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<div align="right">'''''Tim P. van de Hoef, MD'''''</div>
[[Image:Figure1.jpg|300px|right|thumb|'''Figure 1.'''<br>
The endocast is viewed from 5 different perspectives to demonstrate the spatial relationship between right (coloured blue) and left (coloured red) heart chambers and between atria and ventricles. The blue and white arrows represent the right and left ventricular outflow tracts respectively.
]]
<big>Cardiac Anatomy</big>
'''S. Yen Ho,''' ''PhD FRCPath FESC FHEA''
Royal Brompton Hospital


==Case Study==
Traditionally, the heart is described as having left heart and right heart chambers. Current imaging techniques can show in exquisite detail the heart in its anatomical position inside the living patient’s chest and demonstrate the convoluted arrangement of ‘right’ heart chambers relative to ‘left’ heart chambers and the fact that right heart chambers are not strictly right-sided nor are left heart chambers left-sided. These important relationships of the chambers can be replicated with an endocast (Figure 1). In cardiac anatomy, knowledge of the relative disposition of the cardiac chambers is as relevant as the intrinsic chamber morphology. This review considers the cardiac chambers, coronary arteries and the conduction system.
''A 42-year old male patient presents with ongoing fulminant retrosternal chest pain, radiating to the left shoulder and the jaw, with concomitant nausea. The patient awoke with these discerning complaints 21/2 hours ago, and there is no (recent) history of anginal symptoms. His medical history includes human immunodeficiency virus seropositivity since his 24<sup>th</sup>, for which he since successfully receives chronic combined antiretroviral therapy with Truvada (tenofovir/emtricitabine), ritonavir, and atazanavir, with undetectable viral loads. In the presence of hypercholesterolemia, further medication includes ezetemibe solotherapy, since statins were not tolerated. The electrocardiogram shows ST-segment elevation in the anterior precordial leads, and the patient is diagnosed with anterior wall acute myocardial infarction. Emergency coronary angiography is performed without delay, revealing a thrombotic occlusion of the left anterior descending coronary artery. Manual thrombus aspiration and subsequent stent implantation is performed successfully. In addition to lifelong aspirin treatment, and, despite revascularization guideline recommendation, the patient is post-treated with clopidogrel instead of prasugrel or ticagrelor for the first year following the acute myocardial infarction.''


==Introduction==
__TOC__
Contemporary antiretroviral therapy (ART) treatment strategies for human immunodeficiency virus (HIV) infection have led to a decrease in acute immunodeficiency syndrome (AIDS)-related (fatal) events <cite>1</cite>. Consequently, life expectancy of HIV-positive patients has improved dramatically, which is now quite comparable to HIV-negative populations <cite>2</cite><cite>3</cite>. Inferably, there has been a shift from opportunistic AIDS-related diseases to non-infectious co-morbidity, including cardiovascular disease (CVD).<cite>4</cite> The World Health Organization recently estimated that both CVD and HIV will be in the top 3 causes for both global mortality as well as global disability-adjusted life-years in the year 2030, indicating that the interrelation between the two diseases will be an important challenge in global public health in the near future.<cite>5</cite>


Cardiovascular fatal events comprise 7-15% of total fatal events in HIV-infected patients.<cite>6</cite><cite>7</cite><cite>8</cite> Compared with the non-infected population, HIV-infected patients are at increased risk for CVD<cite>9</cite><cite>10</cite>, even in HIV-infected patients treated with antiretroviral drugs.<cite>11</cite> Moreover, the age at which CVD surfaces in HIV-infected patients was found to be substantially lower compared with the general non-infected population, suggesting an accelerated atherosclerotic process.<cite>12</cite> Several recent reports suggest an important association between HIV-infection, ART, and CVD. Most likely, a combination of factors is involved in the relationship between HIV and the heart, which implicates that the HIV-infected population may benefit from a tailored approach to CVD prevention and management. The attributing factors and their relevance in the management of CVD in HIV-positive patients will be discussed in detail in the next paragraphs.
==Position of the heart==
[[Image:Figure 2.svg|300px|left|thumb|'''Figure 2.'''<br>
The long axis of the heart is at an angle to the long axis of the body. Approximately a third of the heart is to the right of the midline of the sternum and the remainder is to the left of the midline.
]]


==Factors contributing to HIV-associated cardiovascular disease==
[[Image:Figure 4.jpg|thumb|300px|right|'''Figure 4.'''<br>
The etiology of cardiovascular disease in HIV-positive patients is most likely multifactorial of nature, and includes traditional risk factors for cardiovascular disease, antiretroviral drug effects, as well as factors directly associated with the HIV-infection itself. As such, HIV seropositivity is known to be associated with all stages of atherosclerosis; from the stage of preclinical endothelial dysfunction<cite>13</cite><cite>14</cite>, and the early subclinical stage of atherosclerosis <cite>15</cite><cite>16</cite><cite>17</cite>, to obstructive (epicardial) coronary artery disease.<cite>18</cite>
'''A.''' This frontal view shows the right and left surfaces of the heart. The left anterior descending coronary artery buried in epicardial fat marks the plane of the ventricular septum.
<br>'''B.''' The obtuse and acute margins of the ventricles are demonstrated in this apical view.]]


