Thomas Kahan, Lennart Bergfeldt

250 Cardiomyopathy LEFT VENTRICULAR HYPERTROPHY IN HYPERTENSION: ITS ARRHYTHMOGENIC POTENTIAL DEVELOPMENT See end of artile for authors affiliations Correspondene to: Professor Lennart Bergfeldt, Department of Cardiology, Sahlgrenska University Hospital/S, S-413 45 Gothenburg, Sweden; lennart.bergfeldt@hjl.gu.se L Thomas Kahan, Lennart Bergfeldt Heart 2005; 91:250 256. doi: 10.1136/hrt.2004.042473 eft ventriular (LV) hypertrophy may reflet physiologial adaptation to an inreased work load of the heart following intense physial training. However, LV hypertrophy often represents a pathophysiologi ondition, and an develop due to intrinsi stimuli (ardiomyopathy), or seondary to extrinsi stimuli, suh as pressure or volume overload aompanying hypertension and valvar disease (fig 1). Myoardial hypertrophy is also part of the remodelling proess following an aute myoardial infartion, and is a ommon finding in patients with ongestive heart failure aused by systoli and/or diastoli LV dysfuntion. The presene of LV hypertrophy is a strong independent risk fator for future ardia events and all ause mortality. 1 The risk for sudden ardia death is inreased in subjets with LV hypertrophy, independent of the aetiology, and this event ours also in individuals with no or only mild prior symptoms related to ardiovasular disease. Intense animal and human researh has identified some ommon features and provided a framework within whih some ruial omponents an be explained. Thus, whether the fous is haemodynami or eletrophysiologi, there seems to be onsensus as to the initiation of a fetal-like gene programme in myoardial hypertrophy. 2 3 The insights into its onsequenes an be applied in the linial management of individual patients. During reent years, experts with different bakgrounds within ardiovasular mediine have aimed to reate a united piture of ardia hypertrophy and sudden ardia death, and to present it in suh a way that in an be integrated and applied into linial ardiovasular pratie. This artile is an attempt to pursue this ambition. We fous on LV hypertrophy in human hypertension as a model of ardia hypertrophy, and myoardial hypertrophy as a ondition with redued repolarisation reserve, w1 and thus a latent aquired long QT syndrome (LQTS). w2 We will not over aspets on hypertrophi ardiomyopathy, a topi whih has already been addressed in an exellent ontribution within this series, w3 and will not attempt to disuss atrial fibrillation, for whih reent exellent guidelines are available, w4 although there are several important relations between these topis (fig 2). OF LV HYPERTROPHY The myoardium has three morphologial ompartments: (1) the musular ompartment onsisting of myoytes, the dominant ell type of the normal heart omprising,30% of the myoardial ells and,70% of ardia tissue volume; (2) the interstitial ompartment formed by fibroblasts and ollagen; and (3) the vasular ompartment with smooth musle and endothelial ells. An inrease in LV wall stress for example, aused by hypertension indued inrease in afterload will stimulate myoyte hypertrophy, ollagen formation and fibroblasts, and thus remodelling of the myoardium with a disproportionate inrease in fibrous tissue. These hanges will subsequently redue LV ompliane, leading to diastoli dysfuntion. Strutural hanges of the oronary arteries and the inrease in both interstitial myoardial fibrosis and in myoardial mass ontribute to redue the vasular oronary flow reserve. In addition, myoardial ishaemi episodes ause transient diastoli dysfuntion (figs 3 and 4). An inrease in LV wall stress is the prinipal mehanial fator in the development of LV hypertrophy, and blood pressure the most powerful determinant of LV mass. However, some additional haemodynami fators play important roles in the development and maintenane of LV hypertrophy (fig 5). 4 Thus, volume overload also ontributes importantly to the development of ardia hypertrophy. Although the exat mehanism by whih sodium intake influenes LV mass is unlear, a high salt intake ould expand intravasular volume and inrease LV preload. Hypertrophy of the arterial resistane vessels with an inreased peripheral vasular resistane is present in established hypertension. w5 Also the arotid arteries and other large arteries show strutural hanges. These strutural vasular hanges with inreased arterial stiffness lead to enhaned refletion of the arterial pulse wave, and the resulting inrease in systoli blood pressure may promote the development of LV hypertrophy. w6 While diastoli blood pressure is more Heart: first published as 10.1136/hrt.2004.042473 on 18 January 2005. Downloaded from http://heart.bmj.om/ on 11 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

