MRTF-A knockout mice exhibited a marked reduction in MI scar size with less myofibroblasts, but no detrimental effect on cardiac rupture or mortality [ 80 ].
MRTF-A may thus represent another potential therapeutic target for reducing adverse cardiac remodelling without compromising infarct scar healing. As discussed earlier, myofibroblasts in the remodelling heart are derived not only from resident cardiac fibroblasts, but also from endothelial cells via EndMT , epithelial cells, mesenchymal stem cells, bone marrow-derived fibrocytes, smooth muscle cells and pericytes [ 6 , 23 ].
Therapeutic manipulation of the mechanisms involved in recruiting myofibroblasts from these different sources may therefore hold potential for modulating cardiac remodelling under different pathological conditions.
Cardiac overexpression of MCP-1 improves post-MI cardiac function and remodelling, at least in part by increasing myofibroblast accumulation [ 82 ]. Hearts from ROCK-1 null mice exhibited reduced numbers of fibrocytes and myofibroblasts, accompanied by reduced fibrosis and reduced cardiac dysfunction compared with wild-type animals [ 84 ].
One should note, however, that chemokines such as MCP-1 have far-reaching activities that are fundamental to the post-MI inflammatory process for example, macrophage recruitment and activity [ 85 ], and thus their targeting affects processes that extend beyond simple modulation of myofibroblast derivation from fibrocytes. Also, as with all animal studies, an element of caution should be exercised when considering knockout mouse results in relation to the situation in humans.
For example, marked differences in MCP-1 expression levels post MI have been noted between mice and humans [ 86 ]. Nevertheless, as our knowledge on the origins of myofibroblasts in the heart increases, this will hopefully reveal novel therapeutic targets in addition to those described above.
For example, it would be interesting to determine the effects of modulating miRb, as this has been shown to be important for regulating EndMT in the heart [ 52 ]. Strategies to target miRs will be discussed in more detail below. Moreover, the tightly regulated cell type specificity of miR expression makes these molecules amenable to modulating function of individual cell types.
Whilst current pharmacological therapies used in the treatment of adverse cardiac remodelling and failure are known to retard its progression, mortality rates remain high and there is a clear need for new therapies [ 87 ].
As such, they have potential to influence complex networks that are activated by a single stimulus reviewed in [ 88 ]. For example, the miR family is remarkably influential in regulating mRNA expression of a variety of collagens [ 56 ].
On the contrary, the breadth of miR-mediated effects also brings potential for disrupting cellular function through unwanted side effects [ 89 ]. Molecular tools for manipulating miR levels through inhibition or mimicry have been an area of rapid development and ongoing refinement [ 88 ]. Preclinical studies manipulating miR and miR have shown beneficial effects on post-MI cardiac remodelling in rodents. Specifically, a miR mimetic has proven successful in a murine model of cardiac fibrosis [ 56 ] and miR inhibition increased survival after MI [ 55 ].
Progressive expansion of our knowledge concerning dysregulation of miRs in cardiac myo fibroblast phenotype and function will undoubtedly lead to strategies that optimise targeted delivery of miR therapeutics. The ability to deliver therapies directly to selected cell types is indeed a realistic option for future medicine. Cardiac myofibroblasts represent a unique, yet developmentally diverse, population of cells that play key roles in post-MI infarct healing, but also in adverse cardiac remodelling, fibrosis and progression to heart failure.
Improved understanding of not only the origins of myofibroblasts in the post-MI heart, but also the capacity to assign specific roles and regulatory mechanisms to them, creates optimism for the future that this multifunctional cell type can be manipulated therapeutically to optimise infarct scar formation, whilst ameliorating reactive fibrosis.
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El-Helou V, Gosselin H, Villeneuve L, Calderone A: The plating of rat scar myofibroblasts on matrigel unmasks a novel phenotype; the self assembly of lumen-like structures. J Cell Biochem. Dev Dyn. Basic Res Cardiol. Rohr S: Myofibroblasts in diseased hearts: new players in cardiac arrhythmias?. Heart Rhythm. Circ Res. Experimental observations and clinical implications. Swynghedauw B: Molecular mechanisms of myocardial remodeling. Physiol Rev. J Cardiovasc Transl Res.
