Outcomes of correcting hyponatremia in patients with myocardial infarction

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1 Clin Res Cardiol (2013) 102: DOI /s z ORIGINAL PAPER Outcomes of correcting hyponatremia in patients with myocardial infarction Waqas Qureshi Syed Hassan Fatima Khalid Mohamed Faher Almahmoud Bhavik Shah Ra ad Tashman Nikhil Ambulgekar Mostafa El-Refai Chetan Mittal Zaid Alirhayim Received: 21 February 2013 / Accepted: 26 April 2013 / Published online: 8 May 2013 Ó Springer-Verlag Berlin Heidelberg 2013 Abstract Background Hyponatremia has significant prognostic implications in patients with heart, failure. However, little data are available regarding its significance in patients presenting with myocardial infarction. In addition, it is not known if correction of hyponatremia impacts outcomes in these patients. The aim of this study was to evaluate the prognostic value of hyponatremia in patients with myocardial infarction and the effect of its correction on allcause mortality. Methods Patients with the discharge diagnosis of myocardial infarction at our institution between 2000 and 2010 with serum sodium levels measured within 24 h of admission were included in this retrospective analysis. Multivariate analysis was used to determine the predictors of all-cause mortality. Cox proportional hazard model was applied to determine the adjusted survival. Results A total of 11,562 patients (67.15 ± 14.6 years, males 56.3 %) were included in the analysis. There were a total of 1,535 (13.3 %) deaths within mean follow-up duration of 5.5 ± 3.3 years. There were 425 (27.9 %) deaths in patients with corrected hyponatremia and 155 (55.3 %) deaths in persistent hyponatremia patients. Multivariate analysis indicated that corrected hyponatremia and persistent hyponatremia were independent predictors of all W. Qureshi S. Hassan (&) F. Khalid B. Shah R. Tashman N. Ambulgekar M. El-Refai C. Mittal Z. Alirhayim Department of Internal Medicine, Henry Ford Health Systems/ Wayne State University School of Medicine, 2799 W Grand Blvd, CFP-1, Detroit, MI 48202, USA drhassan911@gmail.com M. F. Almahmoud Department of Internal Medicine, St. John s Hospital, Gross Pointe, MI, USA cause mortality (p \ ). When analyzing short-term (30 days) and long-term mortality, corrected hyponatremia group did not have associated long term mortality. Various methods to correct hyponatremia were also analyzed and use of vaptans was associated with decrease in mortality in patients with hyponatremia from 115 to 125 (HR 0.45; 95 % CI , p = 0.005). Conclusion Our analysis showed that corrected and persistent hyponatremia in patients presenting with myocardial infarction is a predictor of all-cause mortality, major adverse cardiac events and heart failure related 30 day rehospitalization. In certain cases, correction of hyponatremia may actually improve survival of the patients. Keywords Myocardial infarction Hyponatremia Vaptan Outcomes Introduction For the physician in clinical practice, hyponatremia remains the most commonly faced electrolyte abnormality [1]. Its prevalence estimate ranges from 3.2 million to 6.1 million persons in the US annually [2]. The direct cost of treating hyponatremia in the US on an annual basis is estimated to range between $1.6 billion and $3.6 billion [2]. Mortality rates as high as 60-fold greater have been reported in hyponatremic patients when compared to their normonatremic controls [3]. The severity of the hyponatremia also appears to directly correlate with the risk for such adverse outcomes, particularly in patients with heart failure [3 6]. Whether hyponatremia plays a causative role in this equation remains debatable but the thought is a tantalizing one. In rat ventricular myocytes for instance, hyponatremia in the setting of heart failure has been

