- Email: [email protected]
Systolic blood pressure during exercise testing and the risk of sudden cardiac death
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Letters to the Editor
Systolic blood pressure during exercise testing and the risk of sudden cardiac death☆ Jari A. Laukkanen a,b,⁎, Rainer Rauramaa c,d a
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland Lapland Central Hospital, Department of Internal Medicine, Rovaniemi, Finland Kuopio Research Institute of Exercise Medicine, Kuopio, Finland d Department of Clinical Physiology and Nuclear Medicine, University Hospital of Kuopio, Kuopio, Finland b c
a r t i c l e
i n f o
Article history: Received 5 April 2013 Accepted 6 April 2013 Available online 4 May 2013 Keywords: Systolic blood pressure Exercise testing Prospective study Sudden cardic death
Blood pressure during exercise testing corresponds with blood pressure reactivity during the daily physical activities [1]. Resting blood pressure is a well defined measure for risk stratification in the general population. However, little is known if blood pressure measured during exercise testing provides additional prognostic value in conjunction with the assessment of resting blood pressure in the prediction of the risk of sudden cardiac death (SCD). Our previous study has shown that both resting systolic and diastolic blood pressure were related to the risk of SCD; men with elevated systolic blood pressure (SBP) of N145 mm Hg had a 2.04-fold (95% confidence interval 1.23–2.52, p = 0.003) risk for SCD compared to those men with SBP of b123 mm Hg, after adjustment for age and common cardiovascular risk factors [2]. An abnormally high blood pressure in the arteries during exercise could be a significant factor in the process of unexpected plaque rupture that may lead to SCD. A certain proportion of SCDs have been found to be caused by plaque rupture in patients with hypertension and severe changes in coronary arteries [3,4]. Hypertension has been associated with atherosclerosis progression, impaired endothelium-dependent arterial relaxation, increased susceptibility to intimal tears owing to increased medial collagen synthesis and decreased arterial wall elasticity, and increased hypoxia caused by increased diffusion distances due to intima–media thickening [3,4]. Hypertension with left ventricular hypertrophy may lead to longer action potential durations and vulnerability to fatal arrhythmias [5]. A supplementary analysis showed whether blood pressure from exercise to recovery phase is associated with the risk of SCD. This part of the prospective study was based on data obtained from 2366 participants who had undergone exercise testing with the assessment of blood pressure [6]. A maximal symptom-limited exercise test was performed using a cycle ergometer. The standardized testing protocol consisted of a progressive increase in the workload of 20 W per minute. A total of 30% of the men had diagnosed hypertension, of which 21% were using antihypertensive medication regularly. During the symptom-limited exercise test, mean maximal SBP and SBP at 2 minutes recovery phase from exercise were 203 mmHg and ☆ This work was supported by the Academy of Finland, Helsinki, Finland; the Ministry of Education Helsinki, Finland; City of Kuopio, Kuopio, Finland; Finnish Medical Foundation, Helsinki, Finland, and Finnish Cultural Foundation, Helsinki, Finland. ⁎ Corresponding author at: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. Tel.: +358 17 162950; fax: +358 17 162936. E-mail address: jariantero.laukkanen@uef.fi (J.A. Laukkanen).