==Traditional cardiovascular risk factors==
[[Image:Figure 3.svg|thumb|300px|left|'''Figure 3.'''<br>
Traditional risk factors for cardiovascular disease, in particular smoking, dyslipidemia, diabetes mellitus or impaired glucose tolerance, and hypertension, have been shown to be more prevalent in HIV-infected populations, and moreover to confer into an increased risk for CVD compared with the general non-infected population of equivalent age<cite>19</cite><cite>20</cite><cite>21</cite><cite>22</cite><cite>23</cite><cite>24</cite>. Although the increased prevalence of traditional CVD risk factors plays an important role in the increased CVD risk in HIV-infected populations, it is unlikely that traditional risk factors are the sole origin of the increased CVD risk in HIV-positive patients. Indeed, in several large cohort studies, statistical risk-adjustment for traditional CVD risk factors was shown to only partly explain the increase in CVD-risk in HIV-positive patients<cite>25</cite><cite>26</cite>, supporting the hypothesis that antiretroviral drug effects and HIV-infection-related factors play an important role in the added risk.
'''A.''' Viewed from the front, the right atrium and right ventricle overlaps the left atrium and left ventricle. The atrial chambers are to the right of their respective ventricular chambers.
<br>'''B.''' The four cardiac valves are at different levels and different planes with the pulmonary(P) valve situated the most cephalad. The aortic(A) valve is wedged between the tricuspid(T) and mitral(M) valves.]]


In general, CVD is considered the consequence of a chain of events, initiated by a myriad of risk factors.<cite>27</cite> Intervention anywhere along the chain of events may therefore result in mitigation of the CVD risk, and thereby traditional risk factors constitute an important target for management and prevention of CVD, no less in HIV-infected patients.
The cardiac silhouette is generally taken to be trapezoidal in shape. The rib cage provides good markers for charting the cardiac silhouette. The normal position of the cardiac apex is generally taken to be in the fifth intercostal space in the mid-clavicular line. The lower border is a nearly horizontal line in the area of the left sixth rib to the right sixth costal cartilage (Figure 2). The upper border is hidden behind the sternum at the level of the second and third cartilages. The right margin of the heart peeps out behind the right border of the sternum between the right third and sixth cartilages. In the infant, the upper part of the cardiac shadow is broad owing to the prominence of the overlying thymus gland.  


==Non-modifiable risk factors==
Inferior to the thymus, a fibrous pericardial sac encloses the mass of the heart. The sac has cuff-like attachments around the adventitia of the great arteries and veins as they enter or emerge from the heart. The pericardial cavity is contained between the double-layered serous pericardium. The parietal pericardium is adherent to the fibrous pericardium while the visceral layer is densely adherent to the cardiac surface forming the epicardium. Due to the contours of the heart and great arteries there exist two recesses within the pericardial cavity. These are the transverse and oblique sinuses. The transverse sinus occupies the inner heart curvature and lies between the posterior surface of the great arteries and the anterior surface of the atrial chambers. The reflection of the serous pericardium around the four pulmonary veins and the inferior caval vein forms the oblique sinus.  
Risk factors that do not constitute a modifiable therapeutic target comprise age, sex, and a family history of CVD. With increasing age, structural and hemodynamic changes in the cardiovascular system, oxidative stress, and endothelial dysfunction progress. Moreover, the duration of exposure to pro-atherogenic risk factors accumulates with advancing age. In general, older people have more atherosclerosis that younger people. Thereby, the risk for CVD increases with advancing age.<cite>28</cite> Importantly, age was shown to be a particularly important determinant of CVD risk in HIV-infected patients. In all age subgroups, HIV-infected patients are at increased risk for in particular AMI in comparison with age- and CVD risk factor-matched non-infected controls.
<cite>29</cite><cite>30</cite>


The risk for CVD becomes clinically pertinent for men at younger ages than for women: for men, this is in their mid-forties, while this is at the time of menopause for women. The origin of this sex-difference in not yet fully elucidated, but is at least in part explained by an earlier onset of traditional CVD risk factors, such as hypertension and dyslipidemia, in men, and supposed hormonal protective effects in pre-menopausal women.<cite>31</cite>
When the pericardium is removed, the major part of the heart visible from the front is the ventricular mass. Here, the morphologically right ventricle occupies the greater part (Figure 3). The left ventricle appears only as a narrow slip along the left cardiac border. The shape of the heart is generally likened to a pyramid. The apex points downwards, forwards and to the left while the base faces posteriorly and to the right. While the cardiac apex is usually represented by the vortex of the left ventricle, the cardiac base is less well defined owing to differences in definition.  


A positive family history is a well-known important risk factor for CVD both in men and women, which risk is independent of other concomitant CVD risk factors.<cite>32</cite> Many risk factors are under genetic control (blood pressure, lipid spectra, obesity), but these do not account for the total aggregated risk observed in families<cite>33</cite>, indicating that family history of CVD as a risk factor goes beyond the accumulation of risk from inherited traditional risk factors. It must be noted that while family history is an undisputable risk factor, obviously a large number of modifiable risk factors are found in people with a family history of CVD, adding to the accumulated CVD risk.
The anatomical base is formed mainly by the left atrium receiving the pulmonary veins and to a small extent by the posterior part of the right atrium. The base in clinical practice, however, refers to the portion of the heart near the parasternal parts of the second intercostal spaces. The cardiac long axis, therefore, lies in a line drawn from the left hypochondrium towards the right shoulder. This orientation deviates considerably from the long axis of the body. Furthermore, the position of the cardiac septum at about 45º to the median brings the ‘right heart’ structures anterior to the ‘left heart’ structures (Figure 3A). The ventricles are situated inferior and leftward relative to their corresponding atria.  
Although non-modifiable in nature, these risk factors importantly add to the accumulated CVD risk within a specific patient and therefore play an important role in risk stratification and prevention of CVD, in particular in HIV-infected patients.


