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Vascular disease are disease types affecting the vascular part of the cardiovascular system and, as with all CVD, directly affects and disrupts the systemic transport of

blood. Below follows a short review of some of the most common vascular diseases, with specific focus on the development of atherosclerotic plaque.

a) Atherosclerosis

Atherosclerosis is a systemic, inflammatory disease, characterised by the build-up of intraluminal plaques, protruding into the luminal cavity. As the plaque development progresses, increased regional stenosis and risk for subsequent plaque rupture poses a major health risk, where thrombus formation or complete vascular blockage as a result from a ruptured or eroded plaque often lead to life-threatening complications.

The development of atherosclerotic plaques is a complex and heterogeneous process, and several different plaque types have been identified [139, 140] with a range of different risk-factors deemed influential in the establishment of the disease [141, 142]. However, some general stages have been identified in the development of the disease, as outlined below. A summarising illustration is also provided in Figure 3.9.

i) Atherosclerosis typically initiates from systemic endothelial dysfunction [139]. Specifically, the intima endothelium loses its ability to properly regulate vascular tone and permeability [143], and instead triggers localised inflammation (a wide range of both modifiable and non-modifiable risk factors have been identified in triggering endothelial dysfunction, such as e.g. high blood cholesterol levels [144], hypertension [145], diabetes [146], diet [95], and smoking habits [96]).

ii) The endothelial dysfunction renders an upregulation of vascular permeability of lipoproteins, leading to the initiation of an atheroma beneath the endothelial layer. This is typically formed by neutrophils and monocytes, who in a subsequent step recruit circulating blood cholesterol (low-density lipoproteins, LDL) into the wall. Once inside the wall, oxidised LDL (oxLDL) crystals form so called fatty streaks in-between the intima and media layer – a typical hallmark of early- stage atherosclerosis.

iii) With oxLDL crystals trapped inside the vessel wall, macrophages start to encompass them forming larger so called foam cells, representing the core of the developed plaque [147].

iv) The process in iii) continues with the plaque increasingly protruding into the intraluminal space. At this stage, smooth muscle cells from the media migrate to the intima, producing extracellular matrix molecules and encapsulating the plaque core with a so called collagen- rich fibrous cap [148]. Inefficient clearance of dead cells inside the atheroma might form a lipid-rich necrotic core of the plaque [139],

Figure 3.9: (A) Development stages of atherosclerosis from initiation to rupture, depicting important

progression steps, as well as acting plaque constituents (residual lipoproteins (RLP), low-density lipoprotein (LDL), oxidised-LDL (ox-LDL) and C-reactive protein (CRP)). (B) A few identified vulnerable plaque types. Reproduced with permission [141, 149].

and atheroma macrophage activation might also promote calcium deposition within this necrotic core, forming so called microcalcifications [150].

v) At this stage, the atherosclerotic plaque might develop in many different ways, and the distribution and formation of fibrous cap, necrotic core, and calcifications in iv) varies greatly between different plaques. The further progression of the plaque is thus highly heterogeneous, but using very crude classification one might differentiate between a stable plaque, where an inactive core is covered

by a relatively thick layer of fibrous tissue, and an unstable or vulnerable

plaque, where a highly active and proliferating core is covered by a thin fibrous cap (so called thin-cap fibroatheroma, TCFA) [151, 152]. vi) Both stable and unstable plaques protrude into the intraluminal cavity,

but whilst stable plaques do not develop much beyond v), the thin fibrous cap of the unstable vulnerable plaques are prone to rupture as a consequence of increasing internal load [152] or upon collagen

degeneration [153]. At plaque rupture, thrombogenic factors from the plaque interior attracts platelets in the blood stream, forming a thrombus coagulant that severely disrupts or even fully blocks the downstream blood flow.

Following the established development process, classifications have been proposed in staging atherosclerotic plaque development. A commonly deployed classification score comes from the America Heart Association (AHA), with a conventional (for histopathological analysis) and a modified classification (for image-based MRI analysis), both depicted in Table 3.1 [140].