184 mmHg, respectively. Resting SBP is positively correlated with SBP during recovery (r = 0.53, p b 0.001). A death was determined SCD when it occurred after the onset of an abrupt change in symptoms or within 24 hours of the onset of symptoms and a total of 180 SCDs occurred during the follow-up of 19 years. SBP at 2 minutes recovery from exercise, cardiorespiratory fitness and ischemic ST-depression during exercise were related to the risk of SCD when other conventional risk factors were taken into account. However, after additional adjustment for resting SBP, SBP during recovery from exercise became non-significant whereas cardiorespiratory fitness and ischemic ST-depression during exercise were still associated with the risk of SCD. When maximal SBP and SBP at 2 minutes recovery from exercise were included into the multivariable model with risk factors, SBP during recovery from exercise was a stronger predictor of the risk of SCD. The risk for all-cause death was increased in men with SBP at 2 minutes recovery from exercise N195 mmHg as compared to men with SBP of b175 mmHg, but SBP at 2 minutes recovery from exercise was not related to the risk of non-SCD. The inclusion of SBP at 2 minutes recovery from exercise for the model with risk factors and exercise testing variables did not lead to a significant change in the C-index and net reclassification index. Our study suggested that SBP during recovery from exercise was no longer a significant predictor for SCD after accounting for resting SBP with other risk factors. An independent value of exercise blood pressure is diminished partly due to the relatively strong correlation between resting and exercise blood pressure. This finding is consistent with previous studies showing the value of exercise blood pressure in the prediction of cardiovascular death using an appropriate adjustment for resting blood pressure [7,8]. Secondly, the assessment of resting SBP is an easily available method compared to the definition of SBP during and after exercise testing for the risk prediction of SCD [2]. The routine assessment of SBP during recovery from exercise at a single time-point is not necessary for SCD risk prediction. The significance of SBP during recovery could not have been remarkable since information on SBP at rest with other common risk factors have been evaluated. There may be some patients who had an elevated blood pressure with inadequate treatment as well as subjects with borderline or prehypertensive state without drugs. It has been shown that an elevated blood pressure during exercise identified high risk subjects with either normal or prehypertension at rest and added predictive value to resting blood pressure for the prediction of cardiovascular risk [8]. In our study, a significant relationship between an elevated SBP during recovery from exercise and the risk of SCD was observed in a subgroup of men without previously diagnosed coronary heart disease or the use of antihypertensive medication. Antihypertensive medication and the use of βblockers have normally been recommended for decreasing a high resting blood pressure, and the use of antihypertensive medication may also lead to an attenuated response of blood pressure during exercise. The use of β-blockers might be protective among those with exerciserelated hypertension in the prevention of fatal cardiac outcomes such as SCD in the general population as well as among patients with prevalent coronary heart disease. Previous findings have shown that both low cardiorespiratory fitness and ischemic ST depression during exercise are associated with the risk of SCD [6,9], although the value of SBP during recovery from exercise would be limited in the general population. Exercise testing
Letters to the Editor
should be still considered as an important clinical tool and prognostic measure as both cardiorespiratory fitness and exercise-induced STdepression are risk markers for SCD. References [1] Laukkanen JA, Kurl S. Blood pressure responses during exercise testing – is up best for prognosis? Ann Med 2012;44:218–24. [2] Laukkanen JA, Jennings JR, Kauhanen J, Mäkikallio TH, Ronkainen K, Kurl S. Relation of systemic blood pressure to sudden cardiac death. Am J Cardiol 2012;110:378–82. [3] Burke AP, Farb A, Malcom GT, Liang Y, Smialek JE, Virmani R. Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA 1999;281:921–6. [4] Burke AP, Farb A, Malcom GT, Liang YH, Smialek JE, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276–82.