==Modifiable risk factors==
This results in the right atrioventricular junction being in a nearly vertical plane. The left atrium is the most posterior cardiac chamber being directly anterior to the oesophagus at the bifurcation of the trachea. In frontal projection, only its appendage is visible. The aorta has a deep-seated origin and only becomes part of the cardiac silhouette as it arches upwards and backwards, forming a spiral with the pulmonary trunk. The cardiac valves are offset from one another, in keeping with the disposition of the cardiac chambers and great arteries. When viewed in frontal projection, the pulmonary valve, being the most superior valve, is horizontally situated behind the third costal cartilage. The aortic valve lies posterior and to the right, above the nearly vertically orientated tricuspid valve (Figure 3B). The mitral valve is further posterior, overlapped by the more anterior but inferior tricuspid valve. The aortic valve therefore occupies a central position in the heart, wedged between the two atrioventricular valves.  
Risk factors that comprise modifiable targets for therapeutic strategies include hypertension, dyslipidemia, diabetes, and smoking. Importantly, the prevalence of these traditional risk factors is increased in HIV-positive populations.<cite>34</cite> Compared with the general population, HIV-infected populations in particular have a higher smoking prevalence, and have a diet high in saturated fat. Evidence has accumulated that HIV-infected patients in general have a more atherogenic lipid spectrum, putting them at particular high risk for CVD.<cite>35</cite><cite>36</cite> However, the relative contribution of each traditional risk factor for CVD risk within a patient is comparable in HIV-infected and uninfected populations, irrespective of HIV-infection status.<cite>37</cite> As such, although the risk factor prevalence is increased in HIV-infected populations, it likely does not at itself explain the increased risk of CVD in this population, and, therefore, several HIV-related factors need to be taken into consideration.


==Antiretroviral therapy effects==
The cardiac surfaces are described as the sternocostal, diaphragmatic, left and right (Figure 4). The sternocostal surface is covered anteriorly by the sternum and pleurae. The diaphragmatic surface is horizontally orientated. The sharp angle formed mainly by the right ventricle and occupying the lower heart border is the acute margin of the heart. The rounded obtuse margin of the heart is formed mainly by the left ventricle to the left of the sternocostal surface.
Contemporary ART treatment strategies adhere to a combination of antiretroviral drugs (as such called combined ART (cART)), usually consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with an integrase inhibitor. Several reports have indicated an association between ART treatment and CVD. In particular early studies have reported an increased risk for early acute myocardial infarction (AMI) in patients treated with PIs, which was associated with concomitantly raised cholesterol levels, a known side-effect of PI treatment.<cite>38</cite><cite>39</cite> The associated risk was related to the duration of PI exposure. Nonetheless, the increased risk persisted after statistical correction for lipid concentrations, which implicates an independent direct effect of PI treatment on early occurrence of AMI. Importantly, such increased risk has not been as clearly established for all PIs, and conclusive data remains absent for several ART agents from the PI group. Nonetheless, even in the presence of an increased risk for early AMI, the risk-benefit ratio remains positive towards PI use, due to the unequivocal benefits of cART on survival that outweigh the PI-use associated risk for AMI. For the NRTI group of ART, in particular for abacavir and didanosine, such an association between drugs and CVD is less clearly established, as large cohort studies have yielded conflicting results.<cite>40</cite><cite>41</cite> Nonetheless, there seems to be a consistent reporting of increased AMI risk in HIV-positive populations treated with (c)ART. The complex interrelation of HIV-infection, antiretroviral drugs and concomitant co-morbidities in the presence of traditional CVD risk factors makes it difficult to extract the actual origin of an increased risk for AMI. Nevertheless, an association between ART drugs and AMI must be assumed for all subclasses of ART drugs, although PI use is most consistently found a determinant of early AMI risk.


==HIV-infection related factors==
==The morphologically right atrium==
Besides the CVD risk conferred by the use of aggressive cART, the HIV-infection itself may add to the accumulated CVD risk in HIV-positive patients. HIV-infection related factors include the persistent inflammatory status and immune dysfunction associated with high viral loads, as well as viral load independent factors.
[[Image:Figure 5.jpg|300px|right|thumb|'''Figure 5.'''<br>
'''A.''' This right lateral view shows the right atrium dominated by its large, triangluar shaped appendage. The dots mark the terminal groove. The arrow indicates the crest of the appendage.
<br>'''B.''' The lateral wall of the appendage incised and flipped backward to show the pectinate muscles and the thin, membrane-like atrial wall between the muscle bundles. The terminal crest (dots) marks the border between the pectinated appendage and the smooth-walled venous sinus. The oval fossa is surrounded by its muscular rim. The smooth-walled vestibule leads to the tricuspid valve orifice.]]


===Inflammation===
The right atrium is composed of an anterior appendage, a posterior venous sinus, a septal portion and a vestibule. The junction between the appendage and the venous sinus is marked epicardially by an atrial groove the terminal groove, in which lies the sinus node. Inside the chamber, the terminal groove is represented by a muscle bundle, the terminal crest (crista terminalis), from which pectinate muscles radiate into the appendage (Figure 5). The appendage has a characteristic triangular shape and a wide communication with the venous sinus. The smooth-walled venous sinus receives the superior and inferior caval veins in its cephalic and caudal extremities respectively. The coronary sinus opens close to the septal portion and near the opening of the inferior caval vein. The outlet portion of the atrium, the vestibule leading to the tricuspid valve orifice, is also smooth walled. The obliquely orientated atrial septum extends from right posterior to left anterior position. When viewed from the right atrial aspect, the atrial septum is characterised by a muscular rim – the limbus - which surrounds the flap valve of the oval fossa (Figure 5). The extent of the true septum, however, is limited to the flap valve and the immediate part of its surrounding muscular rim. On the epicardial side much of the rim is filled by the interatrial groove which separates the right atrium from the right pulmonary veins posteriorly and superiorly. In its anterior part, the infolded rim contains the continuation of the interatrial groove and its musculature extends to the anterior wall of the right atrium, directly related to the transverse pericardial sinus. Only a small portion of the inferior rim is part of the true atrial septum. Its major portion is the continuation of the right atrial wall, the vestibule, overlying the crest of the ventricular septum (Figure 5). In fetal life, the flap valve of the oval fossa allows venous return mostly from the inferior caval vein to enter the left atrium. After birth the valve is normally large enough to close the interatrial communication as higher left atrial pressure pushes the valve against the muscular rim forming a complete seal. A probe patency (a probe could be passed from right to left atrium through an unsealed antero-superior part of the rim) exists in about a quarter of the normal population and is generally referred to as a PFO.  
In general populations, persistent inflammation is associated with an increased risk for CVD.<cite>42</cite><cite>43</cite> Markers of inflammation are persistently elevated in HIV-positive patients<cite>44</cite>, which was shown to be directly associated with (increases in) levels of viral loads.<cite>45</cite><cite>46</cite> Different components of HIV are independently associated with increased markers of endothelial cell activation (sVCAM), systemic inflammation (CCL2, IL-10), and adipose tissue activation (adiponectin), which may actively advance atherosclerosis.<cite>47</cite> Moreover, persistent inflammation in HIV-infected patients is directly associated with mortality in this patient population.<cite>48</cite><cite>49</cite> These findings suggest that inflammation itself may explain (part of) the CVD risk in HIV-positive populations additive to traditional risk factors.  


