Cardiac Fibrosis in Hypertension Tracey Keteepe-Arachi and Sanjay Sharma* Department of Cardiovascular Sciences, St George’S University of London, UK

Keteepe-Arachi and Sharma. J Hypertens Manag 2017, 3:023 Journal of DOI: 10.23937/2474-3690/1510023 Volume 3 | Issue 1 Hypertension and Management ISSN: 2474-3690 Review Article: Open Access

Cardiac Fibrosis in Hypertension Tracey Keteepe-Arachi and Sanjay Sharma* Department of Cardiovascular Sciences, St George’s University of London, UK

*Corresponding author: Sanjay Sharma, MD, Department of Cardiovascular Sciences, St George’s University of London, Cranmer Terrace, London, UK, Tel: +442087255939, Fax: +442082979100, E-mail: [email protected]

Abstract [1,2]. Hypertensive heart disease (HHD) represents a con- stellation of sequelae including left ventricular hypertrophy Myocardial fibrosis is the hallmark of myocardial remodelling (LVH), diastolic dysfunction, heart failure and arrhythmia. found in hypertensive individuals. This process adversely affects the outcomes of such patients and results in diastolic Myocardial fibrosis, commonly associated with ischaemic and systolic cardiac dysfunction, electrical dysrhythmia and scar formation, is an important phenomenon in the devel- potentially sudden death. Collagen metabolism has been opment of HHD. highlighted as the primary mechanism by which fibrosis is regulated. However, there are many other facets to the Pathophysiology pathophysiology of myocardial fibrosis including mechanical, cellular and hormonal influences, which may guide therapy Normal myocardium consists of cardiomyocytes and and thereby determine prognosis. extracellular matrix which is composed of fibrillar collagen. Cardiac adaptation in response to hypertension is a Introduction complex and multifaceted process involving cardiomyocyte hypertrophy, fibroblast activation and extracellular Hypertension remains one of the most significant mod- matrix expansion. Mechanisms by which myocardial fi- ifiable causes of morbidity and mortality in the UK. The brosis occurs are being elucidated; both haemodynamic global prevalence of hypertension in the year 2000 was al- and neurohormonal, and various circulating biomarkers most one billion and is set to increase by 29% to 1.56 billion have been identified. In addition, collagen metabolism, by 2025, making the condition a major public health issue which is fundamental to the development of myocardial

Figure 1: Markers of collagen metabolism. PIP = carboxy-terminal propetide of procollagen type, PIIIP = carboxy-terminal propetide of procollagen type III, CITP = carboxy-terminal telopeptide of collagen type I, TIMP-1 = tissue inhibitor of matrix metalloproteinases type I.