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[5] Frohlich ED, Apstein C, Chobanian AV, et al. The heart in hypertension. N Engl J Med 1992;327:998–1008. [6] Laukkanen JA, Mäkikallio TH, Rauramaa R, Kiviniemi V, Ronkainen K, Kurl S. Cardiorespiratory fitness is related to the risk of sudden cardiac death. A Populationbased follow-up study. J Am Coll Cardiol 2010;56:1476–83. [7] Fagard RH, Pardaens K, Staessen JA, Thijs L. Prognostic value of invasive hemodynamic measurement at rest and during exercise in hypertensive men. Hypertension 1996;28:31–6. [8] Weiss SA, Blumenthal RS, Sharrett AR, Redberg RF, Mora S. Exercise blood pressure and future cardiovascular death in asymptomatic individuals. Circulation 2010;121:2109–16. [9] Laukkanen JA, Mäkikallio TH, Rauramaa R, Kurl S. Asymptomatic ST-segment depression during exercise testing and the risk of sudden cardiac death in middleaged men. A population-based follow-up study. Eur Heart J 2009;30:558–65.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.04.129
The maladaptive effects of HIV protease inhibitors (lopinavir/ritonavir) on the rat heart☆ Kathleen M.S.E. Reyskens 1, M. Faadiel Essop ⁎,1 Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa
a r t i c l e
i n f o
Article history: Received 5 April 2013 Accepted 6 April 2013 Available online 11 May 2013 Keywords: HIV-AIDS HIV protease inhibitors Cardiovascular diseases Ischemia-reperfusion Metabolism
Protease inhibitors (PIs) form an integral part of highly active antiretroviral treatment (HAART) and are linked to increased risk for myocardial infarction [1] and cardiovascular abnormalities [2,3], with many changes resembling coronary artery disease [4]. Despite such progress the underlying molecular mechanisms responsible for HAARTinduced cardio-metabolic side effects remain poorly understood and little is known about the earliest events driving this process. We therefore hypothesized that PI treatment detrimentally alters cardiac calcium signaling and energetics, thereby attenuating contractile function at baseline and in response to myocardial ischemia. We investigated our hypothesis by establishing a unique rat model of chronic PI drug delivery and for the first time evaluate ex vivo heart function. Lopinavir/ritonavir (Kaletra™, Abbott Laboratories, Abbot Park IL) was crushed and dissolved in 1% ethanol (vehicle) at human steady-state plasma concentration (7.1 ± 2.9 μg/mL), sterile filtered and injected into a surgically inserted mini-osmotic pump (Alzet, Cupertino CA). Male Wistar rats (180–220 g) received either: mock surgery (sham), vehicle-, or a PI-containing pump for a total of 8 weeks (n = 8 per group). Here we ☆ This work was supported by the South African National Research Foundation and Stellenbosch University (to MFE). ⁎ Corresponding author. Tel.: +27 21 808 3146; fax: + 27 21 808 3145. E-mail address: [email protected] (M.F. Essop). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
attempted to simulate a relatively early stage of PI treatment, i.e. if the average lifespan of 2–3 years is taken for Wistar rats then 8 weeks translates to ~6% of its total lifespan. This would correspond to ~2–3 years of PI treatment for a 30 year-old started on HAART treatment and with a life expectancy of ~60–70 years. Animals were treated in accordance with the Guide for the Care and Use of Laboratory Animals of the National Academy of Sciences (NIH publication No. 85-23, revised 1996) and performed with the approval of the Animal Ethics Committee of Stellenbosch University (South Africa). To assess baseline function, hearts were retrogradely perfused (Langendorff) for 60 min as described before by us [5]. For the ischemia-reperfusion experiments, the 60 min stabilization period was followed by 30 min global ischemia and 60 min reperfusion (functional recovery assessments), while infarct sizes in response to regional ischemia was determined as described [5]. Superoxide, calcium and ATP levels and superoxide dismutase (SOD) activity in heart tissue homogenates were evaluated using standard commercial kits. Western blotting methods were employed for the determination of 5′-AMP-activated protein kinase-alpha (AMPKα) and sarco(endo) plasmic reticulum calcium-2a (SERCA-2a) pump expression levels and beta-actin used as loading control. Data are presented as mean ± SEM and one-way ANOVA performed with the exception of heart function (two-way ANOVA), including