Figure 1 Left ventriular hypertrophy, a ondition with variable bakground. AMI, aute myoardial infartion; CMP, ardiomyopathy. losely related to LV wall thikness probably refleting pure pressure load, systoli blood pressure is more losely related to LV mass, suggesting an influene of both pressure and volume load. However, the modest orrelation between blood pressure and LV mass suggests additional important fators. Important non-haemodynami fators for the development of LV hypertrophy inlude trophi influene mediated by the sympatheti nervous system and the renin angiotensin aldosterone (RAA) system. Noradrenaline (norepinephrine) and other substanes with a1 adrenergi agonist ativity have been shown to indue myoyte hypertrophy in vitro and in vivo. Reent results suggest that an inreased ardia sympatheti neurotransmission plays a part in the inrease in LV mass in human hypertension. 5 However, it is likely that diret haemodynami effets from sympatheti augmentation in hypertension also ontribute to the development of LV hypertrophy. w7 Insulin has trophi effets, and raised levels Figure 2 Common and often o-existing ardiovasular onditions with a risk for adverse events inluding sudden death. of insulin and insulin resistane is more ommon in patients with ardiovasular disease, inluding hypertension. Although insulin may have peripheral haemodynami ations that ould inrease afterload, it appears that it does not have a diret growth promoting effet on the myoardium. w8 Cirulating plasma onentrations of aldosterone and angiotensin II are related to the extent of LV hypertrophy. Angiotensin II promotes myoyte ell growth, and aldosterone inreases the ollagen ontent and stimulates the development of myoardial fibrosis. 6 Cirumstantial evidene suggesting an important role for the RAA system is also the greater redution in LV mass and of myoardial fibrosis by antihypertensive treatment with drugs that interfere with the ations of the RAA system. 7 8 w9 Furthermore, gene polymorphisms of various omponents of the RAA system also predit the response in LV mass to antihypertensive treatment. 9 w10 Demographi determinants suh as age, sex, rae, and body size also play a role in the development of LV hypertrophy. 4 Taken together, geneti as well as non-geneti influenes on haemodynami and non-haemodynami fators seem to ause intraellular stimulation of protein synthesis ultimately influening the development of LV hypertrophy, as summarised in fig 5. DIAGNOSIS OF LV HYPERTROPHY Although a physial examination might reveal signs of hypertension and LV hypertrophy by blood pressure measurement, ausultation of an augmented S2 (A2), and palpation of a broad and/or laterally displaed ardia impulse ( thrusting apex ) ECG and ehoardiography are the most prominent diagnosti tools. ECG is a readily available and fairly simple diagnosti proedure. An inreased load of the left atrium will be refleted in a negative P wave in the preordial leads. Large QRS amplitudes with deep S in the anterior leads and high R in the lateral leads reflet an enlarged LV diameter. A prolonged ventriular ativation time that is, a wide QRS omplex as well as ST T hanges reflet altered myoardial depolarisation and repolarisation, respetively. Furthermore, it appears that an anterolateral fasiular blok (previously 251 Heart: first published as 10.1136/hrt.2004.042473 on 18 January 2005. Downloaded from http://heart.bmj.om/ on 11 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

