"Significance of combined cardiopulmonary and echocardiographic stress test to distinguish the hemodynamic and metabolic responses of hypertensive patients with or without heart failure preserved ejection fraction"

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UNIVERSITÀ DI PISA

Dipartimento di Medicina Clinica e Sperimentale

Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie

in Medicina e Chirurgia

Corso di Laurea Magistrale in Medicina e Chirurgia

TESI DI LAUREA

Significance of combined cardiopulmonary and echocardiographic

stress test to distinguish the hemodynamic and metabolic responses of

hypertensive patients with or without heart failure

RELATORE

Chiar.mo Prof. Roberto PEDRINELLI

CANDIDATO

Matteo MAZZOLA

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Organic summary

Hypertension represents a leading risk factor for the development of symptomatic heart failure and is now considered the factor who carries the highest attributable risk for heart failure in the general population. In terms of prevalence, according to the data from the Olmsted County cohort, 73.6% of patients with Heart Failure with reduced Ejection Frac-tion had hypertension compared with 89.3% of patients with Heart Failure with preserved Ejection Fraction. Cardiopulmonary exercise test (CPET) combined with exercise stress echocardiography (ESE) o↵ers a feasible, non-invasive evaluation of di↵erent cardiac con-ditions, with the possibility of simultaneously exploring the peripheral and central compo-nents of oxygen consumption (VO2). Therefore, we assessed with CPET-ESE the hemo-dynamic and metabolic characteristics of HT subjects with and without HFpEF, including a cohort of healthy controls in order to understand the di↵erences in exercise physiology and their relation with both hypertension related organ damage and transition to failure. We prospectively enrolled HT subjects between September 2017 and May 2019. All pa-tients were clinically stable; we excluded from the study papa-tients presenting with more than moderate primary valvular disease, hypertrophic cardiomyopathy, active ischemia, atrial fibrillation, unable to complete exercise (respiratory exchange ratio [RER] < 1.0), diabetes mellitus or with inadequate acoustic windows. The overall population (n=145) consisted of HT individuals (n = 63) and patients with HT and HFpEF (HFpEF-HT, n=50), including a control group (n = 32) of healthy subjects who demonstrated a normal exercise capacity and ultrasound scan. A symptom-limited graded ramp bicycle exercise test was performed in the semi-supine position on a tilting, dedicated, microprocessor-controlled stress echocardiography cycle ergometer. We estimated the expected peak oxygen con-sumption (VO2) based on patient age, height, weight and clinical history. Then, we cal-culated the work rate increment necessary to reach the patient’s estimated peak VO2 in 8 to 12 min. The protocol included 2 min of unloaded pedaling and 4 min of recovery af-ter peak e↵ort. Breath-by-breath minute ventilation, carbon dioxide production (VCO2),

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and VO2 were measured using a dedicated cardiopulmonary diagnostic software. A com-prehensive echocardiographic examination was performed concurrently with breath-by-breath gas exchange measurements at di↵erent stages of e↵ort: rest, within the first 4 min of exercise (low-load e↵ort), after reaching a stable RER 1.00, and at peak e↵ort. A post-processing speckle tracking analysis (GE healthcare EchoPAC BT 12) to measure global longitudinal strain (GLS) was performed from the apical long-axis view and 2- and 4-chamber views, after ensuring a frame rate > 50 Hz. We reported the average values from the three apical views at rest and low-load e↵ort, while AT and peak images were ex-cluded due to algorithm under sampling at high HR and breathing-induced through-plane motion artifacts. The acquisition protocol included B-lines evaluation at rest at the end of the exercise, after peak-e↵ort image acquisition. HT subjects had a peak VO2 lower than controls but higher than HFpEF-HT. The reduced peak VO2 in HT may be related to an early peripheral dysfunction, expressed by the decreased peak AVO2di↵. Indeed AVO2di↵ (peripheral component of VO2) at rest and low-load e↵ort was similar between groups, but it was significantly reduced in HT and HFpEF-HT in comparison to controls at peak exercise. Moreover, it is possible to identify a mild cardiovascular dysfunction associated with HT. Despite a preserved cardiac output and LVEF increase throughout the exercise, The HT patients during e↵ort reached E/e’ values higher than controls but lower than HT-HFpEF, conversely LV compliance resulted lower than controls but higher than HT-HFpEF, outlining an intermediate profile of HT patients between healthy subjects and HFpEF.

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Introduction

1.1 Arterial hypertension

Essential, primary, or idiopathic hypertension is defined as high blood pressure (BP) in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary hypertension or Mendelian forms (mono-genic) are not present. This condition accounts for 95% of all cases of hypertension and remains a major modifiable risk factor for cardiovascular disease (CVD) despite impor-tant advances in our understanding of its pathophysiology and the availability of e↵ective treatment strategies (1).

1.1.1 Definition and classification

BP is a quantitative trait that is highly variable with normal distribution in the population that is slightly skewed to the right. There is a strong positive and continuous correlation between BP and the risk of CVD (stroke, myocardial infarction and heart failure), renal disease, and mortality, even in the normotensive range, extending from very low levels of BP well below the conventional threshold for raised blood pressure (i.e. SBP > 115 mmHg) (1–3). Thus, the relationship between BP and cardiovascular and renal events is continuous, making the distinction between normotension and hypertension, based on cut-o↵ BP values, somewhat arbitrary (4–6). However, in practice, cut-cut-o↵ BP values are used for pragmatic reasons to simplify the diagnosis and decisions about treatment and ‘hyper-tension’ is defined as the level of BP at which the benefits of treatment (either with lifestyle interventions or drugs) unequivocally outweigh the risks of treatment, as documented by clinical trials (2). For these reasons, the criteria for the definition of hypertension has re-mained unchanged for the last years and are universally recognized as values 140 mmHg systolic blood pressure and/or 90 mmHg diastolic blood pressure, based on the evidence

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from randomized clinical trials that in patients with these BP values treatment-induced BP reductions are beneficial (2,7–9). The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) clas-sified hypertension in adults in di↵erent categories, according to hypertension grade (10). The latest guidelines for the management of hypertension (2) still recommends the use of the JNC VI categories in clinical practice and classify arterial hypertension as shown in Figure 1.1.

Figure 1.1: Classification of office blood pressure and definition of hypertension grades (2018 ESC/ESH Guidelines for the management of arterial hypertension)

1.1.2 Epidemiology

According to the data of NCD Risk Factor Collaboration from 1975 to 2015, the estimated number of patients with hypertension in 2015 was globally 1.13 billion. Looking at the prevalence in the di↵erent regions of the world, in central and Eastern Europe the number was over 150 million. The data standardized for age and sex display a global prevalence of 24% in men and 20% in women (3). Overall, the condition a↵ect almost 30-45% of adults. There is a strict correlation between elevated levels of BP and age, as demonstrated by the high prevalence in the elderly population. In fact, more than 60% of people older than 60 years old indeed has value of BP in hypertensive range (11). Considering a positive trend of aging and body weight, together with a style of life poor in levels of physical exercise, the frequency of hypertension is supposed to rise in the next years. Kearney et al., indeed, estimate an increase of 15-20% of people with hypertension by 2025, according to the projected changes in body size and age in general population (12) (Figure 1.2).

