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BACKGROUND: Acute renal failure (ARF) following renal ischemia-reperfusion (I/R) injury is considered a relevant risk factor for cardiac damage, but the underlying mechanisms, particularly those triggered at cardiomyocyte level, are unknown. METHODS: We examined intracellular Ca2+ dynamics in adult ventricular cardiomyocytes isolated from C57BL/6 mice 7 or 15 days following unilateral renal I/R. RESULTS: After 7 days of I/R, the cell contraction was significantly lower in cardiomyocytes compared to sham-treated mice. It was accompanied by a significant decrease in both systolic Ca2+ transients and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity measured as Ca2+ transients decay. Moreover, the incidence of pro-arrhythmic events, measured as the number of Ca2+ sparks, waves or automatic Ca2+ transients, was greater in cardiomyocytes from mice 7 days after I/R than from sham-treated mice. Ca2+ mishandling related to systolic Ca2+ transients and contraction were recovered to sham values 15 days after I/R, but Ca2+ sparks frequency and arrhythmic events remained elevated. CONCLUSIONS: Renal I/R injury causes a cardiomyocyte Ca2+ cycle dysfunction at medium (contraction-relaxation dysfunction) and long term (Ca2+ leak), after 7 and 15 days of renal reperfusion, respectively.

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Hypertension mediated organ damage (HMOD) refers to structural or functional changes in arteries or target organs that can be present in long-standing hypertension, but it can be also found in naïve never treated patients. Traditionally, cardiovascular risk is stratified with charts or calculators that tend to underestimate the real cardiovascular risk. The diagnosis of HMOD automatically reclassifies patients to the highest level of cardiovascular risk. Subclinical HMOD can be present already at the diagnosis of hypertension and more than 25% of hypertensives are misclassified with the routine tests recommended by hypertension guidelines. Whether HMOD regression improves cardiovascular outcomes has never been investigated in randomized clinical trials and remains controversial. However, different drugs have been probed with promising results in high cardiovascular risk patients, such as the new antidiabetic or the novel non-steroid mineralocorticoid antagonists. Accordingly, trials have shown that lowering blood pressure reduces cardiovascular events. In this narrative review, we will discuss the role of HMOD in cardiovascular risk stratification, the different types of organ damage, and the evidence available to define whether HMOD can be used as a therapeutic target.

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Since the association of microalbuminuria (MAU) with cardiovascular (CV) risk was described, a huge number of reports have emerged. MAU is a specific integrated marker of CV risk and targets organ damage in patients with hypertension, chronic kidney disease (CKD), and diabetes and its recognition is important for identifying patients at a high or very high global CV risk. The gold standard for diagnosis is albumin measured in 24-hour urine collection (normal values of less than 30 mg/day, MAU of 30 to 300 mg/day, macroalbuminuria of more than 300 mg/day) or, more practically, the determination of urinary albumin-to-creatinine ratio in a urine morning sample (30 to 300 mg/g). MAU screening is mandatory in individuals at risk of developing or presenting elevated global CV risk. Evidence has shown that intensive treatment could turn MAU into normoalbuminuria. Intensive treatment with the administration of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, in combination with other anti-hypertensive drugs and drugs covering other aspects of CV risk, such as mineralocorticoid receptor antagonists, new anti-diabetic drugs, and statins, can diminish the risk accompanying albuminuria in hypertensive patients with or without CKD and diabetes.

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Arterial hypertension and chronic kidney disease (CKD) are intimately related. The control of blood pressure (BP) levels is strongly recommended in patients with CKD in order to protect the kidney against the accompanying elevation in global cardiovascular (CV) risk. Actually, the goal BP in patients with CKD involves attaining values <140/90 mmHg except if albuminuria is present. In this case, it is often recommended to attain values <130/80 mmHg, although some guidelines still recommend <140/90 mmHg. Strict BP control to values of systolic BP around 120 mmHg was recently shown to be safe in CKD according to data from the SPRINT trial, albeit more data confirming this benefit are required. Usually, combination therapy initiated with an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEi) and commonly followed by the addition of a calcium channel blocker and a diuretic is needed. Further studies are required as well as new drugs in particular after the positive data obtained from new oral anti-diabetic drugs.

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INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death worldwide. Blockade of this system is commonly used in the treatment of cardiovascular (CV) and renal disease. AREAS COVERED: Data from multiple clinical trials have provided good evidence about the benefit of blocking the system as a therapeutic target to reduce CV and renal events. We have reviewed all the tested combinations of different drugs counteracting the effects of the renin-angiotensin-aldosterone system. EXPERT OPINION: Monotherapy with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) remains valid in all the guidelines, whereas their dual combination has been discarded due to the absence of proven benefits in high CV risk patients and in patients with chronic kidney disease (CKD). The combination of the standard therapy with an ACEi or an ARB with a mineralocorticoid receptor blocker is a valid option, but has the inconvenience of frequent hyperkalemia in patients with CKD. Similarly, the addition of the direct renin inhibitor, aliskiren, to this standard therapy is not particularly supported in diabetic patients. New dual-acting blockers, for example, those combining valsartan and neprilysin inhibitors (LCZ696-Novartis) or endothelin converting enzyme inhibitors and neprilysin inhibitors (ECEI, Daglutril-Solvay), are currently under investigation.

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