Clin Exp Pharmacol Physiol. Curr Biol. Expert Rev Mol Med. Dev Cell. Van Nieuwenhoven FA, Turner NA: The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction.
Vasc Pharmacol. In the ambulance, the patient was conscious and alert, stating that he could not breathe. On arrival at the emergency department, the patient was transferred to a bed and reported to the staff, but then almost immediately suffered a cardiac arrest. Resuscitation was attempted for approximately 1 hour.
The patient could not be resuscitated. Postmortem examination revealed ml of partially clotted blood in the pericardium, associated with a cardiac rupture in the posterior wall of the left ventricle.
The posterior wall of the left ventricle showed a 6. Autopsy also revealed a tiny microscopic old subendocardial myocardial infarction of the septum, passive congestion of the liver, mild steatohepatitis with severe mixed macrovesicular and microvesicular steatosis, and severe acute prostatitis. The antemortem and postmortem evidence suggests that this patient most likely suffered a myocardial infarction during surgery.
He had hypotension during surgery, but not in the postoperative period. He had ST-segment depression on postoperative day 1 and T-wave inversion on postoperative day 2. Neither cardiac biomarkers for infarction nor lead electrocardiography were done because myocardial infarction was not suspected.
The symptoms of the infarction were apparently masked by the expected symptoms following left upper lobectomy. The histopathologic features of the myocardial infarction at autopsy were typical of an infarct nearing the end of the first week, but they are not specific enough to date the infarction to the intraoperative period.
They are specific enough to date the infarction to the perioperative period, and the period of surgery, during which blood clotting is activated, is the most likely time that the thrombosis shown in Figure 2 developed. Ultimately, the infarction led to myocardial rupture and the patient's demise.
Surgery inevitably releases activated clotting factors and platelets into the circulation, so ischemia or infarction of the heart, the brain or other organs at sites of critical atherosclerosis is an inevitable risk of surgery. Clues missed in this case include ST-segment and T-wave changes on the cardiac monitoring for arrhythmias.
If one looks at the cardiac monitor only for arrhythmias, changes of myocardial ischemia or infarction can be overlooked.
Of course, ischemia must involve a substantial amount of heart muscle to cause changes visible on electrocardiography, and smaller areas of myocardial ischemia could cause a fatal arrhythmia. The patient had many major risk factors for atherosclerotic coronary artery disease, including his history of hyperlipidemia, hypertension, severe obesity and smoking, and his family history of the disease.
The results of one study suggested that a pulse pressure over 62 mm Hg could be a useful clinical sign of risk that could guide strategies to decrease the risk. Prevention has been the focus of recent studies. Inhibiting platelets was prospectively studied for the purpose of preventing myocardial injury during noncardiac surgery and the administration of aspirin before surgery and in the early postsurgical period was found to have no significant effect on the rate of a composite of death or nonfatal myocardial infarction, but to be associated with an increased the risk of major bleeding.
The excised mitral valve showing complete rupture of the papillary muscle. Unlike the structural mitral regurgitation, here the valve leaflets and valvular apparatus are normal, even if the coexistence of coronary artery disease and non-ischaemic mitral disease has led to a poor understanding of this clinical entity [ 40 ]. Carpentier described three general types of mitral regurgitation according to different pathophysiologic mechanisms: type I, in which there is a normal leaflet motion, and regurgitation is caused by annular dilatation from ischemia of adjacent ventricular wall or by leaflet perforation; type II, in which we can find an increased leaflet motion, with a prolapse of valve leaflet in this case, regurgitation is caused either by papillary muscle rupture or in papillary muscle elongation due to chronic ischemia, and usually lead to an asymmetric leak ; type IIIa, with leaflet restriction during systole and diastole not seen in ischaemic mitral regurgitation ; type IIIb, leaflet restriction only during systole caused by a dysfunction of ventricular wall, dilated after ischaemic injury, with systolic tethering of papillary muscle as a consequence, there's a failure in mitral coaptation.