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In the analysis of the Global Burden of hypertension, evaluated from 1990 to 2015 and published on Journal of American Medical Association in 2017, almost 10 million deaths are attributable to an elevated BP, making this condition the main risk factor in the occurrence of premature decease. Considering the cause of hypertension-related deaths, ischemic heart disease (4.9 million) and stroke (3.5 million) represent the most common clinical events. The burden of disease, evaluated in terms of disability-adjusted life years (DALYs), has increased by 40% since 1990, despite the improvements in early diagnosis and clinical management. In Fact, hypertension is responsible in 2015 for almost 200 million DALY. Almost the 70% of deaths and burden is produced by a systolic blood pressure at least 140 mmHg (13).

The measurements of BP levels can be classified in office BP (as to say the measure that takes place in physicians’ office) and out-of-office BP comprehensive of both Home BP monitoring (HBPM) and 24-hours Ambulatory BP Monitoring (ABPM). Interesting, both types of techniques provide the clinician with values independently and continuously associated with cardiovascular events (haemorrhagic stroke, ischaemic stroke, acute coro-nary syndromes, sudden death, heart failure, and peripheral artery disease), as well as end-stage renal disease (5). Furthermore, there are new evidence supporting an important link between hypertension atrial fibrillation (AF) (14). A novel field of research is produc-ing also several studies supportproduc-ing the association between early elevations of BP and the development of mild cognitive impairment, cognitive decline and dementia (15,16).

1.1.3 Vascular remodeling

Essential hypertension has multiple pathological e↵ects on vascular system both indirectly as a promoter of atherogenic process and directly as factor related to changes in vascular structures occurring at all levels of the circulation from the large arteries through the mi-crocirculation. These modifications include thickening of the walls of large elastic and muscular arteries, alterations of small muscular arteries, reduced number of vessels in the microcirculation and lengthening of small arteries and are overall defined as “hypertension related vascular remodeling” (17–19)

Along the vascular system until capillary bed, vessels undergoes several changes in both dimension and wall structure according to the functions they have to perform (con-ductance, resistance or di↵usion). Despite these di↵erences, endothelial cells, smooth muscle cells, and fibroblasts represent the main cytotypes. These populations are linked

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Figure 1.2: Number of people with hypertension aged 20 years and older by world re-gion and sex in 2000 (upper) and 2025 (lower) (from Kearney et al. Global burden of hypertension: an analysis of worldwide data)

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morphologically and functionally and are able to communicate with each other. Many authors indeed, in the analysis of the vessels physiology and pathology, consider all these di↵erent cells as a single “autocrine-paracrine complex”. The cellular elements of the vas-cular wall, thanks to the direct contact with hematic flow, are able to obtain several infor-mation about the condition of circulatory system. In fact, every alteration in local or gen-eral vascularization produces hemodynamic and/or neurohumoral changes able to activate these cells. In response to the alteration detected, the di↵erent populations start to produce signaling molecules that act in autocrine and paracrine way. In this phenomenon endothe-lial cells represent the “vascular transducer cells”, able to activate the other in response to di↵erent stimuli (Figure 3). Endothelium, matrix and smooth muscle cells influence each other activities and produce modifications in cellular growth, cellular death, cellular migration and synthesis/degradation of extracellular matrix (ECM). In the development of this adaptation of vascular system, the interplay between hemodynamic stimulations, vasoactive substances and growth factors is pivotal. We can therefore consider vascu-lar remodeling as an active process of functional and structural modification, triggered by durable changes in hemodynamic status and strictly related to the pathophysiology of cardiovascular disease (19,20).

Blood pressure and flow are the main hemodynamic variables influencing the cardio-vascular system and interact with vasculature producing specific mechanical forces. The first is able generate radial and tangential forces that are responsible for the tensile stress of vascular wall, considered as the level of stretch of the vessel. The latter produce forces acting parallel to the vascular surface that result from attrite between blood and vasculature and produce the shear stress. Both shear and tensile stress are able to activate numerous in-tracellular pathway mediated by tyrosine kinase. These signaling transduction systems in endothelial cells are able to produce post-transcriptional modifications and modulate gene expression. The result is pleiotropic and involves activation of ion channels, changes in the interaction between cells and cellular matrix via integrin and release of growth factors (23,24). In agreement with these observations, there are many evidence demonstrating that variations both in blood pressure levels and in haematic flow are able to produce similar modifications in the endothelial cells physiology. Tulis et al. observed that flow regimen is able to influence the structure of arterial vessels using the rat mesenteric arterial system. The longstanding increase of flow in the arterioles of mesenteric circulation promoted the proliferation of both endothelial and vascular smooth cells, resulting in augmentation of connective tissue and medial hypertrophy. Using the same models Allen et al.

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demon-strated that in condition of hypertension the increase in wall stress, independently from the levels of cell stretch, is able to modify gene expression. (25,26).

In the relationship between mechanical stimuli produced by hypertension and the de-velopment of vascular remodeling, an increase number of evidence support the key role of oxidative stress. In animal models of hypertension, the endothelial cells of microcircula-tion display high levels of oxygen radicals as result of xanthine oxidase activity (27). Ox-idative stress display multiple e↵ects in cells and produce an increase in expression of ad-hesion molecules on the surface of endothelium as result of both post-transcriptional mod-ification in intracellular mediators and variation in gene expression. This phenomenon is a pivotal mechanism for the relationship between vasculature and innate immune response, facilitating the adhesion of leukocytes to the endothelial surface (28). Other important e↵ect of oxygen radical is the increase in endothelial permeability that together with the high probability of contact promote the migration of white blood cells within the vascular wall. As result, the cells of innate immunity are in the perfect condition for activation of the inflammatory cascade. This complex system involve several factors and plays an im-portant role in vascular remodeling. Among the several e↵ects, the alteration of integrin signaling together with the increase production of tenacin and epidermal growth factor represent the main drivers for the smooth muscle cells proliferation. Furthermore, the increase production of metalloproteinase can induce an important rehash of extracellular matrix and generate molecules related to an inhibition of cellular apoptosis (29,30).

It is important to underline that beyond the mechanical factors, indipendently related with the development of vascular remodeling and hypertension-mediated organ damage, several neurohumoral elements cooperate in hypertension pathogenesis. Each mediator triggers specific pathway capable to produce systemic e↵ects a↵ecting the progression of the condition regardless of pressure levels (21).

A. Molecular basis The mechanisms underlying the relationship between hypertension and vascular remodeling are complicated and, although decades of researches in experi-mental animal models, only recently the main experts in this this field succeeded in defin-ing an almost complete model of pathogenesis. Thanks to the work of many investigators, we can now outline a chain of events that starts from the modification of endothelial cells activity and extends within the vascular wall with changes in matrix and vascular smooth muscle cells. Furthermore, the phenomenon can involve structures beyond the vessel wall, such as the adventitia and peri-vasal tissues (21). In this context, the endothelial layer

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represents a signal transduction interface that reacts to the variation in circulatory envi-ronment and produce signals for the other parts of vascular wall. This is the functional key for the regulation of vascular tone and chronic structural remodeling of arteries (22) (Figure 1.3).

Figure 1.3: Endothelial cell as vascular transducer cell (from Gibbons et al. 1994 “The emerging concept of vascular remodeling”)

Blood pressure and flow are the main hemodynamic variables influencing the cardio-vascular system and interact with vasculature producing specific mechanical forces. The first is able generate radial and tangential forces that are responsible for the tensile stress of vascular wall, considered as the level of stretch of the vessel. The latter produce forces acting parallel to the vascular surface that result from attrite between blood and vasculature and produce the shear stress. Both shear and tensile stress are able to activate numerous in-tracellular pathway mediated by tyrosine kinase. These signaling transduction systems in endothelial cells are able to produce post-transcriptional modifications and modulate gene expression. The result is pleiotropic and involves activation of ion channels, changes in the interaction between cells and cellular matrix via integrin and release of growth factors (23,24). In agreement with these observations, there are many evidence demonstrating that variations both in blood pressure levels and in haematic flow are able to produce similar

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modifications in the endothelial cells physiology. Tulis et al. observed that flow regimen is able to influence the structure of arterial vessels using the rat mesenteric arterial system. The longstanding increase of flow in the arterioles of mesenteric circulation promoted the proliferation of both endothelial and vascular smooth cells, resulting in augmentation of connective tissue and medial hypertrophy. Using the same models Allen et al. demon-strated that in condition of hypertension the increase in wall stress, independently from the levels of cell stretch, is able to modify gene expression. (25,26).