Citation: Keteepe-Arachi T, Sharma S (2017) Cardiac Fibrosis in Hypertension. J Hypertens Manag 3:023. doi.org/10.23937/2474-3690/1510023 ClinMed Received: October 22, 2016: Accepted: February 11, 2017: Published: February 14, 2017 International Library Copyright: © 2017 Keteepe-Arachi T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. DOI: 10.23937/2474-3690/1510023 ISSN: 2474-3690 fibrosis, can be evaluated by using markers of collagen Mechanical factors such as pressure overload affecting turnover [3,4]. the left ventricle, are implicated in triggering increased collagen synthesis and reduced collagenase activity [15]. In hypertensive heart disease an excess of collagen Concomitant myocyte hypertrophy further alters myo- is found in the extracellular matrix of the myocardium. cardial architecture. This is thought to be due to an imbalance in collagen metabolism resulting from both increased synthesis as well Morphological features secondary to hypertension as normal or reduced degradation [5,6]. Measurements and an increase in CVF include reactive interstitial fi- of collagen turnover are divided into markers of collagen brosis, perivascular fibrosis and reparative fibrosis. The synthesis [carboxy-terminal propeptide of procollagen thickening of pre-existing collagen fibres and the ap- type I (PIP), carboxy-terminal propeptide of procollagen pearance of an increased number of collagen fibres is type III (PIIIP)], markers of collagen degradation [car- termed reactive fibrosis. Perivascular fibrosis indicates boxy-terminal telopeptide of collagen type I (CITP)], collagen accumulation within the adventitia of arterioles markers of inhibitors of collagen degradation [tissue and arteries. Reparative fibrosis occurs because cardiac inhibitor of matrix metalloproteinases type I (TIMP-1)] myocytes are not able to replicate or regenerate as they and markers of fibroblast activity [transforming growth are terminally differentiated, and so fibrillar collagen re- places lost myocytes after necrosis, forming areas of scar factor β1 (TGF β1)] [7] (Figure 1). [6]. Due to adaptation to myocyte necrosis and subse- These markers are altered in hypertensive patients [8]. quent loss of parenchymal tissue, reparative fibrosis acts Many studies have demonstrated that in hypertensive to maintain structural integrity of cardiac tissue. individuals with LVH, serum PIP was found in greater quantities than in normotensive counterparts [5,9,10]. Left Ventricular Hypertrophy In addition these raised levels of PIP corresponded to Hypertension is a pivotal factor in the development increased collagen volume fraction (CVF) found on en- of left ventricular hypertrophy (LVH), which occurs as domyocardial biopsy as well as a reduction in levels cor- a compensatory mechanism to reduce wall stress. In- responding to regression secondary to antihypertensives creased after load causes cardiomyocyte hypertrophy, [11]. In hypertensive individuals with echocardiograph- fibroblast stimulation and collagen synthesis [16]. ic signs of diastolic dysfunction a significant increase in TIMP I was demonstrated when compared to normal Myocardial remodelling ensues with a resultant in- controls [12]. crease in fibrous tissue formation. Athletes also exhibit LVH yet do not suffer from cardiac dysfunction imply- Upregulation of the procollagen type I gene and re- ing that the presence of LVH is not the primary determi- duced collagenase activity have been demonstrated in nant, but the degree of myocardial fibrosis. Physiological experimental research and animal studies [13,14]. LVH represents the normal response to exercise and is

Figure 2: Diagrammatic representation of the classification of left ventricular hypertrophy.

