and revealed, in line with our skinned muscle data, increased myocardial stiffness in vivo. ACF mice also had increased expression of the signaling proteins FHL-1, FHL-2, and CARP that bind to titin's spring region suggesting that titin stiffening is important to the volume overload phenotype. To test this we investigated the effect of volume overload in the RBM20 heterozygous (HET) mouse model, which exhibits reduced titin stiffness. It was found that LV hypertrophy was attenuated and that LV eccentricity was exacerbated. We propose that pure volume overload induces an increase in titin stiffness that is beneficial and limits eccentric remodeling.

The Multiple Mechanistic Faces of a Pure Volume Overload: Implications for Therapy

Mitral regurgitation and other conditions marked by a pure isolated volume overload (VO) of the heart result in a progressive form of eccentric left ventricular remodeling and dysfunction. As opposed to the more extensively studied pressure overload, there are no approved medical therapies because an understanding of the underlying pathological mechanisms at work in VO is lacking. Over the past 20 years, our laboratory has identified multiple key biological functions involved in the pathological remodeling in VO. Specifically, we have noted perturbed matrix homeostasis, detrimental adrenergic signaling, increased intracellular reactive oxygen species and an intense inflammatory response that implicates mast cells and their product chymase, which seems to cause extensive remodeling both inside and outside the cardiomyocyte. How these multiple pathways intersect over the course of VO and their response to various single and combined interventions are now the subject of intense investigation.

Whole-genome profiling highlights the molecular complexity underlying eccentric cardiac hypertrophy

Heart failure is typically preceded by myocardial hypertrophy and remodeling, which can be concentric due to pressure overload (PO), or eccentric because of volume overload (VO). The molecular mechanisms that underlie these differing patterns of hypertrophy are distinct and have yet to be fully elucidated. Thus, the goal of this work is to identify novel therapeutic targets for cardiovascular conditions marked by hypertrophy that have previously been resistant to medical treatment, such as a pure VO. Concentric or eccentric hypertrophy was induced in rats for 2 weeks with transverse aortic constriction (TAC) or aortocaval fistula (ACF), respectively. Hemodynamic and echocardiographic analysis were used to assess the development of left ventricular (LV) hypertrophy and functional differences between groups. Changes in gene expression were determined by microarray and further characterized with Ingenuity Pathway Analysis. Both models of hypertrophy increased LV mass. Rats with TAC demonstrated concentric LV remodeling while rats with ACF exhibited eccentric LV remodeling. Microarray analysis associated eccentric remodeling with a more extensive alteration of gene expression compared with concentric remodeling. Rats with VO had a marked activation of extracellular matrix genes, promotion of cell cycle genes, downregulation of genes associated with oxidative metabolism, and dysregulation of genes critical to cardiac contractile function. Rats with PO demonstrated similar categorical changes, but with the involvement of fewer individual genes. Our results indicate that eccentric remodeling is a far more complex process than concentric remodeling. This study highlights the importance of several key biological functions early in the course of VO, including regulation of matrix, metabolism, cell proliferation, and contractile function. Thus, the results of this analysis will inform the ongoing search for new treatments to prevent the progression to heart failure in VO.

Volume Overload Heart Failure Increases Myocardiac Passive Stiffness in a Mouse Model

Volume overload (VO) heart failure occurs due to pathologies such as mitral valve regurgitation, infarcts and ventricular septal defects, and leads to characteristic eccentric dilation. Changes in passive myocardial stiffness are not well understood and here we dissected the contribution of extracellular matrix (ECM)-based and titin-based stiffness to overall passive stiffness. Titin is a giant protein that regulates passive tension and hence diastolic function in the myocardium. In heart failure, differential splicing and phosphorylation events can occur that alter the stiffness of this protein and influence hemodynamics. Increased diastolic stiffness due to differential splicing and phosphorylation of titin has been observed in pressure overload hypertrophy; however, there are no published studies investigating whether pure LV VO during compensated heart failure leads to changes in titin based passive stiffness. We studied the role of titin in modulating diastolic function in VO induced by aortocaval fistula (ACF) in the mouse. ACF was induced in three-month-old male C57BL/6 animals and allowed to progress for 4 weeks. At 4 weeks, echocardiography confirmed the presence of eccentric dilation and decreased systolic function as expected. Tissues mechanics indicated an increase in titin, which correlated with a significant decrease in N2BA/N2B ratio. ECM based passive stiffness was unchanged in VO. In summary, VO causes an increase in titin based passive stiffness.