In the relationship between mechanical stimuli produced by hypertension and the de-velopment of vascular remodeling, an increase number of evidence support the key role of oxidative stress. In animal models of hypertension, the endothelial cells of microcircula-tion display high levels of oxygen radicals as result of xanthine oxidase activity (27). Ox-idative stress display multiple e↵ects in cells and produce an increase in expression of ad-hesion molecules on the surface of endothelium as result of both post-transcriptional mod-ification in intracellular mediators and variation in gene expression. This phenomenon is a pivotal mechanism for the relationship between vasculature and innate immune response, facilitating the adhesion of leukocytes to the endothelial surface (28). Other important e↵ect of oxygen radical is the increase in endothelial permeability that together with the high probability of contact promote the migration of white blood cells within the vascular wall. As result, the cells of innate immunity are in the perfect condition for activation of the inflammatory cascade. This complex system involve several factors and plays an im-portant role in vascular remodeling. Among the several e↵ects, the alteration of integrin signaling together with the increase production of tenacin and epidermal growth factor represent the main drivers for the smooth muscle cells proliferation. Furthermore, the increase production of metalloproteinase can induce an important rehash of extracellular matrix and generate molecules related to an inhibition of cellular apoptosis (29,30).

It is important to underline that beyond the mechanical factors, indipendently related with the development of vascular remodeling and hypertension-mediated organ damage, several neurohumoral elements cooperate in hypertension pathogenesis. Each mediator triggers specific pathway capable to produce systemic e↵ects a↵ecting the progression of the condition regardless of pressure levels (21).

B. Large Arteries remodeling Essential hypertension a↵ects large arteries both in term of wall morphology and lumen shape and dimensions. Large arteries modifies their struc-ture along the vascular system. Moving away from the heart, they undergo a progressive

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Figure 1.4: Intracellular cascades associated to vascular remodeling (from Renna et al. pathophysiology of vascular remodeling in hypertension)

decrease in elastic components in favor of the muscular ones. These changes in arte-rial wall composition are related to di↵erences in hypertension induced vascular remodel-ing. In fact, while proximal elastic arteries display an increase in intima–media thickness (IMT) together with a lumen enlargement, distal muscular arteries increase IMT without changes in lumen diameter (31,32). Assuming the arteries as “cylinders with thickened walls”, it is possible to determinate circumferential wall stress using Lamé equation:

✓ = P · R_h (1.1)

Where P is pressure, R is radius and h represents wall thickness. Wall stress has an inverse proportional relationship with thickness and results direct proportional to pressure and radius. Thus, as the pressure in the vessel increases, the wall stress rises. In essential hypertension, the thickening of the vessel wall represents therefore a compensatory mech-anism to obtain normal wall stress levels despite the augmentation of BP. Considering the process of increase in wall thickness as the accumulation of material with same physical characteristics, the sti↵ness of the structure should augment for any level of BP (33). In-deed many authors demonstrated that aging and hypertension correlate with the sti↵ening of aorta at any value of BP (34,35). The increase in arterial sti↵ness is a complex process that involves a series of alterations in the vessel wall characteristics and finally results in a

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decrease of arterial compliance. Compliance is a physical property that, mainly at level of thoracic aorta, enables the large arterial structures to dampen the pulsatility of cardiac ac-tivity. Ventricular ejection therefore produce a pulsatile flow in the ascending aorta during systolic phase but, thanks to a low compliance in elastic arteries, the continuity of flow is preserved and energy for organ perfusion remains at low levels. At each beat, during the isotonic phase of ventricular contraction, the left ventricle pumps in the vascular system a volume of blood called Stroke Volume. According to the windkessel model, during this ejective phase the heart pushes into the distal peripheral circulation just part of the stroke volume while an important quantity remains in the proximal elastic arteries and distends their walls, producing an increase in the local levels of BP. In other terms, part of energy of cardiac ejective activity is stored in the vessel walls in form of potential energy. Dur-ing the diastolic phase, the elastic recoil of large proximal artery act as a pump and pulls the blood through peripheral vascular structures. Thus, the potential energy accumulated in the arterial walls becomes kinetic energy for blood movements and the continuity of flow is therefore preserved (Figure 1.4). The levels of arterial sti↵ness and the geometry of vascular structure represent the main variables influencing the correct activity of the system (33,36). Generally, at low levels of arterial sti↵ness and high levels of compliance, the distension of elastic wall is easy and the pressure pulsatility remains within the normal range. In hypertensive patients’ circulation, where the sti↵ness is high and compliance low, the increase of systolic BP represents the only mechanism to obtain the same degree of distension of normal subjects. As result, the blood flow through peripheral circulation becomes more intermittent within the cardiac cycle with a prevalence in systolic phase. At the same time, the pulsatility at level of resistance small arteries increases and the cap-illary transit time results reduced. All these alteration cooperate in the development of hypertension-mediated organ damage (Figure 1.4).

The pulsatility of BP is further exaggerated by the phenomenon of wave reflection. During each cardiac cycle, the flow ejected in the aorta generates a pressure waveform that propagates along the arterial tree with a finite velocity and is reflected at points where impedance changes abruptly (36). Although there are multiple reflection sites in the upper and lower parts of the body, the reflected waves are produced together and at the level of the heart they produce a main reflected wave (37). Backward secondary waves, originating from peripheral reflection sites or generated by re-reflection phenomena, are functionally negligible. In fact, they arrive later and their amplitude is significantly lower than the main component. When the reflected wave is optimally timed, as usually occurs in young

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Figure 1.5: Schematic representation of the role of arterial sti↵ness in assuming blood flow through the peripheral circulation (from Laurent et al. 2015 “The structural factor of hypertension”)

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healthy individuals, the reflected component meets the forward wave in ascending aorta during the early phase of diastole and take part to coronary perfusion (Fig. 1.5a) (38). Conversely, when the arterial system becomes sti↵er (as occurs with normal ageing or in hypertension) the pulse wave velocity increases and the production of forward and back-ward components of pulse wave occurs predominantly in systole (38,39). This condition is able to increase peak systolic pressure and reduce early diastolic pressure in ascending aorta (Fig. 1.5b) (40).

Figure 1.6: Forward and backward waves and morphology of pressure waveforms (from Saba et al. 2014 “ventricular-vascular coupling in hypertension”)

Even though these theory has been widely accepted for many ears, in many studies pa-tients with essential hypertension surprisingly did not display any sti↵ening of the carotid artery wall compared with age-matched normotensives and only young essential hyper-tensive patients had increased sti↵ness of the wall material. Hypertrophy, observed in hy-pertensive patients, was accompanied by a reduced sti↵ness of the wall material (Young’s elastic modulus) and a normal sti↵ness of the artery considered as a whole when compared at a given BP or wall stress (Figure 1.7) (41).