the Bonferroni post-hoc test (GraphPad Prism v5, San Diego CA). PI-treated rats exhibited weight gain 467 ± 18.1 vs. 385 ± 17.2 g (sham) (p b 0.001) and vs. 400 ± 18.1 g (vehicle) (p b 0.001) (Fig. 1A). Ex vivo perfusion data show that PI treatment decreased left ventricular developed pressure (LVDP) to 35.50 ± 1.55 vs. 60.88 ± 2.4 mm Hg (sham) (p b 0.01) and vs. 53.14 ± 6.61 mm Hg (vehicle) (p b 0.001) (Fig. 1B). Likewise, rate pressure product (RPP) was also attenuated in PI-treated hearts (Fig. 1C). Following global ischemia, LVDP was lower in the PI-treated group, i.e. to 3.0 ± 2.36 vs. 35.38 ± 7.03 mm Hg (sham) (p b 0.001) and vs. 27.43 ± 5.07 mm Hg (vehicle) (p b 0.05) (Fig. 1D). A similar pattern was found for RPP (Fig. 1E). PIs also robustly increased infarct size to 79.2 ± 40.7% vs. 46.3 ± 5.7% (sham) (p b 0.01) and vs. 39.4 ± 8.4% (vehicle) (p b 0.01) (Fig. 1 F). Further, the percentage of LVDP recovery after ischemia did not significantly differ for the PI-treated group compared to matched controls (p N 0.05, data not
Letters to the Editor
Systolic blood pressure during exercise testing and the risk of sudden cardiac death☆ Jari A. Laukkanen a,b,⁎, Rainer Rauramaa c,d a
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland Lapland Central Hospital, Department of Internal Medicine, Rovaniemi, Finland Kuopio Research Institute of Exercise Medicine, Kuopio, Finland d Department of Clinical Physiology and Nuclear Medicine, University Hospital of Kuopio, Kuopio, Finland b c
a r t i c l e
i n f o
Article history: Received 5 April 2013 Accepted 6 April 2013 Available online 4 May 2013 Keywords: Systolic blood pressure Exercise testing Prospective study Sudden cardic death
Blood pressure during exercise testing corresponds with blood pressure reactivity during the daily physical activities [1]. Resting blood pressure is a well defined measure for risk stratification in the general population. However, little is known if blood pressure measured during exercise testing provides additional prognostic value in conjunction with the assessment of resting blood pressure in the prediction of the risk of sudden cardiac death (SCD). Our previous study has shown that both resting systolic and diastolic blood pressure were related to the risk of SCD; men with elevated systolic blood pressure (SBP) of N145 mm Hg had a 2.04-fold (95% confidence interval 1.23–2.52, p = 0.003) risk for SCD compared to those men with SBP of b123 mm Hg, after adjustment for age and common cardiovascular risk factors [2]. An abnormally high blood pressure in the arteries during exercise could be a significant factor in the process of unexpected plaque rupture that may lead to SCD. A certain proportion of SCDs have been found to be caused by plaque rupture in patients with hypertension and severe changes in coronary arteries [3,4]. Hypertension has been associated with atherosclerosis progression, impaired endothelium-dependent arterial relaxation, increased susceptibility to intimal tears owing to increased medial collagen synthesis and decreased arterial wall elasticity, and increased hypoxia caused by increased diffusion distances due to intima–media thickening [3,4]. Hypertension with left ventricular hypertrophy may lead to longer action potential durations and vulnerability to fatal arrhythmias [5]. A supplementary analysis showed whether blood pressure from exercise to recovery phase is associated with the risk of SCD. This part of the prospective study was based on data obtained from 2366 participants who had undergone exercise testing with the assessment of blood pressure [6]. A maximal symptom-limited exercise test was performed using a cycle ergometer. The standardized testing protocol consisted of a progressive increase in the workload of 20 W per minute. A total of 30% of the men had diagnosed hypertension, of which 21% were using antihypertensive medication regularly. During the symptom-limited exercise test, mean maximal SBP and SBP at 2 minutes recovery phase from exercise were 203 mmHg and ☆ This work was supported by the Academy of Finland, Helsinki, Finland; the Ministry of Education Helsinki, Finland; City of Kuopio, Kuopio, Finland; Finnish Medical Foundation, Helsinki, Finland, and Finnish Cultural Foundation, Helsinki, Finland. ⁎ Corresponding author at: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. Tel.: +358 17 162950; fax: +358 17 162936. E-mail address: jariantero.laukkanen@uef.fi (J.A. Laukkanen).