Cardiac Kallikrein-Kinin System Is Upregulated in Chronic Volume Overload and Mediates an Inflammatory Induced Collagen Loss

BackgroundThe clinical problem of a “pure volume overload” as in isolated mitral or aortic regurgitation currently has no documented medical therapy that attenuates collagen loss and the resultant left ventricular (LV) dilatation and failure. Here, we identify a potential mechanism related to upregulation of the kallikrein-kinin system in the volume overload of aortocaval fistula (ACF) in the rat.Methodology/Principal FindingsLV interstitial fluid (ISF) collection, hemodynamics, and echocardiography were performed in age-matched shams and 4 and 15 wk ACF rats. ACF rats had LV dilatation and a 2-fold increase in LV end-diastolic pressure, along with increases in LV ISF bradykinin, myocardial kallikrein and bradykinin type-2 receptor (BK2R) mRNA expression. Mast cell numbers were increased and interstitial collagen was decreased at 4 and 15 wk ACF, despite increases in LV ACE and chymase activities. Treatment with the kallikrein inhibitor aprotinin preserved interstitial collagen, prevented the increase in mast cells, and improved LV systolic function at 4 wk ACF. To establish a cause and effect between ISF bradykinin and mast cell-mediated collagen loss, direct LV interstitial bradykinin infusion in vivo for 24 hrs produced a 2-fold increase in mast cell numbers and a 30% decrease in interstitial collagen, which were prevented by BK2R antagonist. To further connect myocardial stretch with cellular kallikrein-kinin system upregulation, 24 hrs cyclic stretch of adult cardiomyocytes and fibroblasts produced increased kallikrein, BK2R mRNA expressions, bradykinin protein and gelatinase activity, which were all decreased by the kallikrein inhibitor-aprotinin.Conclusions/SignificanceA pure volume overload is associated with upregulation of the kallikrein-kinin system and ISF bradykinin, which mediates mast cell infiltration, extracellular matrix loss, and LV dysfunction–all of which are improved by kallikrein inhibition. The current investigation provides important new insights into future potential medical therapies for the volume overload of aortic and mitral regurgitation.

Left Ventricular Eccentric Remodeling and Matrix Loss Are Mediated by Bradykinin and Precede Cardiomyocyte Elongation in Rats With Volume Overload

We hypothesized that left ventricular (LV) remodeling and matrix loss in volume overload (VO) are mediated by bradykinin (BK) and exacerbated by chronic angiotensin-converting enzyme (ACE) inhibition. Chronic ACE inhibition increases anti-fibrotic BK and does not attenuate LV remodeling in pure VO. The relative contribution of changes in extracellular matrix versus cardiomyocyte elongation in acute and chronic LV chamber remodeling during VO is unknown. Echocardiography, LV collagen content, and isolated cardiomyocytes were studied in rats after aortocaval fistula (ACF) of 12 h, 2 and 5 days, and 4, 8, and 15 weeks. We also studied ACF rats after BK2 receptor (BK2R) blockade (2 days) or ACE inhibition (4 weeks). At 2 days after ACF, LV end-diastolic dimension (LVEDD)/wall thickness was increased, and LV interstitial collagen was decreased by 50% without cardiomyocyte elongation. The BK2R blockade prevented collagen loss and normalized LVEDD/wall thickness. From 4 to 15 weeks after ACF, interstitial collagen decreased by 30% and left ventricular end-systolic (LVES) dimension increased despite normal LVES pressure and isolated cardiomyocyte function. The ACE inhibition did not decrease LVEDD/wall thickness, further decreased LV interstitial collagen, and did not improve LV fractional shortening despite decreased LVES pressure. Immediately after ACF induction, eccentric LV remodeling is mediated by interstitial collagen loss without cardiomyocyte elongation. Acute BK2R blockade prevents eccentric LV remodeling and improves function. Chronic ACE inhibition does not prevent eccentric LV remodeling or improve function. These findings suggest that ACE inhibitor-mediated increase in LV BK exacerbates matrix loss and explains why ACE inhibition is ineffective in VO.