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Figure 1.7: Mean carotid artery elastic modulus-stress curves (from Laurent et al. 2015 “The structural factor of hypertension”)

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According to these evidence, the wall-thickening occurring as part of vascular remod-eling is not responsible for the sti↵ening of large arteries. Conversely, we should consid-ered this phenomenon as a modification of the properties of arterial wall, capable to make this structure more suited to higher values of BP. At the same time, the increase in lumen of elastic arteries, although probably passive, can cooperate in keeping a certain value of arterial compliance, expressed as:

C = V

P (1.2)

However, hypertension and aging are able to increase the local pulsatility in the prox-imal elastic arteries producing a longstanding mechanical stress in the structures of the media. This chronic hemodynamic load represents the basis for the development of biome-chanical fatigue that is associated with the loss of the organized arrangement of smooth muscles and extracellular matrix. Many authors demonstrated that elastic fibers in this condition undergo a progressive thinning and fragmentation (42,43). Degeneration of elastic fibers is a progressive phenomenon that correlates with the increase of collagen and ground substance in arterial walls. A deposition of calcium in the site of degener-ation can also occur, as demonstrated with histological analysis. Both the alterdegener-ation of collagen/elastin ratio and the activation of repair mechanism can a↵ect the mechanical properties of the large proximal arteries and be responsible for the decrease in elasticity (42,44). In physiological condition the ratio between the amount of collagen components and elastic ones remains constant thanks to the steady states occurring in production and degradation mechanisms of these elements. During hypertension, just like other disease process, inflammatory cells (macrophages and neutrophils) release both collagenases and elastases and there is an important activation of gelatinases. All these enzyme are able to active degradation mechanism and fasten the turn-over of collagen and elastin. Thus, the inflammatory response can play an important role in the deterioration of elastic properties of arteries. (33).

An interesting theory about the relationship between hypertension and arterial sti↵-ening is the role of aortic vasa vasorum. In hypertensive animal models, the analysis of peri-aortic fat displays an important process of remodeling of these arterial structures. This modification produce a reduction of flow within the aortic wall, resulting in an impairment of nutrition. The phenomenon is probably part of the small arterial remodeling discussed in the further paragraph and is supposed to lead to increased arterial sti↵ness (45).

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Despite all the evidence relating high levels of blood pressure with increased arterial sti↵ness, it is important to underline that the arterial sti↵ness can be a causal factor for the development of elevated systolic blood pressures levels. Looking at the temporal rela-tionship between carotid and aortic sti↵ness and hypertension, many authors support the precursor role of the elastic abnormality in the development of hypertension (46–48). C. Small arteries remodeling Small arteries are characterized by a lumen diameter < 350 µm. Their role in the regulation of BP levels is pivotal, as these arterial structures perform a resistance function. The simplified equation of mean arterial pressure (MAP), considering central venous pressure as almost 0 mmHg, can clarify the relationship be-tween the level of vascular resistance and arterial pressure values:

MAP ⇡ CO · S VR

Where CO represents the Cardiac Output and SVR is the Systemic Vascular Resis-tance (49). Considering the total peripheral resisResis-tance, small arteries and arterioles (lumen diameter < 100 µm) produce almost 45-50% of the overall value. Capillary bed, where vessels show a diameter ⇡ 7 µm, is further responsible for 23-30%. (50–53). According to the Poiseuille’s law, resistance is inversely proportional to the fourth power of radius:

R = 8⌘L ⇡r4

Thus, even little reduction in arterial lumen, as result of variation in vasomotor state or structural modification, produce great increase in arterial resistance (33).

In essential hypertension, small arteries undergo several modifications involving both the vasomotor tone and the structure of the vessels. Hypertensive patients display an increase in media-to-lumen ratio of the resistance small arteries as result of eutrophic re-modeling. Furthermore, a rarefaction of these structures often occurs. A major level of vasoconstriction together with a reduction of vasodilatation reserve represents the main functional e↵ects of hypertension induced vascular remodeling at this site (50–56). Cer-tainly inward eutrophic remodeling should be considered as the central element of vas-cular remodeling as it is supposed to be responsible for almost all the structural changes observed in hypertensive patients’ small arteries (53,56–58). This phenomenon a↵ects the wall of vessels and produces an increase in the thickness of media and a decrease in lumen

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and external diameter. These changes result in a greater media-to-lumen ratio, despite a preserved total amount of wall tissue, as indicated by an unchanged media cross-sectional area (Figure 1.6) (52–54). Folkow demonstrated that the increase in circumferential wall stress, generated as result of high levels of BP, represents an important driver for the devel-opment of hypertrophy. In this context, according to Lamé equation, despite a reduction in the lumen radius, the increase in media thickness without a rise in total amount of wall material is a compensatory mechanism for an e↵ective normalization of stress (54,59). Park et al. in 2001 studying with pressure arteriography resistance arteries dissected from gluteal subcutaneous tissue of hypertensive patients confirmed these characteristics. Ac-cording to this study, the inward eutrophic remodeling resulted to be the most frequent target organ damage in essential hypertension, followed by endothelial dysfunction and ventricular hypertrophy. The alterations in resistance arteries seem to precede the other structural modification induced by high BP values and probably represent the earliest form of remodeling (60).

All the features of inward eutrophic remodeling furthermore are typical of essential hypertension. Indeed, studying resistance arteries of patients with di↵erent from of sec-ondary hypertension (renovascular or aldosteronism) many authors observed a di↵erent kind of remodeling, defined “hypertrophic”. The small vessels in these conditions dis-play a more evident increase of wall material, as result of cell growth induction. The process involves hypertrophy (volume increase) and hyperplasia (cell number increase) of vascular smooth muscles cells (61,62). The progression from eutrophic remodeling to hypertrophic remodeling in patients with essential hypertension in conceivable but there are no experimental evidence supporting this theory. The conversion to a hypertrophic pattern is probably the result of the combined e↵ect of high BP and growth factors such as angiotensin II, endothelin-1 and others (63) (Figure 1.6).

There is a strict relationship between functional and structural modifications in small arteries of hypertensive patients. The same bidirectional relation, as shown in figure 1.9, occurs between the e↵ect of small vessels remodeling and the global hemodynamic.

Vasoconstriction in hypertension occurs mainly in proximal resistance arteries (55). These structures undergo both a reduction lumen diameter as e↵ect of eutrophic remod-eling and a progressive rarefaction, accounting for the most relevant part of structural increase in vascular resistance. The relationship between vasomotor state and structural remodeling has been widely investigated and according to Izzard et al., the chronic vaso-constriction is capable to induce eutrophic remodeling with consequent reduction in lumen

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Figure 1.8: Schematic drawing depicting eutrophic remodeling and hypertrophic remod-eling of resistance arteries in hypertension (Laurent et al. 2015 “The structural factor of hypertension”)

Figure 1.9: Schematic representation of the relationships between eutrophic remodeling and associated function consequences (from Laurent et al. 2015 “The structural factor of hypertension”)

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and distensibility (64). Conversely, the rise in upstream arterial resistance seem to protect partially the distal resistance arteries from the e↵ects of chronic elevation in blood pressure levels (55). Folkow in 1984 made the first observation of the relationship between hyper-tension and vasodilator reserve. He studied the vascular resistance after several vasodila-tor stimuli (such as ischemia or exercise) in animal models and humans and succeeded in demonstrating that even at maximal levels of vasodilation the minimal resistance to flow in hypertensive subjects was increased (54,55). After this first experiment, several author confirmed the Folkow’s results. Furthermore, this evidence confirm a major role of structural increase in vascular resistance than functional alterations as in this experimen-tal setting the influence of vasomotor activity is negligible. Interesting, media-to-lumen ratio calculated in subcutaneous small resistance arteries displays a strict positive correla-tion with vasodilator reserve of both forearm and coronary vascular beds. This evidence demonstrate that small arteries remodeling is a systemic alteration occurring contemporary in di↵erent territories with a particular risk for coronary circulation (65).