===Immune dysfunction and immune activation===
==The morphologically left atrium==
Several studies have indicated that immune dysfunction is associated with CVD risk among HIV-infected patients. CD4+ T-cell counts of <500/IL have been associated with an increase in cardiovascular events, independent of traditional CVD risk factors or ART, carrying an additive risk comparable with that of smoking or sub-optimally treated LDL cholesterol levels ( ). CD4+ T-cell counts of <200/IL were associated with an increased risk of AMI, which was comparable in magnitude to the risk imposed by traditional CVD risk factors ( ). Consistently, episodic CD4+ cell count-guided ART is associated with a substantial increase in risk for AMI compared with continuous ART, indicating an important role of viral load and immune dysfunction for the extent of CVD risk ( ). Moreover, several studies have shown a decrease in non-AIDS related events following the start of ART, and a notable increase in CVD events in patients with incomplete immune recovery following start of ART ( ). In addition, the risk of AMI was recently shown to be significantly increased in patients with a recent episode of immune dysfunction defined as CD4 count <200 or HIV-RNA count of >500 copies ( pmid=22112603). It can therefore be acknowledged that (residual) compromise of immune function is an important determinant of risk for CVD as well.
[[Image:Figure 6.jpg|thumb|300px|right|'''Figure 6.'''<br>
'''A.'''  This view from the left-lateral aspect shows the finger-like left atrial appendage with the left atrium situated posteriorly. The left ventricle tapers to a rounded apex.
<br>'''B.'''  This section through the aortic root and mitral valve displays the left atrial aspect of the septum enface. The crescentic edge (arrow) of the fossa valve has not sealed completely resulting in a PFO. The asterisk marks the location of the transverse pericardial sinus.]]


The left atrium also has a venous component, a characteristic appendage, a septal component and a vestibule that leads to the mitral orifice. Other than the appendage, the main chamber of the left atrium is relatively smooth-walled. The appendage is hook-shaped with a crenelated external appearance and a narrow junction with the venous component (Figure 6). The junction is not marked by any structure comparable to the terminal crest although in many hearts there is a prominent infolding of the atrial wall between the orifice of the atrial appendage and the orifices of the left pulmonary veins. The venous portion is anchored by the pulmonary veins which drain directly into its superior and posterior parts. There are usually four pulmonary venous orifices but variations are not uncommon. The coronary sinus runs inferiorly behind the posterior wall to open into the right atrium. The flap valve of the oval fossa on the septal aspect has a small crescent marking the free edge of the valve at the fossa opening (the site of the PFO) whereas the rest of the valve blends into the atrial wall (Figure 6).


===Virologic Suppression and the Risk of CVD===
==The morphologically right ventricle==
The associations discussed in the previous sections may implicate that suppression of HIV replication, and normalization of inflammation and immune function by (c)ART mitigates the associated CVD risk. However, even viral replication suppression with (c)ART does not fully normalize these processes, and even residual levels may result in adverse cardiovascular outcome. Concordantly, it was shown that carotid intima media thickness is increased in all HIV-infected subgroups compared with controls, including HIV-infected patients that maintain an undetectable HIV viral load without the use of (c)ART ( ). This finding was independent of prior ART exposure duration, viremia, or advanced immunodeficiency. Moreover, a recent large cohort study of HIV-infected patients compared with age and CVD-risk matched non-infected controls including more than 80.000 subjects indicated that, although mitigated by virologic suppression, the risk for CVD, and AMI in particular, remains present despite virologic suppression ( ).
[[Image:Figure 7.jpg|thumb|300px|left|'''Figure 7.'''<br>
'''A.''' The right ventricle is opened to show the septum and the muscular crest separating tricuspid from pulmonary valves. The moderator band (open arrow) extends from the foot of the septomarginal trabeculation to the free wall of the right ventricle. Coarse trabeculations fill the apical component.
<br>'''B.''' This close-up view of the tricuspid valve at the commissure between septal and antero-septal leaflets shows the annulus (broken line) crossing the membranous septum (dots) dividing it into atrioventricular(av) and interventricular(iv) components.]]