2 638 Clin Res Cardiol (2013) 102: demonstrated to result in decreased calcium conductance and hence depressed cardiac contractility [7]. Such a role suggests that its correction may offer novel therapeutic strategies in heart failure management. The mechanisms responsible for hyponatremia in patients with congestive heart failure or acute myocardial infarction appear to operate in a similar fashion. Unlike in heart failure however, literature on patients presenting with acute myocardial infarction and concomitant hyponatremia has produced more mixed results and is less comprehensive. Some studies have shown hyponatremia in patients presenting with acute myocardial infarction (MI) and undergoing percutaneous coronary intervention (PCI) to be independently associated with an increased risk of developing cardiogenic shock [8], inhospital mortality [9], and an overall decline in 1-year long-term survival [8]. However, to our knowledge none of the previous studies have evaluated the changes in serum sodium levels from admission till discharge or death and if correction of the admission hyponatremia is related to improved outcomes. This study was designed to assess the prognostic value of hyponatremia in patients presenting with acute myocardial infarction. In addition, we sought to investigate the impact of correcting hyponatremia on such outcomes, including all-cause mortality. Methods We retrospectively obtained a cohort of consecutive patients that was diagnosed with myocardial infarction from an administrative database at Henry Ford Health Systems, Michigan, encompassing a period of 10 years (January 2000 December 2010). Patients were eligible to be included in the study if they had at least two serum sodium levels measured within 24 h of admission and within 24 h of discharge or death. The study protocol was approved by the institutional review board. A detailed chart review was carried out to ascertain patients with non-st elevation myocardial infarction and ST elevation myocardial infarction. We defined hyponatremia as corrected serum sodium level (Na? (Serum Glucose (mg/dl) - 100) ) B 134 meq/l. Persistent hyponatremia was defined as presence of hyponatremia within first 24 h of admission and within last 24 h prior to discharge or death. Corrected hyponatremia was defined as presence of hyponatremia within 24 h of presentation but normonatremia within 24 h of discharge or death. We defined patients with acute coronary syndrome (ACS) based on the ACC/AHA guidelines, which defines ACS based on symptoms, ECG and cardiac biomarkers. The diagnosis was adjudicated by a panel of three researchers (C.M., F.K., S.H.) who were blinded to the aim of the study. In case of disagreement, consensus was made with mutual agreement. Heart failure-related hospitalization was defined as presentation of the patient within 30 days of discharge with primary or secondary diagnosis of acute heart failure exacerbation. Major adverse cardiac event was defined as a composite outcome of cardiovascular related death, non fatal myocardial infarction and target vessel revascularization. Cardiac biomarkers, troponin and CK-MB were used to identify patients with myocardial infarction. ECG was used to determine STEMI versus non STEMI. Heart failure was defined by the presence of two of the following: symptoms of heart failure, S3, documented pulmonary rales, or chest X-ray findings of heart failure. Method to correct hyponatremia was defined as the last method used prior to correction of hyponatremia. Patients with end-stage liver disease, hypothyroidism, aldosterone deficiency, pseudohyponatremia and patients dying or discharged within 48 h were excluded from the sample. Patients dying within 48 h were excluded so that adequate time is available for sodium to equilibrate. Primary outcome The primary outcome was 30 day short-term and long-term all-cause mortality. Death data were obtained by querying social security index. Secondary outcomes Secondary outcomes were as follows: (a) Composite outcome of non fatal myocardial infarction, target vessel revascularization, and cardiovascular-related death (b) Congestive heart failure-related 30 day rehospitalization. Statistical analysis Continuous variables were expressed as mean ± standard deviation and categorical variables were demonstrated as percentages. Continuous variables were compared using t test and categorical variables were compared using Chisquare analysis or Fischer exact test when appropriate. Cox proportional hazard model was utilized to calculate admission hyponatremia and discharge hyponatremia as predictors for all-cause mortality. Survival analysis was performed using Kaplan Meier s method for patients with persistent hyponatremia, corrected hyponatremia and normonatremia. Area under the curve was calculated from