The structural changes of small resistance arteries are related to myogenic tone in a bidirectional manner (Figure 1.7) (54,55,64,66). An increase in myogenic tone reduces lumen diameter at higher pressures. This phenomenon play a determinant role for blood flow autoregulation as it represents a way to stabilize capillary pressure (33). In response to elevated levels of circumferential wall stress, the entity of myogenic reflex is inversely related to the diameter of the vessel, displaying a greater constriction in arterial structures with a smaller lumen. Precapillary arteries represent the vessel with the greatest myo-genic response to mechanical stress (26). The arteriolar circumferential wall stress, thanks to this autoregulatory system, is kept at normal or reduced levels (67). As discussed in the previous part of the paragraph, circumferential wall stress represents an important trigger for hypertrophic response of arterial wall. Indeed a normal myogenic response, together with an eutrophic arterial remodeling, are able to maintain normal values of mechanical stress an avoid the induction of cellular growth. Conversely, the possibility to prevent an increase in wall material represents the mechanism able to keep eutrophic remodeling in essential hypertension (Figure 1.7) (33). According to this theory, there are evidence about alteration in myogenic response in Type 2 diabetes mellitus and secondary hyperten-sion, resulting in an impossible normalization of circumferential wall stress. In all these conditions, indeed, there is no limitation in the main stimulus for cellular growth and the prevalent form of remodeling is hypertrophic (68). The above evidence furthermore con-firm the theory that the myogenic response of the vessels is a key determinant factor in

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Figure 1.10: The approximate mean of the relationship between mean arterial pressure (MAP) and resistance at maximal vasodilation in normotensive and hypertensive humans (from Folkow 1995 “Hypertensive structural changes in systemic precapillary resistance vessels”)

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the processes that mediate structural changes in hypertension (64). However, in the de-velopment of hypertension, the altered myogenic tone probably plays a minor role than the vasoconstriction induced by neurohumoral stimuli. Even though vascular remodeling should be considered as a systemic phenomenon, the mechanisms of flow autoregulation depends on regional circulation and the myogenic reflex can assume di↵erent roles (55). For instance, in the renal circulation, myogenic tone is the main factor in the development of autoregulatory response and this mechanism is able to create a protection of glomerular structures from hypertensive injury (69).

Several evidence both in humans and animals confirm that a progressive reduction in distensibility of small resistance arteries occurs in hypertension natural history. Assuming unchanged mechanical characteristics of wall material despite remodeling, the reduced distensibility may be considered as the consequence of wall thickening (Figure 1.7). This impairment in mechanical property of small resistance arteries can contribute to reduction of lumen at high BP levels, further increasing the structural component of total peripheral resistance and limiting blood flow to target organs (33). However, according to Folkow, the geometry and distensibility of small arteries tend to be altered to an ideal extent. As result, when hypertension induced modifications in smooth muscle activity occurs, the flow to organs remains in normal range, despite increase in both trans-mural pressures and resistance (55).

D. Capillaries rarefaction Rarefaction corresponds to the reduction in the number of in-terconnected small arteries and capillaries. Evidence of capillary rarefaction in human es-sential hypertension has been obtained by in vivo capillaroscopy of the nail fold microvas-culature and could represent an early structural abnormality in borderline hypertension and in o↵spring from hypertensive parents (70–72) (Figure 1.10). Prewitt et al. in 1982 first speculated that hypertension-induced vasoconstriction leads initially to reversible, func-tional rarefaction (non-perfusion of capillaries), later followed by irreversible structural rarefaction (anatomic absence of capillaries) (73). According to an incremental number of new evidence, increased myogenic tone and arteriolar vasoconstriction are mechanism occurring in order to create a partial protection of downstream capillaries. Despite their positive compensatory role, these two mechanism are also capable to produce functional rarefaction, ultimately leading to structural rarefaction (70). Thus, structural rarefaction could be considered the result either of a progressive degeneration or of insufficient angio-genesis. Angiogenesis can be a↵ected because of a reduction in bioavailability of nitric

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Figure 1.11: Capillary density before and after venous congestion in normotensive pa-tients, patients with established hypertension and patients with borderline hypertension (from Antonios et al. 2001 “Structural skin capillary rarefaction in essential hyperten-sion”)

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oxide. For instance, the alteration of shear stress in non-perfused micro-vessels is sup-posed to decreased nitric oxide production and further induce endothelial cell death via apoptosis and microvascular rarefaction (74).

Although rarefaction of arterioles will increase vascular resistance by elimination of parallel conductance channels, capillary rarefaction may be a compensatory mechanism to balance the blood flow-to-metabolism ratio. If all the resistance increase were in the ar-terioles, the capillary pressure and flow would be normal in the hypertensive animals (73). However, the pressure measurements of Bohlen et al. show a uniform elevation through-out the microcirculation (75). The elevated pressure at the capillary level, if uncontrolled, would result in blood flow in excess of the metabolic needs of the tissue. To control the excess pressure allowed to pass through the arterioles, the capillary resistance must be pro-portionally elevated. Inasmuch as the capillaries cannot constrict, the resistance through the capillary bed can only be elevated at the level of the terminal arterioles by a reduction in capillary density. The result is that the total flow through the muscle is kept normal, the tissue oxygen tension is normalized, and as previously suggested by Bohlen, he surface area for filtration is reduced to balance the increased capillary pressure (73,75). Despite the compensatory role of the rarefaction mechanism, capillary rarefaction, associated with small artery remodeling, impairs tissue perfusion and organ function via three main mech-anisms: the impairment of nutritive support to tissues when there is an increase in demand, the protection of capillary bed from the deleterious e↵ects of longstanding high BP levels and the increase resistance to flow and perfusion (76). For instance, intramyocardial coro-nary rarefaction is related to a reduction in tissue perfusion, increasing the risk of ischemia when there are conditions of high metabolic and oxygen demand (77).

1.2 Hypertension and heart failure

1.2.1 Definition and classification

Heart Failure is a clinical syndrome characterized by typical symptoms (i.e. breathless-ness, ankle swelling and fatigue) that may be accompanied by signs (i.e. elevated jugu-lar venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/ or ele-vated intra-cardiac pressures at rest or during stress (78). Beyond the clinical, instrumental and laboratory diagnostic criteria for Heart Failure, according to the European Society of

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Cardiology Guidelines 2016, the main terminology used to classify Heart Failure is based on the measurement of Left Ventricular Ejection Fraction. HF comprises a wide range of patients, from those with reduced LVEF (typically considered as 40%; HF with re-duced EF, HFrEF) to those with normal LVEF (typically considered as 50%; HF with preserved EF, HFpEF) to those patients with an LVEF in the range of 40–49% represent a ‘grey area’, which we now define as HFmrEF. Di↵erentiation of patients with HF based on LVEF is important due to di↵erent underlying aetiologies, demographics, co-morbidities and response to therapies (78)

Figure 1.12: Morphological characteristics of HFrEF (left) and HFpEF (right) in gross anatomy (upper) and echocardiography (lower) (modified from Guazzi et al. 2017 “Car-diopulmonary exercise test: What is its value?’)