In summary, the available evidence indicates that CVD in HIV-infected population is indeed a complex multi-factorial process, which etiology goes beyond the role of traditional risk factors, and beyond the effects of antiretroviral medication. HIV-infection related factors, as well as persistent inflammation and immune dysfunction most probably constitute important additional factors resulting in premature atherosclerosis and accelerated ageing even when the viral replication is suppressed.
Description of the ventricular chambers is facilitated by considering them in terms of three components - inlet, apical trabecular and outlet. The inlet contains the atrioventricular valve and its tension apparatus; the outlet supports the arterial valve. The apical trabecular portion is the most distinctive in each ventricle being characteristically coarse in the right ventricle (Figure 7A) and fine in the left ventricle. In a similar way, the muscular ventricular septum can be considered in terms of inlet, apical trabecular and outlet portions. A small fibrous area, the membranous septum, is located at this tripartite junction. The attachment of the septal tricuspid valve leaflet divides the membranous septum into atrioventricular and interventricular components (Figure 7B). It is important to appreciate that the entire ventricular septum is not on one plane. Owing to the 'wrap-around' relationship of the right ventricle to the left ventricle, the various portions are arranged at angles to each other. The inlet septum (between the ventricular inlet portions) is more or less at the sagittal plane of the body. Extending out apically and curving between the inlet and outlet components is the trabecular septum. In lateral projection, the right ventricle is seen to sweep from beneath to above the left ventricle. When viewed in frontal projection the right ventricle passes in front of the left ventricle (Figure 1). A prominent Y-shaped muscle band, the septomarginal trabeculation, is adherent onto the septal surface. Clasped in between the limbs of the septomarginal trabeculation is the supraventricular crest, a distinctive feature of the right ventricle. The tricuspid valve is separated from the pulmonary valve by this crest (Figure 7A). Much of the crest is simply the infolded inner heart curvature with fatty tissue containing the right coronary artery on its epicardial aspect. The body of the septomarginaI trabeculation gives origin to the moderator band that crosses the ventricular cavity to insert to the anterior wall. The right ventricular inlet component extends from the tricuspid valve orifice to the attachment of the papillary muscle but a discrete demarcation is not seen. The tricuspid valve lacks a well-formed fibrous annulus. Its three leaflets are not always easy to identify owing to clefts within its major leaflets. The commissural chords will identify the divisions between the three leafets - the antero-superior, the septal and the postero-inferior. The direct attachment of the septal leaflet to the septum is a distinguishing feature of the tricuspid valve.


==Prevention of CVD in HIV-infected patients==
==The morphologically left ventricle==
As a corollary of the aforementioned interplay of CVD risk factors and HIV-infection/–therapy, it may be appreciated that prevention of CVD in HIV-positive patients should be emphasized, especially in the light of the contemporary life expectancy of this patient population. In general, cardiovascular therapy guidelines aimed at prevention of CVD in HIV-patients follow those for the general population, although some HIV-related factors must be taken into consideration ( ).  
[[Image:Figure 8.jpg|thumb|300px|right|'''Figure 8.'''<br>
Special emphasis should focus upon the identification and treatment of dyslypidemia, which is frequently present in HIV-infected patients, and which is known to occur in reponse to the start of (c)ART therapy, with a particular association with PIs ( ) and first generation NRTIs ( ). Therefore, assessment of lipid status, especially triglycerides, should be performed prior to the start of cART therapy, at 3-6 months after initiation of therapy, and at least yearly in the absence of abnormalities. A special point of care lies within lipid-lowering therapy in concomitance with cART treatment, because of the possibility of interaction between statins and for example PIs and NNRTIs ( ). The primary mode of interaction is seen through the cytochrome P450 (CYP) pathway. PIs mainly inhibit CYP, and could therefore lead to toxicity of statins as these drugs are most frequently metabolized through particular CYP pathways. NNRTIs are associated with CYP induction, leading to impairment of statin efficacy. Statins not or only mildly associated with CYP interactions include rosuvastatine and pravastatin, and may therefore be considered in HIV-infected patients on cART. More novel statins, such as pitavastatin, without CYP interaction have not yet been evaluated in this setting. Ezetemibe, which is not metabolized through the CYP pathway, may be considered in addition to statin therapy or as stand-alone therapy when statin therapy leads to unendured side effects. Nonetheless, statin therapy should be tailored to the specific situation and side effects or inefficacy of agents may necessitate statin or cART agent switch along the way. Especially when cART leads to a subsequent severe dyslipidemia, switching to another cART combination may be considered ( pmid=23369416). However, no clinical trials have been performed on this subject, and therefore the best approach remains patient-tailored. Moreover, in the light of the complex interplay between all CVD risk factors discussed in the previous paragraphs, it is important to note that the actual role of statin therapy in primary prevention in HIV-infected patients has not been established to date. Nonetheless, the evidence to date indicates a very important role of dyslipidemia in the CVD-risk associated with HIV-infection and –therapy, and optimal medical therapy should be pursued.
'''A.''' The left ventricle is opened through its outflow tract into the aortic valve. The aortic valve leaflets are in fibrous continuity with the anterior leaflet of the mitral valve. The fibrous continuity is expanded at the right and left fibrous trigones. The right trigone(asterisk) is the landmark for the atrioventricular conduction bundle. Note how the thickness of the left ventricular wall diminishes remarkably at the apex (open arrow).
In addition, smoking cessation should be actively pursued in patients with HIV, because of its high prevalence and associated increase in CVD risk in this patient population, as well as the significant benefit of smoking cessation ( pmid=21251183). The recent smoking cessation guidelines consequently indentified the HIV-infected population as and important target population for smoking cessation therapy, both interms of counseling as well as medical therapeutic strategies ( pmid=18617085).
<br>'''B.''' This dissection shows the central location of the aortic valve. L, N and R are the left-coronary, non-coronary and right-coronary aortic sinuses respectively.]]
In the presence of hypertension, renin angiotensin system blockers are considered first choice owing to their global protective effects on kidney function, glucose metabolism, and the vasculature in general ( pmid=23369416).