MAST CELL BLOCKADE ATTENUATES THE COLLAGEN LOSS AND VENTRICULAR DILATION ASSOCIATED WITH MITRAL REGURGITATION IN DOGS

In a canine model of mitral regurgitation (MR) induced by chordal rupture, we have shown infiltration of LV by mast cells and increased matrix metalloproteinase (MMP) activity, resulting in extracellular matrix (ECM) loss, myocyte and myofiber slippage, LV dilatation and failure. Mast cells release mediators that can affect LV ECM. We hypothesized that mast cell blockade with ketotofen (K, n=6) would result in improved LV remodeling compared to untreated dogs with four weeks of MR (n=6). Mean pulmonary artery pressures (13¡À1 vs. 20¡À3 mmHg, p<0.05) and SVR (1684¡À132 vs. 2151¡À147, p<0.05) were significantly decreased in K-MR vs. MR dogs. K-MR dogs had significantly smaller LV end-diastolic dimensions, left atrium/aortic root ratio, and wall thinning (LVfw) vs. untreated MR dogs. K-MR dogs had significantly less LV hypertrophy vs. MR dogs. LV collagen volume % was significantly higher in K-MR dogs vs. MR dogs (0.50¡À0.033 vs. 0.34¡À0.017, p<0.05). The relative transcript abundance of collagen I ¦Á1 and fibronectin were significantly decreased in MR dogs compared to normal dogs (n=6) while in K-MR these levels did not differ from normal (n=6) (p<0.05). K- MR dogs also had higher collagen III transcript levels vs. MR dogs. Thus, Ketotofen treatment restored synthesis of collagen matrix components and improved LV function and remodeling in MR. This may provide a new form of therapy for pure MR since renin-angiotensin system blockade, which is anti-fibrotic, does not improve LV remodeling and function in the pure volume overload of MR.

Increased adrenergic drive and Angiotensin II promote an anti‐fibrotic phenotype in dog cardiac fibroblasts

We have shown that volume overload (VO) in the canine model of mitral regurgitation (MR) is characterized by LV dilatation and loss of extracellular matrix (ECM), in the presence of increased angiotensin II (Ang II) and catecholamines in the interstitial fluid (ISF). Ang II usually promotes matrix production. In VO, we hypothesize that Ang II and catecholamines decrease fibroblast activation and increase matrix degradation. Cardiac fibroblasts (CFs) isolated from the LV of normal adult dogs were treated with Ang II (100 nM), isoproterenol (ISO, 100 nM) or both agents for 24 hrs then analyzed for myofibroblast activation by α-smooth muscle actin (α-SMA), ECM synthesis, and matrix metalloproteinase-2 (MMP-2) activity. Ang II produced an increase in α-SMA and fibronectin (FN) production. There was a trend towards decreased α-SMA and FN after ISO treatment. However, Ang II + ISO caused a significant decrease in α-SMA and FN expression (18% and 24% respectively). In addition, Ang II + ISO produced an increase in MMP-2 activity that was not found with Ang II or ISO alone. Thus, the synergistic effect of Ang II and increased catecholamines in the cardiac ISF of the volume overloaded heart blunt ECM production and promote MMP activation. This may explain why renin-angiotensin system blockade, which blocks ECM production, is ineffective in attenuating the LV dilatation in the pure volume overload of MR in the dog and the human.