3 Clin Res Cardiol (2013) 102: receiver operating curve with outcome as all-cause mortality with serum sodium as continuous variable. We also performed analysis for various adverse outcomes, for various methods used to correct hyponatremia using Cox proportional hazard model and adjusting for Framingham risk score, obstructive CAD, LDL, diabetes mellitus, prior coronary artery disease, prior aspirin use, beta blocker, angiotensin receptor blocker/angiotensin converting enzyme inhibitor use and race. This analysis was also performed for subgroups of hyponatremia namely, \115, , with outcome as all-cause mortality. Subgroups of patients were divided on the basis of presence of heart failure and ST segment elevation. Results Study population A total of 11,562 patients (67.15 ± 14.6 years, males 56.3 %) were included in the analysis. Out of these, 752 (6.5 %) patients had STEMI and 10,810 (93.5 %) patients with NSTEMI. There were 1,798 (15.5 %) patients with hyponatremia on admission, 280 (2.4 %)patients had persistent hyponatremia, while in 1,518 (13.1 %) patients hyponatremia was normalized at discharge or prior to death. There were 454 (3.9 %) patients that presented with acute heart failure on admission. Baseline characteristics of patients with normonatremia, corrected hyponatremia and persistent hyponatremia are shown in Table 1. Patients were grouped into four groups, namely patients with NSTEMI with heart failure, NSTEMI without heart failure, STEMI with heart failure, STEMI without heart failure. The distribution of serum sodium levels in these different groups is given in Fig. 1. Persistent and corrected hyponatremia patients were more likely than normonatremic patients to have a lower ejection fraction, elevated creatinine on admission, longer length of stay, previous diagnosis of heart failure, previous use of thiazide or loop diuretics but not aldosterone blocker usage, and ICU stay. Persistent hyponatremia patients were more likely to have higher number of inpatient medications. Table 1 Baseline characteristics Variable Total Normonatremia Corrected hyponatremia Persistent hyponatremia p value N 11,562 9,764 (81.1 %) 1,518 (13.1 %) 280 (2.4 %) Age (years) ± ± ± ± Men 6,510 (56.3 %) 5,506 (56.4 %) 850 (55.9 %) 154 (55.0 %) 0.12 Race African American 4,828 (41.7 %) 4,048 (41.4 %) 660 (43.3 %) 120 (42.8 %) 0.45 Caucasians 5,748 (49.7 %) 4,826 (49.4 %) 790 (52.0 %) 132 (47.1 %) 0.23 STEMI without heart failure 540 (4.7 %) 212 (2.2 %) 96 (6.3 %) 20 (7.1 %) Previous history of heart failure 453 (3.9 %) 258 (2.6 %) 137 (9.0 %) 48 (17.1 %) STEMI with heart failure 212 (1.8 %) 114 (1.1 %) 80 (5.2 %) 18 (6.4 %) NSTEMI with heart failure 242 (2.1 %) 144 (1.5 %) 58 (3.8 %) 40 (14.3 %) NSTEMI without heart failure 10,780 (93.2 %) 9,294 (95.2 %) 1,284 (84.5 %) 202 (72.1 %) Hypertension 4,416 (38.2 %) 3,755 (38.4 %) 560 (36.9 %) 101 (36.1 %) 0.06 Diabetes mellitus 5,090 (44.2 %) 4,138 (42.3 %) 786 (51.7 %) 166 (59.8 %) Smoking 4,763 (40.5 %) 4,054 (41.5 %) 598 (39.4 %) 111 (39.6 %) 0.17 Family history of premature cardiac disease 1,544 (13.3 %) 1,301 (13.3 %) 198 (13.0 %) 38 (13.9 %) 0.65 Dyslipidemia 2,675 (23.1 %) 2,238 (22.9 %) 369 (24.3 %) 68 (24.3 %) 0.53 Framingham risk score 12.4 ± ± ± ± Serum creatinine 1.0 ± ± ± ± Revascularization 2,354 (20.4 %) 1,618 (16.6 %) 578 (38.1 %) 158 (56.4 %) Number of inpatient medications (median) 17 (7 27) 16 (7 26) 17 (7 27) 18 (9 27) 0.04 Prior aspirin use 3,538 (30.6 %) 3,018 (30.9 %) 440 (29.0 %) 80 (28.8 %) 0.07 Prior ACE inhibitors or ARB use 3,110 (26.8 %) 2,628 (26.9 %) 409 (26.9 %) 73 (26.1 %) 0.75 Prior aldosterone antagonists use 1,075 (9.2 %) 905 (9.2 %) 145 (9.5 %) 25 (8.9 %) 0.55 Prior loop diuretics 649 (5.6 %) 490 (5.0 %) 136 (8.9 %) 23 (8.2 %) 0.01 Prior thiazide diuretics 2,378 (20.6 %) 1,910 (19.5 %) 395 (26.0 %) 73 (26.1 %) Prior beta blockers 1,789 (15.4 %) 1,506 (15.4 %) 240 (15.8 %) 43 (15.3 %) 0.33 Ejection fraction (mean) 55.8 ± ± ± ± Length of stay 3.4 ± ± ± ± ICU length of stay 1.2 ± ± ± ±