Antiplatelet regimens have not extensively been investigated in HIV-infected populations and it is therefore currently advocated to adhere to general antiplatelet guidelines. In particular aspirin treatment should be initiated as in the general population in the presence of high CVD risk when contraindications are absent ( pmid=22809746). For more aggressive antiplatelet agents, including clopidogrel, prasugrel and ticagrelor, recent investigations have implicated interactions between cART and these potent platelet inhibitors. Ritonavir, a PI-subclass ART, in particular was found to impair prasugrel activity in in vitro experiments ( pmid=21550074). Furthermore, ticagrelor is metabolized by CYP and is contraindicated in patients on PI therapy, in particular in those patients using ritonavir (both ritonavir and ticagrelor are associated with the CYP 3A4/5 pathway) ( pmid=21177984). Although the stent-thrombosis rates in HIV-infected patients after percutaneous coronary intervention and coronary stent implantation have not been found to be substantially higher compared with the general population, it should be borne in mind that evidence on the effectiveness of antiplatelet therapy in terms of platelet activity is very limited, and residual platelet activity levels may well play a role in a particular patient.  
In contrast to the right ventricle, the left ventricle is a conical structure with thick tubular walls tapering to a rounded apex (Figure 6A) where the apical wall becomes as thin as 1-2 mm. Very little of the left ventricle is visible from the front of the heart (Figures 1 and 3A) although in the infant a relatively greater portion may be seen. As with the right ventricle, the left ventricle comprises inlet, trabecular and outlet portions. The acute angle between inlet and outlet portions brings the aortic valve in adjacency and in fibrous continuity with the mitral valve. There is no structure comparable to the supraventricular crest in the left ventricle. There is also no structure corresponding to the septomarginal trabeculation on the smooth septal surface (Figure 8A).


==Clinical presentation and revascularization==
The inlet component surrounds and contains the mitral valve and its tension apparatus. The outlet component supports the aortic valve but only half its circumference is muscular while the other half is an area of fibrous continuity between aortic and mitral valves. The aortic (antero-superior) leaflet of the mitral valve is suspended like a curtain between the inlet and outlet components. The deeply wedged posterior position of the aortic outflow tract displaces the mitral valve leaflets away from the septum as contrasted with the septal attachment of the tricuspid valve. The trabecular component has characteristically fine trabeculations (Figure 8A).  
Clinical presentation of advanced CVD in HIV-infected patients involves an equivalently wide spectrum as in the general non-infected population ( pmid=1731952). Nonetheless, as may be appreciated from the previous sections, clinical presentation is predominated by the occurrence of acute coronary syndrome (ACS) ( pmid=12888138, 12739013). Acute coronary syndrome typically occurs in males, at a relatively young age (<50 years of age), in particular in those patients with a prolonged known HIV-infection (>8 years), who remain on (c)ART. The most frequent presentation occurs with an ST-segment elevation myocardial infarction. Nevertheless, presentation with non-ST-segment elevation myocardial infarction and unstable angina occur frequently as well  pmid=1731952, 12739013, 14691419, 12588205). Contrariwise, stable CVD is less frequent. The extent of coronary artery disease in general does not differ between HIV-infected and non-infected populations (12739013).
Clinical outcome after revascularization (predominantly for ACS) is similar for HIV-infected and non-infected populations, regardless of whether revascularization is performed percutaneously or surgically ( pmid=16537777, 18288976). HIV-infected patients, however, do remain at increased risk for recurrent ACS during follow-up ( pmid=20965887), which is importantly associated with persistently elevated lipid spectra.


{| class="wikitable" border="0"
The mitral valve annulus is thickened at each commissure to form the left and right fibrous trigones. The annular attachment of the aortic (or anterior) leaflet is related to the membranous septum and right fibrous trigone (together making the central fibrous body). The other leaflet of the mitral valve - the mural (or posterior) leaflet - usually has three scallops. The mitral valve is supported by two groups of papillary muscles in antero-lateral and postero-medial positions. Although textbook pictures tend to portray the papillary muscles as arranged far apart, they are in reality situated close to one another. Each papillary muscle supports the adjacent part of both leaflets and the commissures are marked by fan-shaped commissural chords.
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The outlet component supports the aortic valve. The semilunar leaflets are attached within the expanded aortic sinuses (of Valsalva). The sinuses are not strictly in right and left position although they are so designated in consideration of the origins of the coronary arteries. The central position of the aorta places it in close relation to each of the cardiac chambers and valves (Figure 8B).
!Key Points:
 
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The commissure between right and left coronary cusps is usually positioned opposite a commissure of the pulmonary valve. The commissure between the left and non-coronary leaflets points towards the left atrium. The commissure between right coronary and non-coronary leaflets lies above the membranous septum and is closely related to the right atrium and right ventricle and the atrioventricular conduction bundle (Figure 8B).
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*Patients with human immunodeficiency virus infection are at increased risk for cardiovascular disease compared with the general non-infected population.
==The aorta==
*The increased risk originates from an increased pertinence of traditional risk factors for cardiovascular disease, in combination with the detrimental effects of the HIV-infection itself and the adverse (combined) antiretroviral therapy drug effects.
The ascending aorta arises in right posterior position relative to the pulmonary trunk (Figure 1, upper panel). It ascends superiorly, obliquely to the right and slightly anterior toward the sternum. On the right is the medial
*Prevention of cardiovascular disease in HIV-positive patients should in particular focus on prevention of dyslipidemia, and smoking, which are both common in HIV-infected patients, and represent important (modifiable) determinants of the cardiovascular disease risk in these patients.  
wall of the right atrium. Anteriorly are the right atrial appendage, the right ventricular outflow tract and the pulmonary trunk. The transverse pericardial sinus separates the back of the aorta from the left atrium and right pulmonary artery. The arch of the aorta begins just above the cuff of pericardial reflection, proximal to the origin of the brachiocephalic artery. The arch passes superiorly for a short distance before passing posteriorly to the left and finally terminating on the lateral aspect of the vertebral column. In its course, the arch gives origin to the neck and arm arteries. The arterial duct, a patent channel in fetal life, connects the left pulmonary artery to the aorta just distal to the origin of the left subclavian artery. In the adult, the duct is represented by a fibrous ligament.
*Drug interactions in patients treated with (combined) antiretroviral therapy are frequent, especially between antiretroviral therapy and statins or antiplatelet agents such as prasugrel and ticagrelor, which occurs predominantly through the cytochrome P450 pathway.
 