252 Figure 3 Left ventriular hypertrophy from an eletromehanial perspetive. hemi-blok ) in hypertensive patients is suggestive of LV hypertrophy. Various ombinations of riteria have been suggested to identify LV hypertrophy by the ECG. While the speifiity for LV hypertrophy is high (90% or greater), the LV hypertrophy and hypertension Hypertension promotes development of ishaemi injury to myoardium with dereased tolerability to both ishaemia and reperfusion beause of: Aelerated oronary atheroslerosis ausing stenoti lesions Inreased afterload inreasing workload and myoardial oxygen demand Fators related to LV hypertrophy - impaired oronary vasodilator reserve - inreased myoardial ell diameter without proportional proliferation of apillary vessels results in dereased apillary density and inreased diffusion distane - dereased high energy phosphate ontent - impaired fatty aid oxidation - redued myoardial gluose transport into the ell As a result there will be an inreased ishaemi zone on top of a redued repolarisation reserve and hene inreased risk for ventriular fibrillation and sudden ardia death. sensitivity is low (20 40%), although more reent riteria w11 w12 may yield higher diagnosti auray. Ehoardiography an provide relatively aurate measurements of the intraventriular septum, the posterior LV wall thikness, and the LV diameter in diastole. With the appropriate mathematial formulas these measurements an be used to alulate LV mass. Most ommonly this is done aording to the Penn onvention. w13 Beause LV mass is related to body size, an indexation of LV mass to body size is important. Most often this is done by dividing with the body surfae area. This may, however, mislassify obesity indued LV hypertrophy as normal, and indexing LV mass to its allometri power (that is, LV mass/height 2.7 ; g/m 2.7 ) would be a preferred approah in this ase. The presene of LV hypertrophy is often onsidered when LV mass. 116 g/m 2 for men and. 104 g/m 2 for women, w14 or. 125 g/m 2 for men and women, w15 or. 51 g/m 2.7 for men and women. w16 Other partition values have been proposed, and were generally higher in earlier investigations. w17 Ehoardiographi assessment of LV hypertrophy has a high speifiity and sensitivity (both > 80%). Ehoardiography an also provide important additional information, suh as other reasons for LV hypertrophy (for example valvar disease, hypertrophi ardiomyopathy), LV geometri pattern, and information on systoli and diastoli funtion. Reent development in ehoardiographi tehniques suh as Heart: first published as 10.1136/hrt.2004.042473 on 18 January 2005. Downloaded from http://heart.bmj.om/ on 11 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

tissue veloity imaging appear to be more sensitive than traditional Doppler ehoardiography to detet early signs of hypertensive heart disease suh as systoli or diastoli dysfuntion. New three dimensional imaging tehniques, inluding magneti resonane imaging, advaned omputed tomography tehniques and three dimensional ehoardiography, an measure myoardial mass more aurately than onventional ehoardiographi tehniques. This may offer advantages, espeially in relation to mehanisti studies, but may also give additional information on myoardial fibrosis and other strutural alterations. The prevalene of LV hypertrophy inreases with the severity of hypertensive disease. By and large, one third to one half of hypertensive patients have LV hypertrophy. Obviously, the partition values used for the definition of an abnormal LV mass and the diagnosti proedures are ritial. The atual prevalene of strutural hanges of the myoardium in hypertension may, however, be higher. w18 Figure 4 The risk for ardia events in hypertension. LV, left ventriular. Adapted from Kahan. 4 There are four distint patterns of LV geometry in hypertension based on the relation between the avity size and the wall thikness that is, relative wall thikness w19 (fig 6). LV HYPERTROPHY AS A RISK FACTOR Myoardial hypertrophy established by ECG or by ehoardiography is a strong and independent risk fator for ardiovasular morbidity (inluding ongestive heart failure, oronary heart disease, atrial fibrillation, supraventriular and ventriular arrhythmias, and stroke) and mortality, as well as for all ause mortality in the general population, in hypertensive patients, and in those with oronary artery disease. 1 w20 There is a two- to threefold inreased risk for having a non fatal or fatal ardiovasular event in the presene of LV hypertrophy. 1 w20 It appears that LV hypertrophy is a stronger risk fator than blood pressure, smoking, or holesterol, and in multivariate analyses only age and LV Figure 5 Multiple determinants for left ventriular hypertrophy. Adapted from Kahan. 4 253 Heart: first published as 10.1136/hrt.2004.042473 on 18 January 2005. Downloaded from http://heart.bmj.om/ on 11 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