Natural History and Left Ventricular Response in Chronic Aortic Regurgitation

This study was aimed at clarifying the natural history and left ventricular response in aortic regurgitation using M-mode echocardiography. We analyzed the history and echocardiographic data on 94 patients, who were divided into 4 stages according to symptoms. The duration of the asymptomatic period, which represents pure volume overload, is long, and the period of minimal symptoms, combined volume and pressure overload, is relatively short. Patients with overt heart failure due to impaired contractility can survive longer than is usually believed, and the factor that predicted the onset of heart failure was a decrease in fractional shortening > 3.8 percentage points.

The changing unnatural history of valvular regurgitation

In the past 15 years three major advancements have improved the lot of our patients with left-sided valvular regurgitation. First, the concept that mitral and aortic regurgitation were similar volume overloading lesions has changed. Mitral regurgitation constitutes a nearly pure volume overload wherein the excess volume is ejected against relatively low pressure into the left atrium. On the other hand, aortic regurgitation represents a combined pressure and volume overload in which the excess volume being pumped is ejected against the relatively high pressure of the aorta. These differences in loading between mitral and aortic regurgitation produce a different response to operation. Afterload reduction after correction of aortic regurgitation increases ejection performance if it was decreased preoperatively. Conversely, afterload increases after mitral valve replacement, decreasing ejection performance. These differences make the left ventricle in mitral regurgitation less tolerant of preoperative dysfunction than the left ventricle in aortic regurgitation. Second, with respect to aortic regurgitation, reproducible indexes have been developed that identify when left ventricular dysfunction is present, leading to earlier operation in an attempt to avoid permanent ventricular dysfunction. In turn, earlier operation has led to a fall in operative mortality rate and an almost universal increase in left ventricular function if it was depressed preoperatively. Third, with regard to mitral regurgitation, recognition of the importance of the mitral valve apparatus in maintaining left ventricular function has led to an increased emphasis on chordal preservation during mitral valve operations. Early indicators suggest that these techniques will lead to improved postoperative left ventricular function, reduced operative mortality, and enhanced long-term survivorship for patients with mitral regurgitation. Thus, a change in concept regarding the pathophysiology of these lesions, a change in referral for patients with aortic regurgitation, and a change in operation for patients with mitral regurgitation have led to a favorable alteration in the unnatural history of left-sided valvular regurgitation.

Left ventricular passive diastolic properties in chronic mitral regurgitation.

In chronic mitral regurgitation, the myocardium responds to the increased filling volume by geometric alteration and eccentric hypertrophy. This study was designed to evaluate the effects of a pure volume overload on left ventricular diastolic chamber and myocardial properties and to assess the relation of passive diastolic function to systolic ejection performance. By use of simultaneous cineangiography and left ventricular micromanometry, left ventricular passive diastolic stiffness was evaluated in nine normal controls (group 1), 14 patients with chronic mitral regurgitation and a normal ejection fraction (greater than or equal to 57%, group 2), and 13 patients with mitral regurgitation and a reduced ejection fraction (less than 57%, group 3). Passive diastolic function was evaluated by using a three-constant elastic model. Left ventricular chamber properties were represented by the relation of pressure to volume; myocardial properties were evaluated by relating myocardial midwall stress to midwall strain. The constant of left ventricular chamber stiffness was decreased in group 2 compared with controls (p less than 0.05) but it was normal in group 3. The constant of myocardial stiffness was increased in group 3 compared with groups 1 and 2 (p less than 0.01). Among patients with mitral regurgitation, there was a significant inverse relation between ejection fraction and the constant of myocardial stiffness (r = -0.83). The chronic adaptation to volume overload in chronic mitral regurgitation tends to decrease left ventricular chamber stiffness. Patients with mitral regurgitation and a depressed ejection fraction demonstrated diastolic myocardial dysfunction. Compromised diastolic function in patients with chronic mitral regurgitation and reduced systolic performance may contribute to the clinical manifestations of congestive heart failure.