*The increased risk for cardiovascular disease predominantly results in an early occurrence of acute myocardial infarction, for which coronary revascularization is associated with good outcome, although recurrent ischemic events are more common in HIV-infected patients than in the general non-infected population.
==The pulmonary arteries==
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The pulmonary trunk is also covered with a cuff of serous pericardium at its origin. It arises from the anterior aspect of the heart, just behind the left lateral edge of the sternum. It swings diagonally to the left side of the ascending aorta (Figure 1, upper panel). Being a short vessel, it soon bifurcates into the left and right pulmonary arteries. The left pulmonary artery passes in front of the descending aorta and superior to the left main bronchus before branching in the lung hilum. The longer right pulmonary artery traverses the mediastinum under the aortic arch before passing behind the superior caval vein to reach the right lung hilum.
 
==The coronary circulation==
[[Image:Figure 9.svg|thumb|300px|right|'''Figure 9.'''<br>
Diagram showing the right (RCA) and left (LCA) coronary arteries and their main ventricular branches. The left anterior descending (LAD) and posterior descending (PDA) coronary arteries mark the anterior and posterior margins of the ventricular septum.]]
 
As mentioned previously, the left and right coronary arteries emerge from the left and right coronary sinuses respectively. Usually the arteries arise from within the sinus just beneath or at the level of the aortic bar (sinutubular junction). In the left sinus there is usually a single orifice but in the right sinus it is usual to find multiple orifices where the early branches of the right coronary artery take direct origin. The main coronary arteries pass within the fatty tissues of the atrioventricular and interventricular grooves. The left coronary has a short main stem that branches into the anterior descending and circumflex arteries (Figure 9). The circumflex runs in the left atrioventricular groove and the right coronary artery runs in the right atrioventricular groove to variable lengths. From the atrioventricular groove, the encircling arteries give origin to ventricular and atrial branches. An early atrial branch is the sinus node artery which arises slightly more frequently from the right than the left coronary artery. It usually ascends the interatrial musculature to reach the terminal groove but recent evidence has shown a more variable course. In the majority of hearts the posterior descending artery, which runs in the posterior interventricular groove, is a branch from the right coronary artery and this is termed 'right dominance'. In a little under 10% of hearts the posterior descending is a branch of the circumflex giving 'left dominance'. A 'balanced' circulation is seen when both right and left coronary arteries give rise to parallel posterior descending branches. The artery to the atrioventricular node arises from the dominant artery at the cardiac crux.
 
After passing through the capillary network, coronary arterial blood is collected by venules which drain to the cardiac veins. The veins drain either to the coronary sinus or directly to the cardiac chambers. The great cardiac vein ascends along the anterior descending coronary and turns into the left atrioventricular groove. In the posterior atrioventricular groove it becomes the coronary sinus. It is joined near its entrance to the right atrium by the middle cardiac vein which ascends in the posterior interventricular groove and the small cardiac vein. The latter ascends along the marginal coronary artery before entering the posterior atrioventricular groove. Atrial veins also empty into the coronary sinus. A further group of veins, the anterior cardiac veins, run across the anterior aspect of the heart to drain directly into the right atrium. In addition to the coronary arteries and veins, the heart also has an extensive lymphatic network. These are divided into the deep, middle and superficial plexuses which drain into collecting channels accompanying the major arterial stems and finally into primary lymph nodes situated in the anterior mediastinum.
 
==The cardiac conduction system==
[[Image:Figure 10.svg|thumb|300px|right|'''Figure 10.'''<br>
The cardiac conduction system. Normally, the insulating fibro-fatty tissue plane at the atrioventricular junction prevents atrial myocardium from contacting ventricular myocardium. The penetrating bundle is the only muscular bridge.]]
 
The full complement of the histologically specialised tissues making the conduction system of the heart comprises the sinus node and the atrioventricular system (Figure 10). The latter is made up of the atrioventricular node, the penetrating atrioventricular bundle and the ventricular bundle branches. The geometry of the right atrium is such that it is made up of bands of muscle which separate the orifices of the great veins and the oval fossa. The spread of excitation from the sinus to the atrioventricular node has been shown to spread preferentially along these broad bands of ordinary atrial myocardium.
 
==The sinus node==
[[Image:Figure 11.jpg|thumb|left|300px|'''Figure 11.'''<br>
'''A.''' The sinus node (dotted shape) is superimposed onto the terminal groove in this picture of the right atrium viewed from the right side. The arrows indicate the sectioning plane of the histological section shown in B.
<br>'''B.''' This section from an infant heart is stained in Masson’s trichrome stain that colours myocardium red and fibrous tissue blue. The sinus node is readily identifiable by its composition of small myocytes in a fibrous matrix.]]
 
The 'ultimum moriens', the last part of the heart to stop beating when the organ is isolated from the body, first prompted Wenckebach to believe that this may also be the seat of the heart beat.<cite>Wenckebach</cite> The discovery of the sinus node in the heart of a mole culminated in a paper in 1907 in which Keith and Flack described 'a remarkable remnant of primitive fibres persisting at the sino•auricular junction in all mammalian hearts. These fibres are in close connection with the vagus and sympathetic nerves, and have a special arterial blood supply; in them the dominating rhythm of the heart is believed to normally arise'.<cite>Keith</cite> The subsequent elegant combined anatomico-physiological studies of Lewis and the Oppenheimers in 1910 confirmed the pacemaking role of the sinus node.<cite>Lewis</cite>
The sinus node predominantly occupies an antero-lateral location of the superior cavo-atrial junction within the terminal groove (Figure 11A). Only occasionally it is horseshoe-shaped draping over the right atrial summit. In most adult hearts it is shaped like a tadpole measuring about 3mm in diameter at its widest part and 15 to 20mm in length. A tapering 'tail' of the node may be traced from the epicardium to pass intramyocardially toward the inferior part of the terminal crest. The sinus node is easily recognised by the light microscope at low magnification. It is made up of small cells grouped together in interconnecting fascicles set in a fibrous tissue matrix (Figure 11B). The fibrous matrix becomes more prominent with increasing age. At the margins of the node is a short transitional area where nodal cells merge into atrial myocardium. In places, discrete tongues of transitional cells are found which extend into the terminal crest and toward the myocardial sleeve of the superior caval vein. The blood supply to the node shows considerable variation. A main artery penetrating the length of the node is seen in some hearts. In others, the nodal substance is penetrated by ramifications of an artery approaching the node through one or both ends, there being variations in nodal approaches. Even the origin of the sinus node artery is diverse, arising from the right or left coronary artery at different locations. Collections of ganglion cells are usually observed in the epicardium and also in the environs of the sinus node.
 