Even though the acceptance of HFpEF in official nomenclature is quite recent (79,80), Gandhi et al. as early as 2001 first reported a case series of patients presenting with hyper-tensive acute pulmonary oedema and preserved left ejection fraction, both during the acute phase and after successful treatment of their acute presentation, demonstrating that these patients constituted a distinct entity (81). Since this first observation, intense research ac-tivity has been taking place to better identify the characteristics of patients with HFpEF and the strict relationship between this condition and several risk factors. Heart failure

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with preserved ejection fraction is actually defined as a complex syndrome characterized by heart failure signs and symptoms and a normal or near-normal left ventricular ejection fraction where multiple cardiac and vascular abnormalities, cardiovascular risk factors and overlapping extra-cardiac comorbidities may be present in various combinations (82). All these elements overall participate in the determination of the extreme heterogeneity of the HFpEF patients that therefore may be considered the main characteristic of the syndrome (Figure 1.12) (83).

Figure 1.13: Heterogeneity in HFpEF (from Senni et al. 2014 “New strategies for Heart Failure with Preserved Ejection Fraction: the importance of targeted therapies for heart failure phenotypes”)

Extra-cardiac abnormalities and comorbidities, such as hypertension, atrial fibrilla-tion, diabetes, renal or pulmonary disease, anemia, obesity, and deconditioning, may con-tribute to the HF-PEF syndrome. Low-grade inflammation with endothelial dysfunction, increased reactive oxygen species production, impaired nitric oxide (NO) bioavailability,

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and the resulting adverse e↵ects on cardiac structure and function are considered a mech-anistic link between frequently encountered comorbidities and the evolution and progres-sion of HFpEF (82).

1.2.2 Epidemiology

Hypertension represents a leading risk factor for the development of symptomatic heart failure. The relationship between elevated systolic and diastolic pressure values and the manifestations of myocardial failure has been widely investigated. The observational stud-ies based on the Framingham cohort provide us with the most relevant data about the nat-ural history of heart failure and his link with blood-pressure status. In the first analysis, hypertension was arbitrarily defined as two systolic pressure of 160 mmHg or greater or two diastolic pressure of 95 mmHg or greater while normotension was defined as both sys-tolic pressures below 140 and both diassys-tolic pressures below 90. The diagnosis of heart failure was entertained on clinical grounds, chest x-ray and total vital capacity (84,85). According to the data analysis of the first 16 years follow-up observation and using the mentioned criteria, Kannel et al. in 1972 observed that the risk for hypertensive patients to develop heart failure was six times that for normotensive patients. Furthermore, 75% of those who acquired heart failure during the 16 years had prior hypertension (85). In agreement with these conclusions, hypertension is now considered the factor that carries the highest attributable risk for heart failure in the general population (86). Together with the attributable risk, the calculation of lifetime risk is useful for the estimation of cumu-lative risk of developing a disease during the remaining lifespan of an individual with an important application in several conditions (i.e. cancer, dementia, stroke, coronary artery disease) allowing the assessment of the burden of a disease in a population (87). In 2002, Lloyd-Jones et al. calculate the lifetime risk of heart failure, considering the subjects of the Framingham cohort who participated in an examination between 1971 and 1996. They stratified subjects according to the blood pressure in three groups: systolic<140 mmHg and diastolic<90 mmHg; systolic from 140-159 mmHg and diastolic from 90-99 mmHg; almost 160 mmHg of systolic pressure or 100 mmHg of diastolic pressure. They appreci-ated a 2-fold gradient in remaining lifetime risk for heart failure from the lowest to highest blood pressure (88). In other terms, considering a 60 years-old man with blood pressure less than 140 mmHg having a lifetime risk of 17.4%, for a man of the same age with a blood pressure of 160 mmHg or greater the value rises to 29%. Similarly, for 60 years-old

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woman the rise of lifetime risk goes from 14.4% to 27% (88,89). These observations of the strict relationship between hypertension and symptomatic heart failure can be a func-tion of both the wide prevalence of elevated arterial pressures in ageing adults, and the magnitude of the adverse impact high blood pressure has for the manifestation of heart failure (89). Considering the international classification of HF based on Ejection Frac-tion, in terms of prevalence, according to the data from the Olmsted County cohort, 73.6% of patients with HFrEF had hypertension compared with 89.3% of patients with HFpEF (90). In 2009, D.S. Lee et al., in a sub-analysis of Framingham Heart Study, examined pre-onset and time-of-onset characteristics, after age and sex adjustment as predictors of HFpEF versus HFrEF. They included a participant with incident HF occurring between 1981 and 2004 with an evaluation of LVEF. According to this analysis, pre-onset hyper-tension carries a more than two-fold increased odds of HFpEF versus HFrEF. Moreover, at the onset of heart failure, higher systolic blood pressure increases the odds of HFpEF versus HFrEF by 13% for each 10-mmHg increase (91) (Figure 1.14 - 1.15).

Figure 1.14: Age/sex-adjusted ORs of HFPEF using pre-onset factors. OR > 1: greater odds of HFPEF (from DS Lee et al. 2009 “Relation of Disease Pathogenesis and Risk Factors to Heart Failure With Preserved or Reduced Ejection Fraction”)

Later, in 2010, Lam et al. in a meta-analysis delineated the epidemiological char-acteristics of patients with HFpEF. They demonstrated that patients with this condition are usually older, more often female and with a high prevalence of atrial fibrillation and non-cardiovascular co-morbidities. Focusing on cardiovascular risk factors, hypertension

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Figure 1.15: Age/sex-adjusted ORs of HFPEF using characteristics at time of HF onset. OR>1: greater odds of HFPEF (from DS Lee et al. 2009 “Relation of Disease Pathogen-esis and Risk Factors to Heart Failure With Preserved or Reduced Ejection Fraction”) represents certainly the most prevalent one while the prevalence of others was variable de-pending on study setting and diagnostic criteria for the condition (92). Recently, in 2016, Ho et al. examined HF subtype-specific risk profiles by assembling an international con-sortium of four longitudinal community-based cohorts, each of which classified incident HF cases as HFpEF or HFrEF. They observed that the relative risk of HFpEF increased by 14% per 20 mmHg systolic blood pressure and by 42% if taking antihypertensive treat-ment (93)

1.2.3 Pathophysiology

All the epidemiological data are coherent with the current idea that individuals with hyper-tension are at significantly higher risk of developing HFpEF and can be classified as hav-ing stage A HFpEF accordhav-ing to American College of Cardiology Foundation/American Heart Association stages of HF (86,94). Following the natural history of the condition with ACC/AHA classification, asymptomatic hypertensive heart disease represents the stage B HFpEF, and the “transition to failure” with the development of clinically manifest stage HFpEF is an area of intense research in order to identify a mechanism for progression, representing a target for therapeutic or preventive strategies.

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Figure 1.16: ACC/AHA classification of chronic Heart Failure (from SA Hunt et al. 2011 “ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary”)

A. Left ventricular remodelling and dysfunction Arterial hypertension is strictly as-sociated with cardiac remodeling, a complex phenomenon involving changes in left ven-tricular structure and geometry that occurs after myocardial injury and overload (95). In response to the increased afterload imposed by hypertension via elevated arterial pressure and total peripheral resistance, the left ventricular wall thickens. This mechanism can be seen as a compensatory way to minimize wall stress but can lead to left ventricular hypertrophy with concentric pattern (increase in cardiac mass at the expense of cham-ber volume) (96). By a functional point of view, this remodeling phenotype is associated with diastolic dysfunction as evidenced by diminished early diastolic filling and left atrial enlargement (97,98) (Figure 1.17).

