Diuretics and left ventricular hypertrophy regression: The relationship that we commonly forget

Left ventricular (LV) remodeling represents the major factor in hypertensive-induced target organ damage, and although the latest studies are insisting on LV mechanical and functional changes caused by arterial hypertension,1, 2 left ventricular hypertrophy (LVH) still has the central role in the assessment of organ damage and in the evaluation of antihypertensive therapy efficacy. It has been demonstrated that LVH represents one of the most important predictors of cardiovascular events including myocardial infarction, stroke, cardiovascular mortality, and total mortality.3, 4 Numerous studies reported LVH regression after antihypertensive therapy,5 which shows the great importance of this parameter. However, it has always been difficult to distinguish the influence of blood pressure reduction on LVH reduction from the impact of antihypertensive medication itself. The SPRINT study showed that intensive blood pressure lowering (systolic blood pressure <120 mm Hg) resulted in lower rates of new LVH and higher rates of LVH regression in those with the existing LVH comparing with the standard BP lowering (target systolic blood pressure <140 mm Hg).6 However, the authors still did not provide the data regarding the influence of antihypertensive classes and their effectiveness in LVH reduction or prevention of LVH development. Majority of studies included a large group of antihypertensive drugs such as renin-angiotensin-aldosterone inhibitors (RAAS), calcium channel blockers and beta-blockers, and, significantly less concerned, the effect of diuretics. The data regarding the isolated role of diuretic therapy on LVH are scarce. InQuery ID="q4" Text="AUTHOR: Please check and approve the edit made in the sentence “In this…reducing LVH.”" this issue, the Journal by Roush et al7 reported the importance of different diuretic groups in reducing LVH. Namely, the investigators compared hydrochlorothiazide to chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics and their role in the reduction in LVH in hypertensive patients.7 There are several points of this interesting study that deserve to be particularly discussed. This meta-analysis included 2299 patients who were treated with some of the mentioned diuretics.7 The authors showed that a 1% decline in systolic blood pressure predicted a 1% decline in LV mass (LVM). Diastolic blood pressure decline also predicted LVM reduction; however, after adjustment for systolic blood pressure, diastolic blood pressure lost its predictive value as a predictor of LVM.7 The present meta-analysis revealed that Chlorthalidone, indapamide, and potassium-sparing diuretic (CHIP), alone or combined, were superior to hydrochlorothiazide for reducing LVM.7 CHIP diuretics reduced LVM more than hydrochlorothiazide by 105%, and they were about twice as effective as hydrochlorothiazide in reducing LVM. Interestingly, there was no significant difference in the reductions in systolic and diastolic blood pressure between CHIP diuretics and hydrochlorothiazide. The advantage of CHIP diuretics over hydrochlorothiazide was noticed during short and long follow-up trials. The same group of authors recently compared effects of diuretics and RAAS inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) on LV diameter and LVM.8 Hydrochlorothiazide tended to be less effective than RAAS inhibitors for the reduction in LVM. CHIPs were associated with 37% greater reduction in LVM than RAAS inhibitors. CHIPs were also related to significantly more decreased end-diastolic LV internal diameter than RAAS inhibitors.8 Schneider et al9 recently showed that adding eplerenone to antihypertensive therapy in treatment-resistant hypertensive patients significantly decreased LVM in a 6-month period, even though the reduction in blood pressure in placebo and eplerenone groups was similar. The mineralocorticoid receptor antagonist in this study significantly reduced LVM and right ventricular mass (RVM) assessed with cardiac magnetic resonance, but it did not change RV volumes and ejection fraction.9 Kusmala et al10 had previously showed that spironolactone added to angiotensin II inhibitor in antihypertensive therapy in patients with the metabolic syndrome significantly improved LV function and LVH in the period of 6 months. Interestingly, some authors showed that, despite spironolactone significantly reduced LVH, it did not improve LV diastolic function after 6 months of therapy.11 The 4E-Left Ventricular Hypertrophy Study revealed that eplerenone significantly reduced LVM and this reduction was similar to enalapril; however, eplerenone/enalapril combination was more effective than eplerenone alone. All