4 640 Clin Res Cardiol (2013) 102: Patients with persistent hyponatremia There were 425 (27.9 %) deaths, 473 (31.1 %) major adverse cardiac events, 304 (20.0 %) heart failure-related 30 day rehospitalizations in patients with corrected hyponatremia. Corrected hyponatremia was associated with short-term mortality (HR 2.12; 95 % CI , p = ) but not with long-term mortality (HR 1.17; 95 % CI , p = 0.28). It was also associated with high 1-year major adverse cardiac events (HR 1.28; 95 % CI , p = ) and increase in 30 day heart failure rehospitalization (HR 1.73; 95 % CI , p = ). Fig. 1 Box and whisker graph demonstrating the serum sodium levels in various groups of myocardial infarction with and without heart failure Adverse outcomes Adverse outcomes were evaluated for both groups of patients (a) patients with corrected hyponatremia, (b) patients with persistent hyponatremia (Table 2). Patients with persistent hyponatremia There were 155 (55.3 %) deaths, 57 (20.3 %) major adverse cardiac events, 57 (20.3 %) heart failure-related 30 day rehospitalization in patients with persistent hyponatremia. Persistent hyponatremia was associated with short-term mortality (HR 2.12; 95 % CI , p = ) and long-term mortality (HR 5.45; 95 % CI , p = ). It was also associated with high 1-year major adverse cardiac events (HR 1.58; 95 % CI , p = 0.004) and increase in 30 day heart failure rehospitalization (HR 1.53; 95 % CI , p = 0.001). Persistent versus corrected hyponatremia When comparing the corrected hyponatremia with persistent hyponatremia, there was no difference in mortality and major adverse cardiac events but corrected hyponatremia was associated with decrease in 30 day rehospitalization (HR 0.71, 95 % CI , p = 0.04). Achieving normonatremia at discharge had no effect on short-term mortality (HR 0.98, 95 % CI , p = 0.74) but was associated with decrease in long-term mortality (HR 0.24, 95 % CI , p = ) as compared to persistent hyponatremia. When the patients were divided into groups of myocardial infarction with and without heart failure, there was higher number of deaths in the patients with heart failure. Patients with heart failure were also more likely to have persistent hyponatremia as shown in Fig. 2. Target vessel revascularization was an independent predictor of achieving correction of hyponatremia (OR 1.3; 95 % CI , p = ). When comparing 1-year mortality by Kaplan Meier s method, there was a significant difference between the survival between normonatremia, corrected hyponatremia Table 2 Outcomes on the basis of groups of persistent and corrected hyponatremia Outcomes Univariate HR p value Adjusted HR p value Persistent hyponatremia All-cause short-term mortality 2.30 ( ) ( ) All-cause long-term mortality 6.89 ( ) ( ) Heart failure hospitalization 1.67 ( ) ( ) Major adverse cardiac events 1.77 ( ) ( ) Corrected hyponatremia All-cause short-term mortality 2.05 ( ) ( ) All-cause long-term mortality 2.06 ( ) ( ) 0.28 Heart failure hospitalization 1.67 ( ) ( ) Major adverse cardiac events 2.23 ( ) ( )

5 Clin Res Cardiol (2013) 102: Subgroup analysis Various subgroups of hyponatremia by severity were analyzed separately to evaluate the effects of various corrective measures in patients with hyponatremia as shown in Table 4. Vaptan use was associated with decreased short term mortality when correcting hyponatremia in patients with sodium levels meq/l. Serum sodium as predictor of mortality Fig. 2 Bar graph demonstrating the distribution of various groups of hyponatremia amongst classes of myocardial infarction with and without heart failure The optimum cut off calculated from receiver operating curve was calculated to be 134. This value had a sensitivity of 37.5 % and specificity of 87.9 % of predicting 1-year long term all-cause mortality. Area under the curve for serum sodium of 134 was AUC 0.603; 95 % CI , p = The likelihood ratios were in the ranges of 1 2 for serum sodium levels , 2 3 for and [15 for serum sodium B115 for all-cause mortality as outcome. The receiver operating curve is shown in Fig. 4. Discussion Fig. 3 Kaplan Meier s demonstrating 1-year survival probability in various