Keteepe-Arachi and Sharma. J Hypertens Manag 2017, 3:023 • Page 2 of 8 • DOI: 10.23937/2474-3690/1510023 ISSN: 2474-3690 a mechanism by which cardiac output matches demand the main determinant of LVH, which occurs as a direct which is not the case in pathological LVH [17]. result of increased wall stress due to increased cardiac workload. Left ventricular hypertrophy serves to relieve The presence of LVH, detected by electrocardiogram wall tension and thus preserve systolic ventricular func- or echocardiogram is a strong independent risk factor tion. Stimulation of procollagen gene expression, colla- for cardiovascular morbidity and mortality. The reper- gen protein synthesis, collagen deposition and ultimately cussions of hypertension and LVH include development fibrosis are the consequences of chronic pressure over- of atrial fibrillation and potentially fatal ventricular ar- load [3,25]. When exposed to mechanical load, cardi- rhythmia and chronic heart failure [18]. Concentric ac fibroblasts demonstrate an increase in collagen type LVH is a milestone on the journey towards heart failure. I synthesis and a reduction in collagenase expression Excluding age, LVH is the main predictor of adverse car- [15]. The importance of the pressure load mechanism is diovascular outcomes in hypertensive patients. It is an demonstrated by a study by Verdecchia, et al. where hy- independent risk factor for heart failure, cerebrovascu- pertensive patients were divided into two groups: usual lar disease, coronary heart disease and sudden death [2]. control (SBP < 140 mmHg) versus tight control (SBP < Importantly, intervention with antihypertensive treat- 130 mmHg) and the rate of electrocardiographic LVH ment has been shown to reduce the risk of potential ad- was assessed at 2 year follow up. The tight control group verse cardiovascular events in these patients due to their had a rate of 11.4% and the usual control group a rate beneficial effects on left ventricular mass [19,20]. of 17% (p = 0.013) suggesting that progression to LVH Patterns of Left Ventricular Hypertrophy could be reduced with more rigorous control of systolic blood pressure [26]. The increased LV mass response to raised blood pressure is varied among individuals. For example, signifi- Both in vitro and in vivo experiments have demon- cant racial variability exists, with blacks exhibiting great- strated that mechanical load influences collagen me- er increases in LV mass and worse diastolic dysfunction tabolism. The collagen volume fraction (CVF) has been when exposed to comparable levels of hypertension in shown to be significantly increased in biopsy samples contrast to white counterparts [21,22]. and post mortem specimens of patients with hypertensive heart disease compared to samples from normoten- In hypertensive patients, LV mass is increased due sive individuals [27]. to left ventricular wall thickening and/or chamber dilatation [23]. These two patterns of response have been The effects of transmural gradients of wall stress are classified according to echocardiographic criteria using highlighted by a study by Tanaka, et. al. which indicat- relative wall thickness (RWT) as the variable param- ed an increase in CVF from the outer to the inner third eter. RWT is calculated as 2x posterior wall thickness/ of the left ventricular wall [28]. Querejeta, et al. also ob- LV diastolic diameter. When RWT is above 0.42, LVH is served that in patients with HHD, systolic blood pressure termed concentric. LVH is termed eccentric when RWT and pulse pressure were proportional to CVF [10]. is not greater than this value. Concentric remodelling which is a third pattern of LVH is present when RWT is Non-Haemodynamic Precipitants of Left increased but LV mass is not. Patients with hypertension Ventricular Hypertrophy may have any of these patterns of LVH as demonstrated Evidence suggests that biological variables in addi- by multiple echocardiographic studies (Figure 2). tion to mechanical factors, contribute significantly to In a study of 3042 individuals with normal LV func- myocardial fibrosis. In animal models, angiotensin II has tion echocardiography was used to evaluate systolic been identified as a potential mechanism, independent function and LVM at baseline and at 5-years. Interest- of blood pressure, in the development of cardiac fibrosis ingly, concentric LVH typically seen in hypertensive in hypertensive disease [29]. It causes fibroblast prolifer- heart disease, was not shown to be a risk factor for LV ation, changes in collagen turnover, mRNA expression impairment. In contrast eccentric LVH was found to be and type I collagen synthesis is also increased with subse- a predictor for development of reduced LVEF indepen- quent stimulation of aldosterone and deposition of col- dent of coronary artery disease and MI [24]. It remains lagen type I and III fibres and resultant fibrosis [30]. In to be seen as to whether eccentric LVH may be a prog- addition, angiotensin II attenuates the proteolytic activ- nostic marker for those hypertensive patients at risk of ity of collagenase causing progressive collagen accumu- developing a more deleterious LVH phenotype which lation leading to deformation of myocardial tissue and results in systolic LV dysfunction. This suggests a rela- an increase in myocardial stiffness, diastolic dysfunction tionship between geometric patterns of remodelling and and eventually systolic dysfunction. cardiovascular outcomes and mortality. The role of the renin-angiotensin-aldosterone sys- Haemodynamic Precipitants of Left Ventricu- tem (RAAS) in the development of cardiac fibrosis is highlighted by a number of experimental studies. In lar Hypertrophy unilateral renal artery stenosis, the presence of fibrosis In hypertensive individuals systolic blood pressure is has been demonstrated in the normotensive non-hyper-