Table 3.1: Conventional and modified AHA classification of atherosclerotic plaque

Regarding clinical symptoms of atherosclerosis, the increasing protrusion of the plaque will obstruct the flow of blood, giving rise to e.g. angina pectoris, fatigue, or vascular claudication. If ruptured or eroded, more severe thrombotic events might lead to local ischemia or acute emboli formation such as myocardial infarction or stroke, each with its associated clinical indicators. However, a defined complication of atherosclerosis is that patients might be asymptomatic up until relatively Conventional AHA Classification Modified AHA Classification

Type I: Initial lesion with foam

cells Type I-II: Near-normal wall thickness, no calcification Type II: Fatty streak with multiple

foam cell layers Type III: Preatheroma with

extracellular lipid pools Type III: Diffuse intimal thickening or small eccentric plaque with no calcification

Type IV: Atheroma with a confluent extracellular lipid core

Type IV-V: Plaque with a lipid or necrotic core surrounded by fibrous tissue with possible calcification Type V: Fibroatheroma

Type VI: Complex plaque with possible surface defect, haemorrhage, or thrombus

Type VI: Complex plaque with possible surface defect, haemorrhage, or thrombus Type VII: Calcified plaque Type VII: Calcified plaque Type VIII: Fibrotic plaque without

lipid core Type VIII: Fibrotic plaque without lipid core and with possible small

advanced development stages [141]. High-risk patients will be assigned preventive lipid-lowering, antiplatelet therapy [144], and non-invasive imaging has been proposed as a monitoring tool for the progression of atherosclerosis [8, 100]. Once symptomatic, guidelines still however very much rely on evaluating the degree of stenosis, where a stenotic protrusion of above 60-75% generally leads to invasive endarterectomy (surgical removal of the atherosclerotic plaque) [106]. Other invasive procedures also include vascular stenting or bypass surgery [154], to relieve the effect of the developed plaque.

As evident above, the key clinical question in atherosclerosis lies in so called plaque risk stratification – separating vulnerable rupture prone plaques from the more stable plaque formation. This will be discussed in-detail in Section 3.4.1., but in- short the multifactorial background of atherosclerosis makes such differentiation complicated. Whilst we can classify different plaque types morphologically, it is paradoxically not always the plaque with the highest stenosis that is the most rupture-prone [155, 156]. Also, even if morphology seems evidently important, a range of different types of vulnerable plaque types have been identified in literature (including a thin fibrous cap, large necrotic core, increased plaque inflammation, increased neovascularisation, intraplaque haemorrhage, and active plaque inflammation, as shown in Figure 3.9) [141], complicating the diagnosis. The in-vivo

assessment of plaque morphology is also not univocal, and echogenicity [157], inflammation [158] and constitutive behaviour [151, 152] have all been proposed as substitute in deriving plaque vulnerability.

Lastly on specific hemodynamic considerations of atherosclerosis, it is clear how atherosclerotic development and local stenotic protrusions disrupt blood flow and increase local blood velocities and pressure drops. Hence, assessment of absolute velocity magnitudes or absolute pressure drops through invasive catheterisation has been used to analyse plaque development or evaluate the need for coronary stenting [159, 160]. Another interesting hemodynamic factor is evident in how local

atheroma and lipid-retention is triggered from a generally systemic endothelial

dysfunction. For such, increased wall shear stresses and non-laminar flow around vascular bifurcations have been identified as possible hemodynamic factors initiating plaque development [51]. Hypertension has also been identified as a risk factor for atherosclerosis [145], even though the isolated influence of elevated pressure on plaque formation are still under investigation.

b) Hypertension

Hypertension is a pathological state in which the arterial blood pressure is elevated above normal values, and where the cardiovascular system consequently has to work against a persistently higher work-load. Even though varying between individuals, guidelines cut-off values for diagnosed hypertension are set at systolic blood pressures ≥ 140 mmHg and diastolic blood pressures ≥ 90 mmHg (albeit isolated systolic hypertension is also identified) [161].