categories of hyponatremia and persistent hyponatremia groups (Log rank = , Fig. 3). Methods to correct hyponatremia At least one method was identified that was used to correct hyponatremia in 1,558 (87.0 %) of the patients with hyponatremia. The most common method employed to correct hyponatremia was water restriction (1,321, 73.8 %), however another method was used frequently that eventually led to the correction of hyponatremia. Most common method that corrected hyponatremia was the use of a diuretic (Table 3). The findings of this study demonstrate that both persistent and corrected hyponatremia are predictors of adverse outcomes, and that most methods instituted in correction of hyponatremia, with the exception of vaptans, had no short term mortality benefit in patients presenting with myocardial infarction. Consistent with prior studies, we found persistent hyponatremia conferred increased risk of adverse outcomes including short, long term mortality, and readmissions. Prior to this study, it remained unknown whether correction of hyponatremia had any influence on these adverse outcomes. When compared to patients with persistent hyponatremia, we found patients with hyponatremia that had corrected at discharge experienced a reduction in long term risk of mortality and rehospitalization. Previous studies had evaluated hyponatremia only in the context of an adverse biomarker that predicts mortality and morbidity. We hypothesize from our findings that hyponatremia in itself may have a pathophysiological effect on body fluids and myocardium that might lead to increase in mortality and morbidity. Very little is known about the effects of hyponatremia on the myocardium but evidence has shown a decreased extracellular sodium level to result in decreased calcium conductance into myocardial cells and depress cardiac contractility [7]. Hyponatremia has been associated with ventricular ectopy [10], known to trigger cardiac conduction defects and even apical ballooning [11, 12].

6 642 Clin Res Cardiol (2013) 102: Table 3 Methods to correct hyponatremia and association with 30 day adverse outcomes Outcomes Diuretics p value Vaptans p value 3 % normal saline p value Water restriction p value Persistent hyponatremia n All cause 30 day mortality 1.01 ( ) Heart failure hospitalization 0.46 ( ) Major adverse cardiac events 0.58 ( ) Corrected hyponatremia ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) n All cause 30 day mortality 1.08 ( ) 30 day Heart failure hospitalization 0.81 ( ) Major adverse cardiac events 0.86 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Analysis adjusted for Framingham risk score, obstructive CAD, LDL, diabetes mellitus, prior coronary artery disease, prior aspirin use, beta blocker, angiotensin receptor blocker/angiotensin converting enzyme inhibitor use and race Table 4 Subgroup analysis of various corrected hyponatremia ranges and short term 30 day mortality Serum sodium Vaptans p value Diuretics p value 3 % normal saline p value Water restriction p value \ ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.24 Analysis adjusted for Framingham risk score, obstructive CAD, LDL, diabetes mellitus, prior coronary artery disease, prior aspirin use, beta blocker, angiotensin receptor blocker/angiotensin converting enzyme inhibitor use and race Fig. 4 Receiver operating curve demonstrating the sensitivity and specificity for predicting death when sodium was B134 Not all methods of hyponatremia correction appear to be equal however. Our initial analysis of ACS patients achieving correction demonstrated no mortality benefit and, in some instances like hypertonic saline, led to increased readmission rates and adverse cardiac outcomes. When subgroup analysis was performed, correction achieved through vaptan use was associated with significant reduction in 30 day mortality when initial serum sodium levels lay between 115 and 125 meq/l. No such benefit was seen in sodium levels outside this range or on long-term mortality. These findings led us to propose varying roles for sodium and AVP in the initial hours of an MI where hyponatremia is likely a bystander, early days to weeks where AVP drives hyponatremia, and later weeks and months when LV remodeling finally results. Early in acute MI, even in the absence of coexisting heart failure, there is intense sympathetic neural hyperactivity [13]. This results in increased levels of hormones such as AT II, aldosterone, ANP and catecholamines which correlate directly with infarct size. Similar to mechanisms operating in heart failure, the profound neurohormonal activation in acute MI