184 mmHg, respectively. Resting SBP is positively correlated with SBP during recovery (r = 0.53, p b 0.001). A death was determined SCD when it occurred after the onset of an abrupt change in symptoms or within 24 hours of the onset of symptoms and a total of 180 SCDs occurred during the follow-up of 19 years. SBP at 2 minutes recovery from exercise, cardiorespiratory fitness and ischemic ST-depression during exercise were related to the risk of SCD when other conventional risk factors were taken into account. However, after additional adjustment for resting SBP, SBP during recovery from exercise became non-significant whereas cardiorespiratory fitness and ischemic ST-depression during exercise were still associated with the risk of SCD. When maximal SBP and SBP at 2 minutes recovery from exercise were included into the multivariable model with risk factors, SBP during recovery from exercise was a stronger predictor of the risk of SCD. The risk for all-cause death was increased in men with SBP at 2 minutes recovery from exercise N195 mmHg as compared to men with SBP of b175 mmHg, but SBP at 2 minutes recovery from exercise was not related to the risk of non-SCD. The inclusion of SBP at 2 minutes recovery from exercise for the model with risk factors and exercise testing variables did not lead to a significant change in the C-index and net reclassification index. Our study suggested that SBP during recovery from exercise was no longer a significant predictor for SCD after accounting for resting SBP with other risk factors. An independent value of exercise blood pressure is diminished partly due to the relatively strong correlation between resting and exercise blood pressure. This finding is consistent with previous studies showing the value of exercise blood pressure in the prediction of cardiovascular death using an appropriate adjustment for resting blood pressure [7,8]. Secondly, the assessment of resting SBP is an easily available method compared to the definition of SBP during and after exercise testing for the risk prediction of SCD [2]. The routine assessment of SBP during recovery from exercise at a single time-point is not necessary for SCD risk prediction. The significance of SBP during recovery could not have been remarkable since information on SBP at rest with other common risk factors have been evaluated. There may be some patients who had an elevated blood pressure with inadequate treatment as well as subjects with borderline or prehypertensive state without drugs. It has been shown that an elevated blood pressure during exercise identified high risk subjects with either normal or prehypertension at rest and added predictive value to resting blood pressure for the prediction of cardiovascular risk [8]. In our study, a significant relationship between an elevated SBP during recovery from exercise and the risk of SCD was observed in a subgroup of men without previously diagnosed coronary heart disease or the use of antihypertensive medication. Antihypertensive medication and the use of βblockers have normally been recommended for decreasing a high resting blood pressure, and the use of antihypertensive medication may also lead to an attenuated response of blood pressure during exercise. The use of β-blockers might be protective among those with exerciserelated hypertension in the prevention of fatal cardiac outcomes such as SCD in the general population as well as among patients with prevalent coronary heart disease. Previous findings have shown that both low cardiorespiratory fitness and ischemic ST depression during exercise are associated with the risk of SCD [6,9], although the value of SBP during recovery from exercise would be limited in the general population. Exercise testing
Letters to the Editor
should be still considered as an important clinical tool and prognostic measure as both cardiorespiratory fitness and exercise-induced STdepression are risk markers for SCD. References [1] Laukkanen JA, Kurl S. Blood pressure responses during exercise testing – is up best for prognosis? Ann Med 2012;44:218–24. [2] Laukkanen JA, Jennings JR, Kauhanen J, Mäkikallio TH, Ronkainen K, Kurl S. Relation of systemic blood pressure to sudden cardiac death. Am J Cardiol 2012;110:378–82. [3] Burke AP, Farb A, Malcom GT, Liang Y, Smialek JE, Virmani R. Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA 1999;281:921–6. [4] Burke AP, Farb A, Malcom GT, Liang YH, Smialek JE, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276–82.