The association between left ventricular concentric hypertrophy and diastolic dysfunc-tion represents the main myocardial structural and funcdysfunc-tional abnormality associated with hypertensive heart disease and Heart failure with preserved Ejection Fraction (97,99). Thus, these pathological conditions can be seen as a “continuum”. Sustained pressure overload, indeed, leads to the progression of diastolic dysfunction and the decompensat-ing of the concentric remodeled left ventricle, producdecompensat-ing the transition to the Heart failure with preserved Ejection Fraction. In contrast, when volume overload is sustained, LV dilatation progresses, the eccentric remodeled LV decompensates, and HF with reduced ejection fraction (HFrEF) occurs (Figure 1.17) (100).

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Figure 1.17: Algorithm for diagnosis of left ventricular (LV) diastolic dysfunction in in-dividuals with normal LV ejection fraction and no myocardial disease suggested by the American Society of Echocardiography and the European Association of Cardiovascular Imaging (from W. Nadruz 2017 “Diastolic Dysfunction in Hypertension”)

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Figure 1.18: Staging of Hypertensive Heart Disease (from H. Messerli et al. 2017 “The transition from hypertension to Heart Failure”)

Beyond this “classic” model, the structural and functional alterations moving the tran-sition from hypertension to heart failure are much more complex and nowadays still un-clear. Focusing on remodeling, the role of ventricular hypertrophy with the eccentric pattern is an intense field of research. Looking at the hypertensive population, great het-erogeneity has been reported in the prevalence of LV geometric patterns with 25% of the patients presenting eccentric LV hypertrophy (101) (Figure 1.17).

This di↵erence seems to have a prognostic value: subjects with concentric hypertro-phy are predisposed to the highest cardiovascular risk while those with eccentric hyper-trophy are at an intermediate risk between concentric hyperhyper-trophy and normal geometry (102). On the other hand, in Olmsted County Cohort, one the largest and most compre-hensive epidemiologic evaluations of cardiac structure and function in Heart Failure with preserved Ejection Fraction, LV eccentric hypertrophy was noted in 16% of participant (103). There are no accepted theories about the development of eccentric hypertrophy in the natural history of hypertension. Other factors than hemodynamic pressure overload, are supposed to play a role in the development of a di↵erent cardiac remodeling: intravas-cular volume status, levels of RAAS and sympathetic drive activation, ethnicity and many others. Interestingly, results from the Losartan Intervention For Endpoint Reduction in

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Figure 1.19: Pathways of LV remodeling progression secondary to systemic hypertension (from W Nadruz 2015 “Myocardial remodeling in hypertension”)

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Hypertension (LIFE) study demonstrated that treatment with losartan or atenolol induced conversion from concentric to eccentric hypertrophy in 34% of individuals with hyperten-sion and baseline concentric hypertrophy. Therefore, the presence of an eccentric pattern may represent a di↵erential response to anti-hypertensive medications (102,104). By a functional point of view, impairment in contractile function, despite a preserved ejection fraction, is nowadays considered an important driver of the transition from hypertensive heart disease to heart failure with Preserved Ejection Fraction, together with diastolic dys-function. The evidence of alteration in systolic performance in patients with HF with Preserved Ejection Fraction in terms of global longitudinal strain, quantified by speckle tracking echocardiography, is reported in several studies (105–107). Furthermore, myocar-dial contractile dysfunction is considered a prognostic marker in these patients, correlating with increased mortality, hospitalization for heart failure, cardiovascular death or aborted cardiac arrest (108). The alteration in systolic cardiac contractile performance seems to be an early phenomenon in the linear progression from hypertension to HF with preserved ejection fraction. Thus, the abnormal regional systolic function was reported in hyper-tensive heart disease with concentric cardiac remodeling, both with echocardiography and MRI (109,110). In the last years, the focus on the role of eccentric remodeling and systolic dysfunction in heart failure with preserved ejection fraction has been arousing great inter-est in cardiovascular research. Recently Katz et al. succeeded in characterizing the subset of patients with eccentric hypertrophy and heart failure with preserved ejection fraction. Compared to an individual with concentric hypertrophy, these patients have lower blood pressure, better kidney function, higher LV compliance, but lower contractility (111). B. Left atrial remodelling and dysfunction Left atrium structural remodeling is the complex phenotypic expression that results from changes in left atrial size, shape and architecture whose clinical hallmark is represented by Left atrium enlargement (112). This alteration may be considered as an expression of global cardiac remodeling and shows a strong correlation with both Left ventricular hypertrophy and diastolic dysfunc-tion (113,114). In hypertensive populadysfunc-tion, the prevalence of left atrial enlargement is high ranging from 46%, as observed in data from LIFE trial, to 54.9%, according to the observational study of Su et al. in the Chinese hypertensive population (115,116). Atrial remodeling seems to occur before left ventricular hypertrophy and to be much more common (up to three-fold), as an early marker of hypertensive heart disease (116). In hypertensive patients with Heart Failure with preserved Ejection Fraction, compared to

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the hypertensive population without heart failure, left atrial enlargement is more prevalent and left atrial volume is 40% larger (117). Beyond the structural remodeling, looking at data from PARAMOUNT trial, HFpEF patients show a lower atrial function, evaluated with systolic atrial strain, involving all the three phases of the atrial cycle (reservoir, con-duit and pump) (Figure 1.20). The deteriorating of atrial function in these patients occurs independently of LA dilatation or remodeling caused by Atrial Fibrillation (118). This functional alteration of atrium seems to be related with the inability to increase left an atrial contribution to left ventricular filling during the e↵ort, a cofactor for the raise of filling pressure and the development of breathless in patients with HFpEF during exercise (119). Furthermore, left atrial dysfunction represents an important prognostic factor both in hypertensive patients and in patients with HFpEF (120,121). The development of atrial fibrillation may be considered the ultimate expression of atrial dysfunction in patients with HFpEF as an intimate relationship where one condition begets the other. Atrial fibrillation indeed was found to occur in 60% of patients with HFpEF during their disease (122). C. Myocardial fribrosis and biochemical alterations A substantial increase in fibrillar collagen deposition has been observed in the cardiac ventricles of animals and humans with arterial hypertension and represents an important histological feature of hyperten-sive heart disease (123). This process occurs as a result of both increased collagen type I and III syntheses by fibroblasts and unchanged or decreased extracellular collagen degra-dation (124,125). Hemodynamic and nonhemodynamic factors are involved in this pro-cess, and several experimental studies provide evidence that the RAAS system can medi-ate myocardial fibrosis independently of a mechanical load either directly or via specific growth factors (126,127). Fibrosis is a slow progressive phenomenon that is related to diastolic dysfunction leading to myocardial sti↵ening with obstacle both in suction and filling (128,129). Together with myocardial atrophy and necrosis, the alteration in the ex-tracellular matrix may contribute to the impairment of systolic performance and represents a structural basis of myocardial failure (130–132). In the context of HFpEF indeed, my-ocardial fibrosis is an important histological alteration (133) and is nowadays considered one of the most relevant pathophysiological features (134). Furthermore, the estimation of extracellular matrix with Cardiac Magnetic Resonance T1 Mapping is a useful marker of HFpEF associated with adverse outcomes (135). Beyond the quantity of collagen de-position, recently the evaluation of collagen cross-linking, as the ratio between insoluble and soluble collagen in endomyocardial biopsies, was found to be increased in patients

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Figure 1.20: Comparison of left atrial function (reservoir, conduit and pump function) between healthy controls (gray bar) and HFpEF patients (black bar) (from AB Santos 2014 “Impaired left atrial function in heart failure with preserved ejection fraction”)

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with hypertensive heart failure compared with controls and associated with a higher risk of subsequent hospitalization for heart failure (136). Together with collagen deposition, alterations in Titin, in term of isoform and phosphorylation status, seem to account for a larger portion of left ventricular sti↵ness at short sarcomere lengths in patients with HF-pEF compared with controls and hypertensive patients without heart failure (137) (Figure 1.21).