7 Clin Res Cardiol (2013) 102: serves to impair sodium and water delivery at the collecting ducts of the kidney and results in hyponatremia [14 17]. It is likely that in the very initial hours of an MI, hyponatremia is more likely a bystander or marker of disease severity. Even in these initial hours, AVP levels begin to rise concomitantly with the activation of other neurohormones [14]. It takes at least a few days however before increased vasopressin levels translate into increased aquaporin in the collecting duct cells of the kidney since transcription of the AQP-2 gene and rise in its mrna levels must take place first [18, 19]. We theorize that early effects of AVP are still reversible, explaining why vaptan may have shown benefit in 30 day mortality. It is probably at this phase, where the prescribed method of correcting hyponatremia i.e. AVP antagonism assumes the greatest importance. In the weeks and months that follow an acute MI, ventricular remodeling continues to take place through neurohormonal mechanisms, including AVP [20]. Such effects of AVP on mammalian myocardium include continued myocardial protein synthesis and fibroblast proliferation further resulting in irreversible structural changes [21]. At this juncture, AVP antagonism may already be too late. Indeed some experimental models of myocardial infarction have succeeded in preventing heart failure by employing AVP antagonism with agents such as conivaptan and tolvaptan [22]. When sodium levels are\115 meq/l, detrimental effects of hyponatremia tend to be accentuated hence offsetting any potential benefit vaptan may have. Overly rapid correction of hyponatremia is also likely more dangerous at lower sodium levels, something which vaptan itself can cause [23]. These findings suggest that correction of hyponatremia is as important as selection of the timing and method of correction. In addition to mortality reduction, we found patients with hyponatremia corrected at discharge had lower 30 day rehospitalization rates compared to patients who were not corrected. Such information will likely be important to the internist managing the patient with myocardial infarction and persistent hyponatremia. Our data only took into account admission and discharge hyponatremia and did not take into account fluctuations in sodium levels during the hospitalization. Further studies are required to evaluate the fluctuations of serum sodium levels during hospitalization and whether they are related to adverse outcomes. Finally, given the vastly different effects of vasopressin on the heart [24], further study is needed to assess which patients with myocardial infarction are likely to reap the greatest benefit from AVP antagonists. Limitations Several limitations of our study deserve mention. Most importantly, this was a single site retrospective study and the effect of confounding or unmeasured factors can influence outcomes. We did not evaluate for fluctuations of hyponatremia during inpatient hospitalization, the study was not adequately powered to detect differences for some of the methods used in correction of hyponatremia. We did not have data regarding levels of neurohormones, which likely played a crucial role in development of hyponatremia. Conclusion In conclusion, persistent and corrected hyponatremia were both predictive of adverse outcomes. We also demonstrated short-term mortality benefit when vaptan use achieved correction of serum sodium levels between 115 and 125 meq/l. The study also offered insight into the importance of timing and methods of hyponatremia correction likely to achieve benefit. References 1. Anderson RJ, Chung HM, Kluge R, Schrier RW (1985) Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. 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