Elevated blood pressure is generally asymptomatic, but the connection between increased blood pressure and cardiovascular risk has been extensively investigated [162], with hypertension deemed an independent risk factor for stroke, myocardial infarction, heart failure, and sudden cardiac death [161], to name only a few. Hypertension is also a highly prevalent disease, with an estimated 25-45% of the entire adult population identified as hypertensive [161, 163], with numbers increasing with increasing age.

Hypertension is a multifactorial disease, and the underlying causes are difficult to isolate. For some specific pathology such as renal or endocrine disease, hypertension is identified as secondary following the onset of the primary pathology [164]. However, so called primary hypertension is more diffusely developing without any cofounding pathophysiological initiation, and only specific risk factors such as genetic variations, smoking, obesity, or age have been identified to increase the risk for the disease [161].

From a hemodynamic perspective hypertension greatly influence the behaviour of the cardiovascular system. The increased arterial blood pressure is equivalent to an increased afterload, which the heart needs to work against to maintain sufficient ejection of blood. By that, a hemodynamic reaction of increasing intraventricular velocities and increasing intraventricular blood acceleration [165] is observed, which may further trigger pathological remodelling through hypertrophy or dilation [166]. The hypertensive hemodynamics also leads to increased turbulent and erratic flow, through which hypertension is a risk factor for valvular stenosis [61]. Conversely, pulmonary hypertension (increased blood pressure in the pulmonary circulation) typically affects the diastolic abilities of the left heart, being a hypothesised component in diastolic heart failure [167], as well as being a risk factor for right ventricular failure [168].

The relation between hypertension and arterial stiffening is also worth mentioning. The increase in arterial stiffness with age is evident [169], so is the increasing prevalence of hypertension [163]. That the two coincide is not surprising: with increasing blood pressure the arteries have to withstand increased exerted load, triggering arterial remodelling and upregulation of collagen production. Conversely, stiffened aortas will decrease distensibility, and hence increased pressures are required to maintain systemic circulation. The order in which the two manifest themselves are still under evaluation, but it has been hypothesised that slight vascular stiffening might precede the onset of clinically evident hypertension [170, 171].

c) Other vascular disease

Even though atherosclerosis and hypertension are by far the most common vascular diseases, a few other vascular complications are worth mentioning within the scope of this thesis. Specifically, aortic coarctation and aortic dissection are mentioned in brief.

i) Aortic coarctation

Aortic coarctation is a generally congenital condition, represented by a local narrowing of the aorta typically in or around the initial aortic bend. The disease accounts for around 4-6% of all congenital heart defects, with an overall prevalence of around 4 per 10 000 births [172]. Hemodynamically, the narrowing can be treated as a local stenotic region, where the cardiovascular system needs to overcome an additionally imposed pressure gradient to successfully pump blood through the systemic circulation. Thus, assessing local pressure drops are part of guidelines for aortic coarctation monitoring [59], and systemic arterial hypertension is common among this specific patient cohort [173]. This increased afterload will render compensatory effects on the cardiac side, leading to potential cardiovascular remodelling.

ii) Aortic dissection

Aortic dissection is a pathological condition where an intraluminal injury allows blood to tear open and flow in-between the layers of the arterial wall. By so the condition represents a serious cardiovascular event, associated with high mortality and the need for acute surgical repair [174]. The disease is not congenitally present, but high incidence-rates are reported in patients with a congenital bicuspid aortic valve potentially following the disrupted outflow [175], as well as in patients with other more rare congenital heart conditions [176]. However, severe hypertension and aortic stiffening have also shown to correlate to aortic dissection, where the risk of initiating vascular damage seems elevated [176]. Hemodynamically the opening of a parallel false lumen severely complicates blood flow, induces regions of high turbulence and irregular flow [177].