254 hypertrophy remain independent prognosti fators. Of note, the risk for an event is lowest in hypertensive patients with normal LV geometry, followed by those with onentri remodelling, those with eentri LV hypertrophy, and is highest among those with onentri LV hypertrophy. 10 Regression of LV hypertrophy by antihypertensive treatment redues ardiovasular morbidity and mortality and thus improves prognosis. 11 These results, based on ehoardiographi evaluation of LV hypertrophy, are onsistent with earlier observations using serial assessment of ECG. Several mehanisms ontribute to the inreased risk for a ardia event in the hypertensive patient. First, the development of LV hypertrophy and myoardial fibrosis leads to LV diastoli dysfuntion, an important fator in the evolution of ongestive heart failure. Seond, hypertension promotes the development of oronary artery atheroslerosis, whih inreases the risk for an aute myoardial infartion, with subsequent systoli dysfuntion and ongestive heart failure. Indeed, hypertension remains the most important aetiology for the development of ongestive heart failure, followed by ishaemi heart disease. w21 w22 In addition, the inrease in arterial stiffness and subsequent afterload aused by atherosleroti disease augments myoardial oxygen demand and an ause myoardial ishaemia. Furthermore, an inreased myoardial mass and interstitial myoardial fibrosis is assoiated with a redued oronary flow reserve. Consequently, not only is there an inreased risk for myoardial ishaemia, but the tolerability is impaired. w23 w24 Thus, intermittent myoardial ishaemia, with transient diastoli dysfuntion, may lead to myoardial sarring and systoli LV dysfuntion, and also promote potentially malignant arrhythmias. Importantly there is also an inreased risk for atrial fibrillation, an important risk fator for ongestive heart failure and thromboemboli ardiovasular ompliations. ARRHYTHMOGENESIS IN LV HYPERTROPHY A strong hain of evidene for the mehanisms behind ventriular arrhythmia in myoardial hypertrophy has been Figure 6 Left ventriular (LV) geometry in hypertension: four patterns with different prognosti impliations. LV hypertrophy and hypertension: linial impliations In hypertensive patients, evaluate left ventriular geometry and funtion by ehoardiography Reognise hypertension indued left ventriular hypertrophy as a latent long QT syndrome Treat high blood pressure and reverse hypertrophy Avoid hypokalaemia, bradyardia, and QT prolonging drugs that is, anything that prolongs repolarisation time established. There is also a strong link between ventriular arrhythmias and ongestive heart failure. 3 w2 Thus, a relation between prolongation and heterogeneity (dispersion) of repolarisation and polymorphi ventriular arrhythmia, espeially torsade de pointe ventriular tahyardia, has been established, 3 12 13 as outlined below. Prolonged ation potential duration is a salient feature in myoardial hypertrophy, independent of ause. This may lead to early after depolarisations and triggered ativity, and in the intat heart inreased dispersion of repolarisation may sustain the arrhythmia. In the hypertrophi myoardium myofibrillar disarray, heterogeneous gap juntion distribution, and fibrosis are additional potentially arrhythmogeni omponents. Torsades de pointes ventriular arrhythmias are typially rate dependent, following sequenes of short-long RR intervals. Consistent with these observations is the steeper relation between the QT and RR intervals (QT/RR relation) indued by drugs known to be proarrhythmi. w25 w26 This phenomenon, referred to as reverse use dependene, is also present in LV hypertrophy. w27 Of interest is that this pattern is typial also in the ongenital LQTS, w28 and was reently found to be preditive of sudden death in post-myoardial infartion patients. w29 This suggests eletrophysiologial similarities between hypertensive LV hypertrophy and other onditions assoiated with proarrhythmi potential, suh as Heart: first published as 10.1136/hrt.2004.042473 on 18 January 2005. Downloaded from http://heart.bmj.om/ on 11 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