Figure 1.21: Collagen-dependent and titin-dependent myocardial stress at a sarcomere length (SL) of 2.6 µm (from Zile et al. 2015 “Myocardial Sti↵ness in Patients with Heart Failure and a Preserved Ejection Fraction”)

D. Peripheral factors Hypertension is associated with many modifications of vascular structures, including thickening of the walls of large elastic and muscular arteries and remodeling of small muscular arteries with an increased wall to lumen ratio (17). Thus, hypertension is viewed as an accelerated form of vascular ageing that leads to macrovascu-lar sti↵ening with augmentation in both aortic sti↵ness and arterial pulse wave reflection velocity, key determinants of the central systolic pressure (138,139). The interplay be-tween arterial hypertension and arterial sti↵ening is complex, and the evidence supports

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the idea that one condition can generate and worsen the other (140). By functional points of view, in patients with arterial hypertension in order to maintain a maximal cardiac ef-ficiency, there is a proportional augmentation in both arterial and ventricular end-systolic sti↵ness with a preserved vascular-ventricular coupling (141). Looking at patients with HFpEF, they display similar alterations in term of arterial sti↵ness and vascular ventricu-lar coupling compared with elderly hypertensive non-failing patients (117,142,143).

Figure 1.22: [A] Left ventricular end systolic elastance (Ees); [B] A normal adult has relatively a coupling ratio around unity; [C] older aged, hypertensive and HFpEF have increases in ventricular and arterial elastance (from BA Borlaug et al. 2008 “Ventricular-vascular coupling in Heart Failure”)

However, during exercise, as a result of limitations both in chronotropic-contractile re-serve and vasodilation, they show a markedly impaired ventricular-arterial coupling, that is related to reduced exercise capacity (144). The combined end-systolic and arterial sti↵en-ing indeed, by limitsti↵en-ing the mechanisms of cardiovascular reserve and augmentsti↵en-ing systolic pressure sensibility to load, can exacerbate diastolic abnormalities and potentially raise cardiac energy demand with a consequent deterioration of cardiac performance during e↵ort (145). Beyond macrovascular alterations, alterations in microcirculation are an im-portant field of research in pathophysiology of heart failure with HFpEF. Compared with hypertensive subjects matched for age, sex and diabetes, HFpEF patients demonstrated a lower resting endothelial-related microvascular vasomotion and impaired reactive hyper-emia (146). Microvascular dysfunction may result in impaired stress-induced myocardial perfusion and coronary microvascular rarefaction, playing a role in limiting systolic and diastolic reserve in HFpEF (133,147). Furthermore, the alteration in microcirculation may

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Figure 1.23: Proposed role of endothelial and microvascular dysfunction in HFpEF (from G. Giamouzis 2016 “Growing Evidence Linking Microvascular Dysfunction with Heart Failure with Preserved Ejection Fraction”)

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be involved in a reduction in peripheral oxygen extraction observed in HFpEF and con-tribute to the exercise intolerance (148). According to these observations, a unifying, but untested, the theory of the pathophysiology of HFpEF suggests that comorbidities (i.e. Hypertension) lead to a systemic inflammation, which triggers endothelial and microvas-cular dysfunction, moving the transition to failure (149) (Figure 1.23).

1.3 Cardio-pulmonary exercise test and exercise stress

echocar-diography

1.3.1 Cardio-pulmonary exercise test (CPET)

CPET involves the measurement of respiratory gas exchange breathe-by-breathe: oxygen uptake (VO2), carbon dioxide output (VCO2), and minute ventilation (VE), in addition to monitoring electrocardiography, blood pressure, and pulse oximetry, during a symptom-limited maximal exercise tolerance test. The technique provides a complete evaluation of the exercise performance and is capable to analyze the integrative activity of the pul-monary, cardiovascular and skeletal muscle systems during e↵ort. The global assessment is indeed more adequate than the evaluation of the single system function in describing the physiological adaptation to exercise (150). Furthermore, in the context of cardiopul-monary disorders, where exercise intolerance is a major clinical feature from an early stage, CPET enables the clinician to quantify the functional impairment, di↵erentiate the cardiac from pulmonary disorders and objectively determine targets for therapies (151). For these reasons, nowadays the application of CPET involves di↵erent fields of clini-cal practice, and the major recommendations are represented by evaluation of exercise tolerance and undiagnosed exercise intolerance (i.e. unexplained dyspnea); evaluation of respiratory diseases-symptoms; preoperative assessment; exercise evaluation and pre-scription for pulmonary rehabilitation; quantification of impairment-disability and finally evaluation of patients with cardiovascular diseases (150,152) (Figure 1.24).

The application of CPET in cardiology was introduced in the early 1980s by Weber et al, whose work provided the landmark classification of patients with HF with reduced ejection fraction (HFrEF) based on peak oxygen consumption (VO2), from A (peak VO2 > 20 ml/kg/min) to D (peak VO2 < 10 ml/kg/min) through B (peak VO2 15 ml/kg/min) and C (peak VO2 < 15 and 10 ml/kg/min) (153). Few years later Mancini et al.

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demon-Evaluation of exercise tolerance

• Determination of functional impairment or capacity (peak V˙ O2)

• Determination of exercise-limiting factors and pathophysiologic mechanisms

Evaluation of undiagnosed exercise intolerance

• Assessing contribution of cardiac and pulmonary etiology in coexisting disease • Symptoms disproportionate to resting pulmonary and cardiac tests

• Unexplained dyspnea when initial cardiopulmonary testing is non-diagnostic

Evaluation of patients with cardiovascular disease

• Functional evaluation and prognosis in patients with heart failure • Selection for cardiac transplantation

• Exercise prescription and monitoring response to exercise training for cardiac rehabilitation (special circumstances; i.e., pacemakers)

Evaluation of patients with respiratory disease

• Functional impairment assessment (see specific clinical applications) • Chronic obstructive pulmonary disease

- Establishing exercise limitation(s) and assessing other potential contributing factors, especially occult heart disease (ischemia)

- Determination of magnitude of hypoxemia and for O2 prescription

- When objective determination of therapeutic intervention is necessary and not adequately addressed by standard pulmonary function testing

• Interstitial lung diseases

- Detection of early (occult) gas exchange abnormalities - Overall assessment/monitoring of pulmonary gas exchange - Determination of magnitude of hypoxemia and for O2 prescription - Determination of potential exercise-limiting factors

- Documentation of therapeutic response to potentially toxic therapy • Pulmonary vascular disease (careful risk–benefit analysis required)

• Cystic fibrosis

• Exercise-induced bronchospasm

Specific clinical applications

• Preoperative evaluation Lung resectional surgery Elderly patients undergoing major abdominal surgery Lung volume resectional surgery for emphysema (currently investigational)

• Exercise evaluation and prescription for pulmonary rehabilitation • Evaluation for impairment–disability

• Evaluation for lung, heart–lung transplantation

Figure 1.24: Indication for CPET according to the guidelines of American Thoracic So-ciety (ATS) and the American College of Chest Physician (ACCP) (modified from 2002 ATS/ACCP statement on cardiopulmonary exercise testing