Gadi Shlomai

The association between normal-range admission potassium levels in Israeli patients with acute coronary syndrome and early and late outcomes

AbstractAbnormal serum potassium levels are associated with an increased risk of ventricular arrhythmias and mortality in patients with acute myocardial infarction (AMI). The aim of the present study was to evaluate whether different levels of serum potassium, within the normal range, are associated with worse outcomes. The present study comprised 1277 patients with AMI and normal-range admission potassium levels (3.5–5.2 mEq/L), who were enrolled and prospectively followed up in the Acute Coronary Syndrome Israeli Survey between 2010 and 2013. Patients were divided into 4 quartiles based on admission potassium levels; “normal-low” (K ≥ 3.5 and K ⩽ 3.9), “normal-moderate” (K > 3.9 and K ⩽ 4.18), “normal-high” (K > 4.18 and K ⩽ 4.45), and “normal-very high” (K > 4.45 and K ⩽ 5.2). We analyzed the association between admission serum potassium levels and 7 days in-hospital complication rates, and 30-day and 1-year all-cause mortality rates. Patients with “normal-very high” potassium displayed increased frequency of baseline clinical risk factors and experienced a higher rate of acute kidney injury during hospitalization compared with the “normal-low” group (7.7% vs 2.4%; P = 0.002). However, the rate of in-hospital ventricular arrhythmias was similar across the range of admission potassium levels (overall P = 0.26), Multivariate analysis showed that compared with “low-normal” potassium values, patients with “normal-very high” potassium levels experienced increased risk for 30-days (adjusted hazard ratio 2.88, 95% confidence interval 1.05–7.87, P = 0.039) and 1-year all-cause mortality (adjusted hazard ratio 1.98, 95% confidence interval 1.05–3.75, P = 0.034). In patients admitted with AMI, admission serum potassium levels of 4.45 to 5.2 mEq/L are not associated with in-hospital ventricular arrhythmias, but are associated with increased short and long-term mortality.

Serum potassium levels predict blood pressure response to aldosterone antagonists in resistant hypertension.

The objective of this study was to identify factors associated with the blood pressure (BP) response to spironolactone—aldosterone receptor antagonist as an add-on therapy in patients with resistant hypertension (HTN). We retrospectively reviewed the data of subjects with resistant HTN who were treated with add-on spironolactone in a large HTN clinic. A paired Student’s t-test was used to assess the differences between the BP values before and during spironolactone administration, and multivariate analysis was used to assess the predictors of a satisfactory BP response (a decrease in systolic BP >10%). We analyzed the data of 48 hypertensive participants. The add-on spironolactone therapy had a significant BP-lowering effect in both systolic and diastolic BP values (P<0.01 for both). Baseline serum potassium levels of <4.5 mEq l−1 were associated with a satisfactory BP response (P<0.01). Furthermore, every decrement of 1 mEq l−1 of serum potassium was independently associated with a fivefold higher rate of achieving a satisfactory BP response to spironolactone therapy (P=0.024). Additional factors independently associated with an improved systolic BP response were old age (P=0.033), body mass index (P=0.033) and high baseline systolic BP (P=0.004). Our results support the use of add-on spironolactone therapy in patients with resistant HTN who are elderly and obese and have high systolic BP and serum potassium levels <4.5 mEq l−1.

Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice.

BACKGROUND & AIMS ER stress promotes liver fat accumulation and induction of inflammatory cytokines, which contribute to the development of steatohepatitis. Unresolved ER stress upregulates the pro-apoptotic CHOP. IL-1α is localized to the nucleus in apoptotic cells, but is released when these cells become necrotic and induce sterile inflammation. We investigated whether IL-1α is involved in ER stress-induced apoptosis and steatohepatitis. METHODS We employed WT and IL-1α-deficient mice to study the role of IL-1α in ER stress-induced steatohepatitis. RESULTS Liver CHOP mRNA was induced in a time dependent fashion in the atherogenic diet-induced steatohepatitis model, and was twofold lower in IL-1α deficient compared to WT mice. In the ER stress-driven steatohepatitis model, IL-1α deficiency decreased the elevation in serum ALT levels, the number of apoptotic cells (measured as caspase-3-positive hepatocytes), and the expression of IL-1β, IL-6, TNFα, and CHOP, with no effect on the degree of fatty liver formation. IL-1α was upregulated in ER-stressed-macrophages and the protein was localized to the nucleus. IL-1β mRNA and CHOP mRNA and protein levels were lower in ER-stressed-macrophages from IL-1α deficient compared to WT mice. ER stress induced the expression of IL-1α and IL-1β also in mouse primary hepatocytes. Recombinant IL-1α treatment in hepatocytes did not affect CHOP expression but upregulated both IL-1α and IL-1β mRNA levels. CONCLUSION We show that IL-1α is upregulated in response to ER stress and IL-1α deficiency reduces ER stress-induced CHOP expression, apoptosis and steatohepatitis. As a dual function cytokine, IL-1α may contribute to the induction of CHOP intracellularly, while IL-1α released from necrotic cells accelerates steatohepatitis via induction of inflammatory cytokines by neighboring cells.

Assessment of target organ damage in the evaluation and follow-up of hypertensive patients: where do we stand?

Hypertension is associated with damage to the heart, kidneys, and vascular tree. Assessment of target organ damage (TOD) allows better prediction of cardiovascular risk than conventional risk assessment. Regression of TOD during antihypertensive treatment, which depends on the blood pressure (BP) reduction and the specific ancillary properties of each drug, may indirectly indicate that BP is well controlled. It is unclear whether regression of TOD during treatment is associated with favorable outcome and should be used as a surrogate endpoint. There is evidence that regression of left ventricular hypertrophy and albuminuria are associated with a favorable outcome. However, recent studies cast doubts on this evidence. Thus, assessment of TOD is important to define cardiovascular risk, but, so far, regression of TOD cannot be regarded as a major surrogate therapeutic target. The present paper will provide a critical overview of the data available in the literature.