An assessment of left ventricular systolic function in pressure and volume overload heart with two shell compartment model of ellipsoid revolution.

Left ventricular (LV) midwall mechanics were evaluated in normal, pressure overload due to hypertension, and volume overload hearts due to aortic (AR) and mitral regurgitations (MR) using a 2 shell compartment model of ellipsoid revolution. While ejection fraction (EF) was in the normal range, midwall fractional shortening (MFS) was depressed with low end-diastolic and end-systolic stress in hypertrophied hearts with pressure overload. Not only LV volumes but also LV systolic pressure and wall thickness were increased in AR. LV end-diastolic pressure was elevated, and EF and MFS were reduced in patients with AR and congestive heart failure (CHF). In patients with MR and CHF, pulmonary capillary wedge pressure was elevated, LV volumes were enlarged and end-systolic stress was high, but LV wall thickness and MFS remained in the normal range. It is concluded from this observation that: 1) myocardial contractility is already depressed with normal systolic function in hypertrophied ventricle with pressure overload. 2) AR can be considered to be the disease of both pressure and volume overload, and symptoms of CHF are the result of depressed myocardial contractility. 3) MR is the disease of pure volume overload. Myocardial contractility is well preserved even with the presence of severe CHF in MR.

A simple method for producing graded aortic insufficiencies in rats and subsequent development of cardiac hypertrophy

Selective perforation of the right cusp of the aortic valve alone (1V) or in combination with that of the left valve cusp (2V) by a plastic rod inserted from the right common carotid artery was performed to cause aortic insufficiency (Al) in rats. The development of cardiac hypertrophies subsequent to these interventions to cause graded cardiac volume overloads was followed up every week till the end of week 4 after the operations by radiographic measurement of the cardiothoracic ratio (CTR). Rats were killed 2 and 4 weeks after the operations, and the density of β-adrenoceptors in hypertrophied cardiac muscle membranes was determined by radioligand binding assay and compared with sham-operated (sham) rats. Production of Al resulted in an enlargement of the cardiac shadow in 1VAI and 2VAI rats, with significant graded increases in the CTR at the end of week 3. The occurrence of graded cardiac hypertrophies was well revealed in graded increases of the heart weight/body weight ratio among the sham, 1VAI, and 2VAI rats at the end of both week 2 and week 4. There was a tendency to stepwise increases due to graded AI in the density of binding sites for 3H-dihydroalprenolol, with a significant increase in 2VAI rats at the end of week 2. At the end of week 4, plasma norepinephrine levels of 2VAI rats was raised significantly as compared with the sham rats. Selective perforation of either one or two cusps of the aortic valve can be performed with ease using touch alone and provides us with a simple method for producing graded cardiac hypertrophies in rats due to pure volume overload.

Ritodrine hydrochloride infusion in pregnant baboons: II. Sodium and water compartment alterations

To evaluate the effects of intravenously administered ritodrine hydrochloride on sodium and water metabolism, a pregnant baboon model was studied. Animals given ritodrine retained significantly more sodium (p < 0.001) and administered fluids (p < 0.002) compared with control animals. Although plasma volume did not change significantly within or between the two groups, extracellular volume increased by a mean of 1,480 ml in those given ritodrine compared with 790 ml in the control animals. There was no significant difference between animals given ritodrine and their controls regarding serial hematocrits, serum sodium, or colloid oncotic pressures. From this we conclude that the retained sodium and water was in the interstitial space. Since plasma volume was unaltered by ritodrine administration it seems unlikely that pure volume overload can explain the pulmonary edema induced by β-mimetics. Combined with the prior observation that direct pulmonary capillary membrane toxicity does not occur, the likely pathophysiology of β-agonist-induced pulmonary edema invclves left ventricular failure.