IMR could be acute or chronic, but both result from ischemia of ventricular wall and missed coaptation. The remodelling secondary to acute and chronic ischemia remains the principal mechanism for IMR and depends on apical tethering and an excessive tenting volume, which cause coaptation failure of the mitral leaflets.
Mild-to-moderate mitral regurgitation is often clinically silent and detected on Doppler echocardiography performed during the early phase of myocardial infarction.
Risk factors are advanced age, female sex, large infarct, multivessel coronary artery disease, and, unlike other mechanical complications, history of a previous myocardial infarction or recurrent ischemia. The acute onset of severe IMR is a life-threatening complication and arises from a few hours to weeks after myocardial infarction; in this case, a sudden volume overload is imposed on the left ventricle, increasing preload and a small increase in total stroke volume.
Acute mitral regurgitation usually results from the rupture of papillary muscles or chordae tendineae: haemodynamic deterioration is sudden, because no compensatory structural changes in atrium and ventricle are possible. Pulmonary congestion, as well as cardiogenic shock, may occur. Clinical features include pulmonary oedema, chest pain, and dyspnoea.
A new pansystolic murmur can be detected, best heard at the apex [ 40 , 44 ]. Chronic IMR occurs as a consequence of ventricular dilatation secondary to ischaemic ventricular remodelling both regional or global , with papillary muscle displacement and failure of leaflet coaptation. During chronic onset of the disease, the left atrium and ventricle may develop an offsetting hypertrophy and dilatation.
Enlargement of the left atrium allows volume overload, but may cause arrhythmias, such as atrial fibrillation, and the formation of thrombi.
Until systolic dysfunction prevents effective ventricular contraction, patients are asymptomatic. After that, exertional dyspnoea and fluid retention may be present [ 40 ]. The gold standard diagnostic tool is echocardiography, both transthoracic and transeosophageal, which assess mitral valve apparatus, the mechanism of regurgitation, and the ventricular function [ 3 , 15 ].
Medical therapy may have a supportive role in case of acute onset of mitral regurgitation, while in chronic cases it is useful in decreasing the regurgitant volume and improve ventricular function by using ACE-inhibitors, and to reduce remodelling by using beta-blockers. Most patients with acute mitral regurgitation are managed with percutaneous coronary intervention PCI or thrombolysis.
Surgery is usually reserved for acute and severe cases, which do not ameliorate after these approaches, and for chronic patients symptomatic for coronary disease. Repair versus replacement of the mitral valve is still debatable.
Mitral valve repair is generally preferred whenever possible based on valve pathology and patient stability: it avoids long-term anticoagulation, decreases infective endocarditis risk, and provides greater leaflet durability. Among repairs, different techniques are available, but annuloplasty with prosthetic ring is the gold standard [ 41 , 42 ]. On the other hand, valve replacement is usually reserved for situations where the valve cannot be reasonably repaired, or when repair is unlikely to be tolerated clinically.
Moreover, it being a faster procedure is better in high-risk surgical candidates. Mitral valve replacement could be managed by using the chordal-sparing techniques, a range of procedures that permit the resuspension of chordae and the preservation of subvalvular anatomy [ 43 ]. Percutaneous approaches are available, but often limited to patients with lots of comorbidity and a poor surgical outcome [ 40 ].
The earliest reports of a ventricular aneurysm appeared in , during an autopsy managed by Galeati and Hunter; but the first surgical approach to this pathology was performed in by Beck. A true aneurysm is the result of the gradual thinning and the expansion of the scarred left ventricular wall after transmural infarction.
This is a different entity from a pseudoaneurysm, which does not contain all the three layers of the myocardium and is frequently lined by pericardium and mural thrombus [ 45 , 47 , 49 ]. Two types of true aneurysm are present: a traditional aneurysm, namely a region of myocardium with an abnormal diastolic contour and a systolic dyskinesia, with a paradoxic bulging; and a functional aneurysm, in which bulging is not present, but is characterised by large areas of akinesia, that affects ventricular function.
They originate from two distinct phases of myocardial infarction. First, an early expansion phase defined as the deformation or stretch of infarcted myocardium during the first week after the ischaemic injury: wall thinning due to the degradation of collagen matrix and dilatation lead to an augmentation in both systolic and diastolic wall stress, following LaPlace law, and to a greater request of oxygen supply.