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Figure 3: Precipitants and clinical sequelae related to LVH and myocardial fibrosis. LVH = left ventricular hypertrophy, LV = left ventricle. trophied right ventricle as well as the hypertensive, hy- lation of collagen in the heart. Campbell, et al. evaluated pertrophied left ventricle. In contrast, infra renal aortic autopsy proven adrenal adenomas and demonstrated the banding where RAAS is not activated did not result in presence of reactive fibrosis in hypertrophied hearts [37]. cardiac fibrosis despite comparable increases in blood Patients diagnosed with primary hyperaldosteronism pressure and extent of LVH [31]. Supporting the argu- who underwent adrenalectomy benefited from signifi- ment for RAAS activation in the aetiolgy of myocardial cant reductions in interventricular septal thickness, pos- fibrosis is the finding that it is not seen in LVH secondary terior wall thickness and LVM index [38]. In addition, to volume overload states such as atrial septal defects or pharmacological intervention with aldosterone antago- arteriovenous fistulae where the pathway is not activat- nists such as spironolactone have revealed a reduction ed and therefore collagen concentration remains normal in circulating levels of procollagen type III N-terminal [32,33]. amino peptide in patients with stable chronic heart failure [39]. Angiotensin II stimulates the production of aldosterone and studies suggest both direct effects on the heart The Randomised Aldactone Evaluation Study as well as indirect effects such as sodium retention, vol- (RALES) demonstrated a 30% reduction in mortality ume expansion and resultant hypervolaemia. Direct ef- with the administration of spironolactone plus conven- fects of aldosterone in the heart rely on the presence of tional therapy in patients with NYHA class III and IV mineralocorticoid receptors in cardiac cells. Silvestre, et. symptomatic heart failure [40]. al. demonstrated the existence of aldosterone synthase A study by Amanuma, et al. evaluated 29 patients in the rat heart confirming synthesis adrenocortical hor- with graded severities of hypertension (slight, moderate mones within the heart [34]. Subsequent studies have and severe) using endomyocardial biopsy of both the suggested the presence of a complete pathway resulting right and left ventricle. Breadth of the myocytes and the in aldosterone synthesis. degree of interstitial fibrosis in both ventricles increased Brilla, et. al. demonstrated that both aldosterone and in proportion to the severity of hypertension [41]. These angiotensin II could induce myocardial fibrosis in rats findings have also been observed in the interventricular irrespective of LVH [35]. In vivo experiments have im- septum [10] and the atria [42] supporting the argument plied that aldosterone is involved in the production and for neurohormonal mechanisms in the development of deposition of collagen and therefore subsequent devel- fibrosis. opment of myocardial fibrosis. Uninephrectromised rats on a high sodium diet were exposed to 8 weeks of aldo- Consequences sterone infusion. CVF increased significantly at week 6 Diastolic dysfunction and week 8 in left and right ventricles with a progressive Diastole is comprised of an early phase, during which increase from week 4 [36]. Brilla and Weber demonstrat- negative intraventricular pressure causes a suction effect ed similar findings with uninephrectomised rats drink- and thus rapid filling. Diastasis is then followed by ac- ing 1% NaCL solution on an aldosterone infusion for 8 tive filling, secondary to atrial contraction. In contrast to weeks. A significant increase in the deposition of inter- normal cardiac physiology where the majority of blood stitial and perivascular collagen was observed [37]. flow in diastole occurs during the early phase, in diastolic Patients with adrenal adenomas where there is chron- dysfunction there is reliance on atrial systole for as much ic activation of RAAS demonstrate significant accumu- as half of the filling volume. In patients with hyperten-