The association between admission systolic blood pressure of heart failure patients with preserved systolic function and mortality outcomes

INTRODUCTION Heart failure is a major cause of death and disability and poses a significant public health concern. Approximately half of the patients admitted with heart failure, have preserved left ventricular ejection fraction. The association between systolic blood pressure (SBP) and long-term outcome in this group has not been well established. AIM The aim of our study is to evaluate the association between admission SBP and short term and long-term mortality outcomes in patients with heart failure and preserved systolic function. METHODS 1230 consecutive patients presenting with preserved left ventricular (LV) systolic function (defined as an LV ejection fraction ≥40%) were included in this survey. Patients were divided into quartiles according to admission SBP: low admission SBP (<127mmHg), intermediate admission SBP (128-145mmHg), high admission SBP (146-170mmHg) and very-high admission SBP (>170mmHg). Primary outcome included in hospital, one and four year mortality rates. RESULTS Elevated admission SBP was found to be associated with improved short and long-term mortality (HR=0.25 95% CI - 0.09-0.7, p=0.007 and HR=0.7 95% CI - 0.56-0.88, p=0.002 for the highest versus low SBP group, respectively). This finding was most notable in patients with acute heart failure and patients with ejection fraction≥50%. CONCLUSION Elevated admission SBP is associated with a favorable short and long-term outcome in patients with heart failure and preserved systolic function. KEY MESSAGE Low admission SBP is an independent predictor for short and long-term mortality in patients with HF and PSF.

Treating hypertension in type 2 diabetes

Introduction: The co-existence of hypertension and diabetes mellitus is very common. Hypertension remarkably increases the cardiovascular risk in diabetic patients. Lowering blood pressure (BP) in these patients is particularly beneficial. Areas covered: This paper will discuss what the target BP is for diabetic patients and how that target can be reached. Expert opinion: Previous guidelines recommended lowering BP < 130/80 mmHg in diabetic patients. However, recent studies did not support this target and accordingly most recent guidelines recommend lowering BP to < 140/90 mmHg in diabetic patients. Non-pharmacological approaches are recommended in all patients. If BP levels are above the target despite non-pharmacological treatment, drug therapy should be initiated. Despite the lack of clear evidence, blockers of the renin–angiotensin–aldosterone system (RAAS) represent the cornerstone of the antihypertensive arsenal; however, in most patients combination therapy is required. Combination of RAAS blocker and a calcium antagonist is the preferred one. In many patients three or four drugs are needed. Treatment should be individualized according to concomitant risk factors and diseases and according hemodynamic and laboratory parameters as well as age. In order to maximally reduce cardiorenal risk, lipid and glycemic control should also be achieved.

Knockdown of interleukin-1α does not attenuate LPS-induced production of interleukin-1β in mouse macrophages

IL-1α and IL-1β are synthesized as 31kDa cell-associated precursors following TLR-4 stimulation, but their processing to the mature form and secretion require a second intracellular stimulus. The unique localization of the precursor of IL-1α (pro-IL-1α) to the nucleus suggested a role in transcriptional regulation of inflammatory cytokines. We explored the hypothesis that pro-IL-1α is involved in regulation of IL-1β expression following TLR-4 stimulation. IL-1β mRNA and protein levels were specifically decreased in macrophages from IL-1α-deficient mice following TLR-1/2, TLR-4 or TLR-9 stimulation, supporting the hypothesis. However, activation of the main upstream regulators of IL-1β expression, IRF3, NFkB and p38/JNK, were not reduced in macrophages from IL-1α-deficient mice. In order to assess the specific role of IL-1α in macrophages, we generated mice with myeloid cell deficiency of IL-1α (LyzMCre-loxp). Despite over 90% knockdown of IL-1α, TLR-4 stimulated macrophages from LyzMCre-loxp mice did not produce lower levels of IL-1β compared to IL-1α-loxp-flanked mice. In order to overcome the possibility that effects are caused by the incomplete deficiency of IL-1α, we generated new whole-body IL-1α knockout mice (GeneralCre-IL-1α) and the findings were similar to myeloid cell-deficient IL-1α. Collectively, our findings do not support the previously suggested role of nuclear IL-1α in gene regulation of IL-1β. Rather, they suggest that IL-1α acts mainly as an alarmin that is sequestered in the nucleus following stimulation with TLR-4.

Should we change the target blood pressure in diabetic patients

Hypertension is a major modifiable risk factor for cardiovascular morbidity and mortality in diabetic patients. Guidelines recommend lowering blood pressure (BP) to less than 130/80 mmHg in diabetic patients. These recommendations are based on several studies in diabetic patients that showed the benefit of intensive BP control. However in all the studies the achieved BP was higher than 130/80 mmHg. Re‐evaluation of earlier studies, as well as more recently accumulated data suggest that intensive BP control is associated with a significant reduction in all‐cause mortality and stroke rate, but with no benefit for other microvascular or macrovascular (cardiac, renal and retinal) outcomes. Intensive BP control is associated with an increased risk of serious adverse effects, particularly for systolic BPs levels lower than 130 mmHg. When determining the target BP in diabetic patients one should balance the potential cerebrovascular protection against the increased risk of serious side effects, and the absence of benefit for other circulatory system. It seems therefore, that lowering BP to levels close to 130/80 mmHg should be the main goal of treatment in diabetic patients.