the LQTS, all of whih are related to polymorphi ventriular tahyardia. The repolarisation time and its dispersion are related to the degree of LV hypertrophy. Antihypertensive treatment redues LV mass. w30 32 Furthermore, it redues both repolarisation time and its dispersion, 14 17 w33 the inidene and severity of ventriular arrhythmia, 18 and the risk for ardiovasular events. 11 19 w34 As disussed, the RAA system plays an important role for the ontrol of LV mass and struture. Consequently, reent interest has foused on angiotensin II type 1 reeptor blokade (ARB), beause this lass of drugs might interat with several possible arrhythmogeni mehanisti fators indued by angiotensin II ating on its prinipal reeptor, the type 1 reeptor (fig 7). Animal studies have shown important arrhythmogeni effets of angiotensin II on the ardia ondution system, whih has a high density of angiotensin II type 1 reeptors. Angiotensin II redues intraellular resistane, dereases ondution veloity, and shortens the refratory period in ardia myoytes. w35 w36 Loal appliation of angiotensin II to the heart auses inreased dispersion of the ation potential durations. w36 In addition, it has been shown in a rat model of eentri LV hypertrophy indued by aorti banding, that ARB prevents the development of disorganised ell-to-ell onnetions, as assessed by the distribution of gap juntion protein Cx 43. w37 Angiotensin II an failitate noradrenaline release by ativation of prejuntional angiotensin II type 1 reeptors. w38 Abnormal myoardial fibrosis is a ommon finding in LV hypertrophy, w39 but is redued by drugs that blok the ations of the RAA system, 11 w40 whih thereby may redue the risk for malignant arrhythmia and sudden death. Also, regression of strutural vasular hanges that auses a redued oronary flow reserve w41 ould probably ontribute to redue the risk of arrhythmias. Finally, animal data provide intriguing results, sine not only streth indued by inreased afterload but also streth indued by sudden inreases in preload might provoke arrhythmias. w42 This is of potential interest in the linial setting of hypertension and eentri LV hypertrophy, in whih an inrease in preload often is present. CLINICAL IMPLICATIONS Torsades de pointes ventriular tahyardias are unommon both in the ongenital and aquired forms of LQTS. Furthermore, these arrhythmias are potentially life threatening, and diffiult to predit on the individual level, although risk fators have been identified. Therefore prevention is of utmost importane, whih requires knowledge about risk onditions that is, about onditions with a redued repolarisation reserve and about fators influening ventriular repolarisation. Anything that might add risk, suh as hypokalaemia and bradyardia, should be avoided. Furthermore, beause the arrhythmia risk is so losely related to struture, imaging tehniques should be applied for proper identifiation of risk individuals, and treatment that an reverse myoardial hypertrophy should be applied. New drug lasses interating with the RAA system suh as angiotensin onverting enzyme (ACE) inhibitors, ARBs, and aldosterone reeptor antagonists ould be the beginning of a new era of antiarrhythmi drug treatment. We may see the fous shift from the more seondary eletrophysiologial aspets and their treatment to the arrhythmia substrate itself and to 255 Heart: first published as 10.1136/hrt.2004.042473 on 18 January 2005. Downloaded from http://heart.bmj.om/ Figure 7 Some angiotensin II related effets of relevane for arrhythmogenesis. See text for details and referenes. NA, noradrenaline/ norepinephrine. on 11 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