treatments significantly reduced systolic and diastolic blood pressures from baseline. Interestingly, there was no significant difference in efficacy in blood pressure reduction between enalapril and eplerenone groups, but the reduction was somewhat higher in the eplerenone/enalapril group.12 All these findings only confirm that there are other important mechanisms responsible for LVH regression during mineralocorticoid antagonist therapy beyond blood pressure reduction. LVH is caused by cardiomyocyte hypertrophy and fibrosis. Procollagen serum levels have been associated with LV fibrosis.13 Some studies showed that eplerenone treatment was associated with the reduction in procollagen peptide and not only with blood pressure lowering alone.9 This implies that eplerenone has also antifibrotic effects in patients with therapy-resistant hypertension. Aldosterone is related to increase in intracellular calcium concentration, which could also lead to hypertrophy of the myocyte. Furthermore, aldosterone may increase the number of AT1 receptors and tissue ACE (angiotensin-converting enzyme) activity, which could induce a vicious cycle with either aldosterone or angiotensin II. Schneider et al9 showed that eplerenone therapy significantly reduced not only LMV, but also RVM. Considering the fact that the RV is not exposed to the systemic circulation and high systemic pressure, this is an argument for BP-independent effects of mineralocorticoid receptor blockade on cardiac structure and regression of hypertrophy. Favorable effects of thiazide diuretics on LVH have also been studied, but usually in combination with some of RAAS antagonists. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study showed that hydrochlorothiazide use was related to greater regression of LVH in ECG and this effect was greater in the patients on losartan- than atenolol-based therapy, independent of baseline LVH in ECG and blood pressure reduction during therapy.14 The other study reported greater reduction in LVH estimated by ECG criteria in the patients treated with losartan and hydrochlorothiazide than in those treated only with losartan.15 However, the recent meta-analysis showed superiority of CHIP diuretics over hydrochlorothiazide and even renin-angiotensin system inhibitors in the regression of LVH.8 The present study confirmed that CHIP diuretics surpassed hydrochlorothiazide in reducing LVM.7 An interesting recently published meta-analysis that included 7684 hypertensive patients showed that reduction in LV mass was significantly greater with calcium channel blockers than with beta-blockers (P < 0.02) without other significant differences between antihypertensive classes.5 However, the authors did not investigate the influence of different diuretics on LVH regression. Thiazide diuretics are blocking renal tubular reabsorption of sodium, which further reduces extracellular fluid volume and peripheral resistance. This can induce the activation of the renin-angiotensin and sympathetic nervous systems, which increases sensitivity of the AT1 receptor and enhancing the response to RAAS inhibitors. This is the reason why thiazides are more effective in combination with RAAS inhibitors, whereas CHIPs have an independent effect and therefore are more potent in LVH regression. One should not forget the potential adverse effect of diuretics, and this particularly refers to serum electrolyte levels. Chlorthalidone, indapamide, and hydrochlorothiazide have similar effects on serum potassium and could induce hypokalemia. On the others hand, spironolactone and eplerenone could induce hyperkalemia. This is the reason why serum electrolytes must be monitored before and during the treatment with these medications. It is also important to emphasize that indapamide not only has longer action duration than hydrochlorothiazide, but it also has a calcium channel blocker action.16 Furthermore, there is consistent evidence of greater hypotensive effect of indapamide and chlorthalidone compared to hydrochlorothiazide.17 In the conclusion, the present meta-analysis is providing evidence regarding beneficial effects of various diuretics on the regression of LVH in hypertensive population and represents an important part in the puzzle of evidence that diuretics should not be neglected in antihypertensive therapy not only in resistant hypertension, but also in other hypertensive patients. Considering the fact that the latest guidelines are recommending combined therapy as the first-line antihypertensive treatment, the present meta-analysis is providing additional evidence that diuretics in combination with other antihypertensive classes could be used as the first-line therapy in majority of hypertensive patients. None declared.