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Figure 4: Aetiology of ventricular arrhythmias in hypertension. LVH = left ventricular hypertrophy, BP = blood pressure. sive heart disease and left ventricular hypertrophy, dia- Conrad, et al. demonstrated that heart failure in the stolic dysfunction is common (Figure 3). spontaneously hypertensive rat (SHR) was associated with histologically and biochemically determined myocardi- Both animal and human studies have demonstrated that al fibrosis and impaired contractility when compared to hypertension induced cardiac fibrosis results in diastolic non-failing SHR hearts and normotensive rats [25]. In dysfunction. Increased deposition of Type I collagen, which humans, the greater the degree of myocardial fibrosis the has a tensile strength comparable to steel, makes the in- greater the impairment of cardiac function, with advanced crease in stiffness within myocardial tissue predictable. Dia- heart failure patients demonstrating more extensive myo- stolic heart failure accounts for up to 50% of heart failure in cardial fibrosis [48]. In end-stage heart failure a significant clinical practice and causes symptoms in a substantial num- increase in CVF has been demonstrated. ber of hypertensive patients especially in the elderly [43]. There has long been an assumption that dilated car- Echocardiography is the modality of choice for assess- diac failure occurs as a result of concentric LVH. This ing diastology and the use of tissue Doppler has demon- has previously been demonstrated in animal models as strated that even in hypertensive individuals without well as in humans with aortic stenosis and hypertrophic LVH, diastolic function is impaired [44]. The degree of cardiomyopathy [49,50]. myocardial fibrosis when assessed by collagen markers is inversely related to echocardiographic markers of dia- LVH may well be a precursor to LV systolic dysfunc- stolic function [3,4]. tion independent of prior ischaemic events however myocardial infarction plays an important role in the pro- Previous rat models have been able to explicate the gression to dilated heart failure in hypertensive patients. role of cytokines and inflammatory molecules such as There is an association between LVH and subclinical ath- TGF-β which acts via fibroblast activation. Kuwahara, erosclerosis and a study using serial cardiac catheteriza- et al. found that myocardial fibrosis could be prevent- tion has also demonstrated that plaque rupture is more ed by blocking TGF-β activity thus improving diastolic common in patients with LVH [51,52]. A retrospective dysfunction [45]. Further studies in rats have implicated study analysed 159 individuals with concentric LVH and macrophages in the development of myocardial fibrosis normal LV function at baseline echocardiography. Af- and it has been suggested that inhibiting inflammation ter an average follow-up period of four years a further using neutralising antibodies could attenuate the pro- study was performed demonstrating that only 18% had gression to diastolic dysfunction [46]. impaired LV function. Importantly almost half had suf- Systolic dysfunction fered an MI in the interval period [53]. It is well documented that heart failure may occur in Arrhythmia and Sudden Death association with normal left ventricular ejection fraction (LVEF) or with reduced LVEF. Myocardial fibrosis, due to Atrial fibrillation both ischaemic and non-ischaemic aetiologies is thought to In a study of almost 9000 hypertensive patients with play a pivotal role in the development and progression of no evidence of atrial fibrillation (AF) at baseline, echo- systolic cardiac dysfunction [47] (Figure 3). cardiographic evidence of LVH was a strong indepen-