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[5] Frohlich ED, Apstein C, Chobanian AV, et al. The heart in hypertension. N Engl J Med 1992;327:998–1008. [6] Laukkanen JA, Mäkikallio TH, Rauramaa R, Kiviniemi V, Ronkainen K, Kurl S. Cardiorespiratory fitness is related to the risk of sudden cardiac death. A Populationbased follow-up study. J Am Coll Cardiol 2010;56:1476–83. [7] Fagard RH, Pardaens K, Staessen JA, Thijs L. Prognostic value of invasive hemodynamic measurement at rest and during exercise in hypertensive men. Hypertension 1996;28:31–6. [8] Weiss SA, Blumenthal RS, Sharrett AR, Redberg RF, Mora S. Exercise blood pressure and future cardiovascular death in asymptomatic individuals. Circulation 2010;121:2109–16. [9] Laukkanen JA, Mäkikallio TH, Rauramaa R, Kurl S. Asymptomatic ST-segment depression during exercise testing and the risk of sudden cardiac death in middleaged men. A population-based follow-up study. Eur Heart J 2009;30:558–65.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.04.129
The maladaptive effects of HIV protease inhibitors (lopinavir/ritonavir) on the rat heart☆ Kathleen M.S.E. Reyskens 1, M. Faadiel Essop ⁎,1 Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa
a r t i c l e
i n f o
Article history: Received 5 April 2013 Accepted 6 April 2013 Available online 11 May 2013 Keywords: HIV-AIDS HIV protease inhibitors Cardiovascular diseases Ischemia-reperfusion Metabolism
Protease inhibitors (PIs) form an integral part of highly active antiretroviral treatment (HAART) and are linked to increased risk for myocardial infarction [1] and cardiovascular abnormalities [2,3], with many changes resembling coronary artery disease [4]. Despite such progress the underlying molecular mechanisms responsible for HAARTinduced cardio-metabolic side effects remain poorly understood and little is known about the earliest events driving this process. We therefore hypothesized that PI treatment detrimentally alters cardiac calcium signaling and energetics, thereby attenuating contractile function at baseline and in response to myocardial ischemia. We investigated our hypothesis by establishing a unique rat model of chronic PI drug delivery and for the first time evaluate ex vivo heart function. Lopinavir/ritonavir (Kaletra™, Abbott Laboratories, Abbot Park IL) was crushed and dissolved in 1% ethanol (vehicle) at human steady-state plasma concentration (7.1 ± 2.9 μg/mL), sterile filtered and injected into a surgically inserted mini-osmotic pump (Alzet, Cupertino CA). Male Wistar rats (180–220 g) received either: mock surgery (sham), vehicle-, or a PI-containing pump for a total of 8 weeks (n = 8 per group). Here we ☆ This work was supported by the South African National Research Foundation and Stellenbosch University (to MFE). ⁎ Corresponding author. Tel.: +27 21 808 3146; fax: + 27 21 808 3145. E-mail address: [email protected] (M.F. Essop). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
attempted to simulate a relatively early stage of PI treatment, i.e. if the average lifespan of 2–3 years is taken for Wistar rats then 8 weeks translates to ~6% of its total lifespan. This would correspond to ~2–3 years of PI treatment for a 30 year-old started on HAART treatment and with a life expectancy of ~60–70 years. Animals were treated in accordance with the Guide for the Care and Use of Laboratory Animals of the National Academy of Sciences (NIH publication No. 85-23, revised 1996) and performed with the approval of the Animal Ethics Committee of Stellenbosch University (South Africa). To assess baseline function, hearts were retrogradely perfused (Langendorff) for 60 min as described before by us [5]. For the ischemia-reperfusion experiments, the 60 min stabilization period was followed by 30 min global ischemia and 60 min reperfusion (functional recovery assessments), while infarct sizes in response to regional ischemia was determined as described [5]. Superoxide, calcium and ATP levels and superoxide dismutase (SOD) activity in heart tissue homogenates were evaluated using standard commercial kits. Western blotting methods were employed for the determination of 5′-AMP-activated protein kinase-alpha (AMPKα) and sarco(endo) plasmic reticulum calcium-2a (SERCA-2a) pump expression levels and beta-actin used as loading control. Data are presented as mean ± SEM and one-way ANOVA performed with the exception of heart function (two-way ANOVA), including the Bonferroni post-hoc test (GraphPad Prism v5, San Diego CA). PI-treated rats exhibited weight gain 467 ± 18.1 vs. 385 ± 17.2 g (sham) (p b 0.001) and vs. 400 ± 18.1 g (vehicle) (p b 0.001) (Fig. 1A). Ex vivo perfusion data show that PI treatment decreased left ventricular developed pressure (LVDP) to 35.50 ± 1.55 vs. 60.88 ± 2.4 mm Hg (sham) (p b 0.01) and vs. 53.14 ± 6.61 mm Hg (vehicle) (p b 0.001) (Fig. 1B). Likewise, rate pressure product (RPP) was also attenuated in PI-treated hearts (Fig. 1C). Following global ischemia, LVDP was lower in the PI-treated group, i.e. to 3.0 ± 2.36 vs. 35.38 ± 7.03 mm Hg (sham) (p b 0.001) and vs. 27.43 ± 5.07 mm Hg (vehicle) (p b 0.05) (Fig. 1D). A similar pattern was found for RPP (Fig. 1E). PIs also robustly increased infarct size to 79.2 ± 40.7% vs. 46.3 ± 5.7% (sham) (p b 0.01) and vs. 39.4 ± 8.4% (vehicle) (p b 0.01) (Fig. 1 F). Further, the percentage of LVDP recovery after ischemia did not significantly differ for the PI-treated group compared to matched controls (p N 0.05, data not