==The atrioventricular conduction system==
[[Image:Figure 12.jpg|thumb|300px|left|'''Figure 12.'''<br>
'''A.'''  This view of the right atrium and right ventricle shows the anterior and posterior borders of the triangle of Koch (broken lines) that mark location of the atrioventricular node and bundle (orange shapes). The arrows B, C, D indicate the cuts made through the conduction system as shown on the histologic sections.
<br>'''B''', '''C''' and '''D''' are step sections stained with Masson’s trichrome technique and displayed in similar orientation tracing the atrioventicular conduction system from the AV node (AVN) that adjoins the central fibrous body (cfb), to the penetrating His bundle (H), and the branching bundle (BB) dividing into the left (LBB) and right (RBB) bundle branches.]]
 
[[Image:Figure 13.jpg|thumb|300px|right|'''Figure 13.'''<br>
This picture from Tawara’s monograph (1906) shows the tree-fascicular arrangement of the left bundle branch in man.  
(Tawara S 1906 Das Reizleitungssystem des Säugetierherzens. Eine Anatomisch-Histologische Studie Über das Atrioventrikularbündel und die Purkinjeschen Fäden. Gustav Fischer, Jena.)]]


==References==
Occasional reference to this as the system of His-Tawara gives credit to two of the pioneering investigators in this field. The myocardial bridge that connects atrial myocardium to ventricular myocardium across the insulating fibro-fatty tissues of the atrioventricular junction was found by His in 1893 and given the appellation ‘penetrating bundle of His’.<cite>HisW</cite> Tawara's monograph<cite>Tawara</cite> accompanied by colour plates in 1906 gave a detailed description of the atrioventricular node and how it was a continuum with the bundle described by His and the ventricular fibres previously described by Purkinje.<cite>Purkinje</cite> This firmly estabIished the presence of an atrioventricular conduction system (Figure 10) and was subsequently confirmed by Keith and Flack in the same year.<cite>Flack</cite> Gross anatomical landmarks to the location of the atrioventricular system are invaluable guides to cardiac surgeons and interventionists who have to perform intracardiac procedures since trauma to any part of the system can produce dire complications.
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The atrioventricular node is located at the apex of an angle formed by the tendinous continuation of the Eustachian valve (tendon of Todaro) and the annular insertion of the septal leaflet of the tricuspid valve (Figure 12). The coronary sinus completes the base of the triangular shape which bears the name 'triangle of Koch' in recognition of Koch's elegant descriptions.<cite>Koch</cite> The tendon of Todaro inserts into the central fibrous body. In the adult the atrioventricular node measures about 4 mm in width and 8 mm in length. In histological sections the compact part of the node is easily recognisable being composed of interconnecting fascicles of small cells, closely adherent to the central fibrous body. In cross•section the node appears like a haIf-oval lying against the fibrous body (Figure 12D). A transitional zone of attenuated myocardial cells extends into the atrial myocardium. The node becomes the penetrating bundle as the conduction system passes through the central fibrous body (Figure 12C).


The penetrating bundle veers to the left as it continues into the branching bundle to emerge in the left ventricle beneath the commissure that separates the right-coronary and non-coronary aortic valve leaflets. The bifurcation into left and right bundle branches marks the beginning of the branching bundle (Figure 12B).
The right bundle branch is cord-like and frequently is the continuation of the nodal-bundle axis. It turns downwards and passes intramyocardially into the substance of the septomarginal trabeculation directly beneath the medial papillary muscle complex. It then passes subendocardially towards the right ventricular apex and crosses the ventricular cavity within the moderator band before ramifying. The left bundle branch is morphologically different from the right bundle branch. It descends from the nodal-bundle axis as a sheet of cells within the subendocardial tissues of the aortic outflow tract. Tawara's original reconstructions show the bundle radiating in fan-like fashion into three major divisions which are interconnected distally by a subendocardial network that ramifies into the ventricular myocardium (Figure 13).<cite>Tawara</cite> Later investigations using careful serial reconstructive techniques support the trifascicular concept seemingly in conflict with the 'hemiblock' theory which promotes a bifascicular morphology.<cite>Rosenbaum</cite>


==References==
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|-
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<biblio>
#Wenckebach Wenckebach KF. ''Beiträge zur Kenntnis der menschlichen Herztätigkeit.'' Arch Anat Physiol l907; 2:1.
#Keith1907 pmid=17232727
#Lewis Lewis T. Oppenheimer BS, Oppenheimer A. ''Site of origin of the mammalian heart beat: the pacemaker in the dog.'' Heart 1910;2:147
#HisW His W Jr. ''Die Thatigkeit des embryonalen Herzens und deren Bedeutung für die Lehre von Herzbewegung beim Erwachsenen.'' Ar Med Klin Leip 1893:14.
#Tawara Tawara S. ''Das Reizleitungssystem des Saugetierherzen.'' Gustav Fischer, Jena. 1906
#Purkinje Purkinje JE. ''Mikroskopisch neurologische Beobachtungen.'' Archiv Anat Physiol u Wiss Med I845;12:28I.
#Flack1906 pmid=15485521
#Koch Koch W. ''Der funktionelle Bau des menschlichen Herzens.'' Berlin: Urban v Schwarzenburg,1922:92.
#Rosenbaum Rosenbaum MB, Elizari MV, Lazzari JO. ''The hemiblocks.'' In: Tampa Tracings. Oldsmar, Fla. 1970.
</biblio>
</biblio>
|}
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