Keteepe-Arachi and Sharma. J Hypertens Manag 2017, 3:023 • Page 5 of 8 • DOI: 10.23937/2474-3690/1510023 ISSN: 2474-3690 dent predictor of new onset AF [54]. This intimate rela- assessment of myocardial tissue is well established using tionship between hypertension and AF means that strict techniques such as M-mode and 2-dimensional evalu- control of BP may prevent atrial fibrillation. The LIFE ation of scar including akinesis and increased acoustic study also demonstrated that maintaining the systolic BP brightness. Tissue Doppler imaging may demonstrate below 130 mmHg led to a reduced risk of new-onset AF reduced measures of cardiac function in the fibrotic compared to those with systolic BPs above 142 mmHg heart, such as myocardial tissue velocity and deforma- [55]. tion parameters. Assessment of longitudinal function in hypertensive hearts has been shown to be the most The prevention of diastolic dysfunction and atrial sensitive marker of subclinical disease. The mechanism stretch using antihypertensives, in particular ACE inhib- reflects increased radial contraction to preserve cardiac itors and ARBs, may also reduce the risk of AF. A me- function due to involvement of subendocardial and mid- ta-analysis of 56 308 patients found that RAS inhibitors wall fibres [66]. reduced the relative risk of AF by 28% [56]. However there are mixed opinions, as only the LIFE study which Echocardiographic deformation techniques i.e. strain recruited high- risk patients with LVH, demonstrated a and strain rates, are more sensitive than other echocar- benefit of losartan over atenolol in the reduction of AF. diographic techniques and may demonstrate abnormal- Studies recruiting from the general population did not ities in early cardiomyopathic processes and can detect demonstrate such a benefit. This may imply that preven- subclinical heart disease. The anti fibrotic effect of al- tion of AF is most effective in hypertensive patients with dosterone antagonism has been demonstrated with im- haemodynamic complications. proved parameters in diastolic dysfunction [67]. It must be noted that echocardiographic assessment of LV hy- Ventricular arrhythmia pertrophy and geometry is limited by geometric assump- There is a significantly greater prevalence of ventric- tions which may result in reduced reproducibility, reli- ular arrhythmia and ventricular ectopy in patients with ability and accuracy when compared to measurements hypertension and LVH compared to those without LVH made using CMR [68]. or normotensives [57] (Figure 3). The Framingham group has previously reported a two-fold increase in Cardiac magnetic resonance mortality in those with LVH and asymptomatic ventric- CMR imaging is the non-invasive gold standard for ular arrhythmias [58]. The extent of myocardial fibrosis the quantification of focal myocardial fibrosis. Myocar- present in the heart has been implicated in slowing of dial fibrosis, which occurs secondary to ischaemia is conduction and an increased susceptibility to arrhyth- easily detected using delayed contrast enhancement on mias due to interruption of coordinated transmission cardiac magnetic resonance imaging (CMRI) [69]. How- of electrical impulses. Other aetiological mechanisms ever, this technique when used in hypertensive patients include microvascular angina, which may occur in the has previously demonstrated non-specific, non-isch- absence of LVH, myocardial under perfusion due to dis- aemic patterns of fibrosis [70]. A major flaw in utilising proportionate muscular hypertrophy compared to cor- this method to assess diffuse myocardial fibrosis is that it onary artery growth and excess fluctuation in arterial is qualitative rather than quantitative. In addition, image pressure which may be arrhythmogenic [59-63] (Figure contrast relies upon the difference in signal intensity be- 4). LVH has thus been identified as an independent risk tween the areas of scarred myocardium and normal myo- factor for the development of arrhythmia. cardium, but in non-ischaemic cardiomyopathy collagen deposition is typically diffuse resulting in a lack of re- Supporting this observation, a study in a cohort of gional scarring when evaluated with delayed contrast en- 196 elderly hypertensive patients with LVH but without hancement. A quantitative tissue characterisation meth- coronary artery disease demonstrated significant risk of od is available which measures the T1 relation time of developing ventricular fibrillation or sudden death com- the myocardium. The presence of expanded extracellular pared to 358 patients without LVH (31% vs. 10%) [62]. space secondary to myocardial fibrosis, scar formation Detection or infiltration results in a greater distribution volume. The reduction in T1 relaxation time is thus more evident Endomyocardial biopsies, although the gold-stan- compared to normal myocardium. Using pre and post dard for assessment of myocardial CVF, have limited use contrast T1 maps and the haematocrit, the extracellular in antemortem studies due to the invasive nature of the volume fraction (ECV) may also be calculated. ECV has test. Other methods for evaluating cardiac fibrosis have been shown to correlate with the extent of myocardial been developed including echocardiographic parame- fibrosis and CVF [71]. ters, measurement of hormones and biochemical markers [63-65]. Previous studies in hypertensive rat hearts and human papillary muscles have identified variation of the T1 Echocardiography mapping time with fibrosis, which correlates with myo- The use of ultrasound as an inexpensive, non-invasive cardial collagen composition [72,73].