256 reversing strutural remodelling similar to what has been suggested for the treatment of atrial fibrillation, for 20 w43 example.... Authors affiliations T Kahan, Karolinska Institutet, Division of Internal Mediine, Danderyd Hospital, Stokholm, Sweden L Bergfeldt, Sahlgrenska Aademy, University of Gothenburg, Sahlgrenska University Hospital/S, Gothenburg, Sweden REFERENCES 1 Vakili BA, Okin PM, Devereux RB. Prognosti impliations of left ventriular hypertrophy. Am Heart J 2001;141:334 41. A reent meta-analysis of the prognosti impliations of LV mass. 2 Lips DJ, dewindt LJ, van Kraaij DJW, et al. Moleular determinants of myoardial hypertrophy and failure: alternative pathways for benefiial and maladaptive hypertrophy. Eur Heart J 2003;24:883 96. A reent review of the moleular bakground to left ventriular hypertrophy with a haemodynami fous. 3 Paifio A, Henry PD. Strutural pathways and prevention of heart failure and sudden death. J Cardiovas Eletrophysiol 2003;14:764 75. Myoardial disease assoiated with heart failure and sudden ardia death reviewed from a marosopi and mirosopi anatomy perspetive with a fous on the prevention of sudden ardia death. 4 Kahan T. The importane of left ventriular hypertrophy in human hypertension. J Hypertens 1998;16(suppl 7):S23 9. 5 Shlaih MP, Kaye DM, Lambert E, et al. Relation between ardia sympatheti ativity and hypertensive left ventriular hypertrophy. Cirulation 2003;108:560 5. 6 Weber KT, Brilla CG, Campbell SE, et al. Myoardial fibrosis: role of angiotensin II and aldosterone. Basi Res Cardiol 1993;88:107 24. Exellent overview of the importane of the renin angiotensin aldosterone system in the development of myoardial hypertrophy and fibrosis. 7 Klingbeil AU, Shneider M, Martus P, et al. A meta-analysis of the effets of treatment on left ventriular mass in essential hypertension. Am J Med 2003;115:41 6. 8 Brilla CG, Funk RC, Rupp H. Lisinopril-mediated regression of myoardial fibrosis in patients with hypertensive heart disease. Cirulation 2000;102:1388 93. This study shows that treatment with an ACE inhibitor redues myoardial fibrosis, evaluated by endomyoardial biopsies, and improves diastoli funtion. These effets go beyond the effets of blood pressure redution alone. 9 Kurland L, Melhus H, Karlsson J, et al. Polymorphisms in the angiotensinogen and AT1-reeptor gene are related to hange in left ventriular mass during antihypertensive treatment. J Hypertens 2002;20:657 63. 10 Koren MJ, Deveraux RB, Casale PN, et al. Relation of left ventriular mass and geometry to morbidity and mortality in unompliated essential hypertension. Ann Intern Med 1991;114:345 52. Seminal work on the prognosti impliations of different left ventriular geometries in hypertensive patients. 11 Verdehia P, Angeli F, Borgioni C, et al. Changes in ardiovasular risk by redution of left ventriular mass in hypertension: a meta-analysis. Am J Hypertens 2003;11:895 9. A reent meta-analysis on the prognosti impliations of hanges in LV mass by antihypertensive treatment. 12 Aronson R. Mehanisms of arrhythmias in ventriular hypertrophy. J Cardiovas Eletrophysiol 1991;2:249 61. Referenes 12 and 13 review important in vitro and in vivo studies. 13 Hart G. Cellular eletrophysiology in ardia hypertrophy and failure. Cardiovas Res 1994;28:933 46. 14 Gonzalez-Juanatey JR, Garia-Auna JM, Pose A, et al. Redution of QT and QT dispersion during long-term treatment of systemi hypertension with enalapril. Am J Cardiol 1998;81:170 4. 15 Karpanou EA, Vyssoulis GP, Psihogios A, et al. Regression of left ventriular hypertrophy results in improvement of QT dispersion in patients with hypertension. Am Heart J 1998;136:765 8. 16 Lim PO, Nys M, Naas AA, et al. Irbesartan redues QT dispersion in hypertensive individuals. Hypertension 1999;33:713 8. 17 Malmqvist K, Kahan T, Edner M, et al. Comparison of ations of irbesartan versus atenolol on ardia repolarization in hypertensive left ventriular hypertrophy: results from the Swedish irbesartan left ventriular hypertrophy investigation versus atenolol (SILVHIA). Am J Cardiol 2002;90:1107 12. 18 Messerli FH. Hypertension and sudden ardia death. Am J Hypertens 1999;12:181S 8S. 19 Lindholm LH, Dahlöf B, Edelman JE, et al. Effet of losartan on sudden ardia death in people with diabetes: data from the LIFE study. Lanet 2003;362:619 20. 20 Members of the Siilian Gambit. New approahes to antiarrhythmi therapy. Emerging therapeuti appliations of the ell biology of ardia arrhythmias. Eur Heart J 2001;22:2148 63. An eletrophysiologial approah to antiarrhythmi treatment desribing the arrhythmogeni myoardial substrate, geneti fators, and environmental stresses, and priniples of rational drug design. Additional referenes appear on the Heart website http://www.heartjnl.om/supplemental Heart: first published as 10.1136/hrt.2004.042473 on 18 January 2005. Downloaded from http://heart.bmj.om/ on 11 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om