Fibre stretching is progressive until fibrosis and scarring. Increased diastolic stretch, elevated catecholamines and stimulation of natriuretic peptides may demonstrate increased fibre shortening and myocardial hypertrophy as adaptive changes. The second phase is constituted by late remodelling. Here, the aneurysm is composed of scar tissue; systolic and diastolic ventricular dysfunctions are present, in fact aneurysm does not contract nor distend this impairs diastolic filling and increases left ventricular end-diastolic pressure.
Mechanism of compensation such as chamber dilatation, hypertrophy, and changes in ventricular geometry lead to a poor contractile function, and eventually heart failure [ 46 , 48 ]. Atrial and ventricular arrhythmias may occur in the scar tissue, producing palpitations, syncope, and even sudden death.
Even if echocardiography is a useful diagnostic tool capable of identifying false aneurysm and assessing ventricular function, angiography and left ventriculography is the gold standard, estimating the size of aneurysm and evaluating cardiac function and kinesis, as well as coronary status.
Tomographic three-dimensional echocardiography and magnetic resonance imaging are the most reliable means of evaluating left ventricular volume. Positron emission tomography PET can be helpful in an early phase to differentiate true aneurysm from hibernating myocardium with reversible dysfunction. Even magnetic resonance imaging can be useful, but cannot assess coronary anatomy. Medical therapy aims to minimise the remodelling of the left ventricle: both in acute and chronic heart failure; ACE inhibitors may reduce ventricular wall stress, as well as ventricular dilatation.
Beta-blockers do the same. Nitrates may reduce hypertrophy, but it seems they don't affect mortality. Anticoagulation with warfarin is indicated for patients with a mural thrombus. Patients should be treated initially with intravenous heparin, with a target aPTT of 50—70 seconds.
Warfarin is started simultaneously, and the INR target is 2—3 for a period of 3 to 6 months. The use of anticoagulation without the presence of a thrombus is controversed. Anticoagulation should be reinitiated if a new thrombus develops, and an echocardiographic follow up must be done [ 54 ]. Asymptomatic patients with a small aneurysm may be treated medically.
When refractory heart failure or ventricular arrhythmias are present, as well in the presence of a huge aneurysm, surgery is indicated. Resection of the aneurysm may be followed by conventional closure or newer techniques to maintain LV geometry. In the plication technique, a direct closure of the aneurysm without excision is performed; this is usually done for very small aneurysms without internal thrombus [ 55 ]. Another conventional strategy, the linear repair, was first introduced by Cooley in In this technique, the incision is extended round the aneurysm leaving a rim of scar tissue and buttressed mattress sutures are placed successively.
With this technique, changing ventricular geometry is possible [ 55 ]. Other newer techniques aim to maintain ventricular geometry by using the external patch procedure performed by Daggett or inverted T closure of ventriculotomy as done by Komeda [ 56 ], or circular patch technique for posterior aneurysms [ 57 ].
Finally, endoaneurysmorraphy, a procedure proposed by Jatene, Dor, and Cooley, positions an endocardial patch in order to preserve both normal ventriculum and septal geometry [ 58 , 59 , 60 ]. Cardiogenic shock is a clinical syndrome characterised by end-organ hypoperfusion, due to a rapid worsening of ventricular function.
Cardiogenic shock may also occur in 2. Moreover, cardiac tamponade or massive pulmonary embolism may lead to this kind of shock [ 60 , 61 , 62 , 63 , 64 ]. Risk factors are directly related to the principal trigger. In the context of myocardial infarction, risk factors may include older age, hypertension, diabetes mellitus, multivessel coronary artery disease, prior myocardial infarction or angina, anterior location of infarction, prior diagnosis of heart failure, STEMI, and left bundle-branch block.
Considering the ischaemic aetiology of cardiogenic shock, pathological mechanism starts with the ischaemic injury of myocite, with loss of effective contractility, and a systolic and diastolic dysfunction. Thus, the present cohort might be slightly healthier than the background population but it is unlikely that this has affected the results in any important way.
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