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A recent study by Treibel, et al. demonstrated diffuse demonstrated significant reductions in CVF and left ven- myocardial fibrosis evaluated by T1 mapping in hyper- tricular chamber stiffness after 12 months of treatment tensive patients was raised but only occurred in those with losartan [83]. The Losartan Intervention for End- with LVH [74]. This study implies that hypertensive pa- point Reduction in Hypertension (LIFE) study demon- tients exhibit both diffuse and focal myocardial fibrosis strated a reduction of LVH in response to losartan, inde- associated with LVH. Kuruvilla, et al. documented that pendent of lowering blood pressure [84]. hypertensive patients with LVH exhibited higher extra- Interference with collagen turnover using ACE-in- cellular volumes and longer native T1 mapping times hibitors and angiotensin receptor blockers appears to with an associated decrease in peak systolic circumfer- have greater effect on diastolic dysfunction than reduc- ential strain in contrast to hypertensive patients with tion in arterial pressure or regression of LVH. no LVH and controls [75]. CMR T1 mapping has great potential for evaluating cardiac fibrosis in hypertensive Attenuation of ventricular arrhythmias can also be patients. achieved by reducing LVH in hypertensive patients. A reduction in ventricular ectopy has been demonstrated with Treatment and Regression of Myocardial Fi- the use of calcium channel blockers, β-blockers and ACE brosis inhibitors suggesting the anti-arrhythmic effect is associ- Regression of myocardial fibrosis with pharmacolog- ated with the reduction in LVH rather than the effects of ical therapy is an important prognostic intervention for the drug only. Gonzalez-Fernandez, et al. demonstrated a patients with hypertension. Various studies have indicat- significant reduction in LVH and associated ventricular ec- ed functional benefits, particularly with the use of ACE topy with the use of an ACE inhibitor compared to progres- Inhibitors and angiotensin receptor blockers (ARBs) sion of LVH and no change in the frequency of ventricular [76-78]. ectopy in the placebo group [85]. Animal studies evaluating the efficacy of antihyper- The Aliskiren in Left Ventricular Hypertrophy (AL- tensive drugs in myocardial regression demonstrated LAY) study demonstrated that Aliskiren (acting to in- zofenapril and labetalol could regress myocardial fibro- hibit renin) alone or in combination with losartan was sis in rats with renovascular hypertension and LVH [79]. associated with a greater reduction in aldosterone compared to losartan alone. The reduction in plasma aldoste- Specific to diastolic dysfunction Brilla, et al. exam- rone was associated with a corresponding regression of ined male spontaneously hypertensive rats (SHRs) with LV wall thickness and LV myocardial index reduction. cardiac fibrosis and LVH, and administered a 12 week This study provides supporting evidence that regression course of ACE inhibitor. The high dose normalised ar- of LVH may be caused by aldosterone inhibition [77]. terial blood pressure and regressed LVH, the low dose achieved neither end point. Rats in both high and low A meta-analysis of 39 clinical trials found that ACE dose treatment groups demonstrated regression in car- Inhibitors were the most potent at reducing left ventric- diac fibrosis as well as recovery of diastolic function to a ular mass index. Calcium channel blockers had an inter- level comparable with normotensive control rats [Wis- mediate effect with beta blockers and diuretics having tar-Kyoto rats (WKYs)] [80]. Importantly these find- even less effect [86]. A study supporting this showed that ings emphasise the disassociation between LVH and left telmisartan reduced LV mass to greater extent than hy- ventricular stiffness, and the significance of myocardial drochlorothiazide [87]. The same group demonstrated a quality over quantity. A further SHR study by the same similar finding when comparing telmisartan with carve- group evaluated older rats with more established fibro- dilol [88]. Similar studies using CMR to assess changes sis and LVH. They were treated with a longer course of in LVH and LV mass support this finding. Due to the lisinopril, which resulted in partial regression of fibrosis widespread availability and safety of echocardiography, and myocardial stiffness to measurements comparable it is the cornerstone of cardiac imaging in cardiomyop- to age-matched WKY controls [81]. Subsequently Brilla athy. However, a study of more than 200 hypertensives and colleagues published a pivotal study evaluating the demonstrated that Eplerenone wasjust as effective com- effects of lisinopril versus hydrochlorothiazide in pa- pared to enalapril in both LVH regression and blood tients with established hypertension, LVH and diastolic pressure control. LV mass and systolic blood pressure dysfunction on echocardiography [82]. Endomyocardi- could be reduced more effectively by combining eplere- al biopsy was performed before and after treatment and none and enalapril [89]. It is likely that more studies will morphological (CVF) and biochemical (hydroxyproline) arise using CMR to assess LV geometry and the effects of parameters were used to quantify fibrosis. Regression of pharmacological intervention on these parameters. myocardial fibrosis and improvement in echocardio- The importance of identifying patients with hyper- graphic measurements of diastolic stiffness were demon- tension and LVH cannot be underestimated when there strated in the lisinopril group after six months of therapy. is such convincing evidence that anti-hypertensive drugs In a study by DIez, et al. hypertensive patients with have the potential to reduce morbidity and mortality in severe fibrosis assessed using endomyocardial biopsy these individuals.

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