A cross-species validation of single-beat metrics of cardiac contractility.

The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross-species study using small and large animals, we comprehensively tested the agreement and validity of multiple single-beat surrogate metrics of LV contractility against the field-standard metrics derived from inferior vena cava occlusion (IVCO). Fifty-six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single-beat metrics of LV contractility. All single-beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load-independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single-beat metrics, only LV maximal pressure normalized to end-diastolic volume (EDV), end-systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate-to-excellent agreement with their IVCO-derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large-animal models. Our findings demonstrate that single-beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small- and large-animal models KEY POINTS: Validating and comparing indices of cardiac contractility that avoid caval occlusion would offer considerable advantages for the field of cardiovascular physiology. We comprehensively test the underlying assumptions of multiple single-beat indices of cardiac contractility in rodents and translate these findings to pigs and conscious dogs. We show that when performing caval occlusion is unfeasible, single-beat metrics can be utilized to accurately quantify cardiac inotropic function in basic and preclinical research employing various small and large animal species. We report that maximal left-ventricular (LV)-pressure normalized to end-diastolic volume (EDV), LV end-systolic pressure normalized to EDV and the maximal rate of rise of the LV pressure waveform normalized to EDV are the best three single-beat metrics to measure cardiac inotropic function in both small- and large-animal models.

Arterial Baroreflex Inhibits Muscle Metaboreflex Induced Increases in Effective Arterial Elastance: Implications for Ventricular-Vascular Coupling.

The ventricular-vascular relationship assesses the efficacy of energy transferred from the left ventricle to the systemic circulation and is quantified as the ratio of effective arterial elastance to maximal left ventricular elastance. This relationship is maintained during exercise via reflex increases in cardiovascular performance raising both arterial and ventricular elastance in parallel. These changes are, in part, due to reflexes engendered by activation of metabosensitive skeletal muscle afferents-termed the muscle metaboreflex. However, in heart failure, ventricular-vascular uncoupling is apparent and muscle metaboreflex activation worsens this relationship through enhanced systemic vasoconstriction markedly increasing effective arterial elastance which is unaccompanied by substantial increases in ventricular function. This enhanced arterial vasoconstriction is, in part, due to significant reductions in cardiac performance induced by heart failure causing over-stimulation of the metaboreflex due to under perfusion of active skeletal muscle, but also as a result of reduced baroreflex buffering of the muscle metaboreflex-induced peripheral sympatho-activation. To what extent the arterial baroreflex modifies the metaboreflex-induced changes in effective arterial elastance is unknown. We investigated in chronically instrumented conscious canines if removal of baroreflex input via sino-aortic baroreceptor denervation (SAD) would significantly enhance effective arterial elastance in normal animals and whether this would be amplified after induction of heart failure. We observed that effective arterial elastance (Ea), was significantly increased during muscle metaboreflex activation after SAD (0.4 ± 0.1 mmHg/mL to 1.4 ± 0.3 mmHg/mL). In heart failure, metaboreflex activation caused exaggerated increases in Ea and in this setting, SAD significantly increased the rise in Ea elicited by muscle metaboreflex activation (1.3 ± 0.3 mmHg/mL to 2.3 ± 0.3 mmHg/mL). Thus, we conclude that the arterial baroreflex does buffer muscle metaboreflex induced increases in Ea and this buffering likely has effects on the ventricular-vascular coupling.

Reversal of SARS-CoV2-Induced Hypoxia by Nebulized Sodium Ibuprofenate in a Compassionate Use Program.

INTRODUCTION: Sodium ibuprofenate in hypertonic saline (NaIHS) administered directly to the lungs by nebulization and inhalation has antibacterial and anti-inflammatory effects, with the potential to deliver these benefits to hypoxic patients. We describe a compassionate use program that offered this therapy to hospitalized COVID-19 patients. METHODS: NaIHS (50 mg ibuprofen, tid) was provided in addition to standard of care (SOC) to hospitalized COVID-19 patients until oxygen saturation levels of > 94% were achieved on ambient air. Patients wore a containment hood to diminish aerosolization. Outcome data from participating patients treated at multiple hospitals in Argentina between April 4 and October 31, 2020, are summarized. Results were compared with a retrospective contemporaneous control (CC) group of hospitalized COVID-19 patients with SOC alone during the same time frame from a subset of participating hospitals from Córdoba and Buenos Aires. RESULTS: The evolution of 383 patients treated with SOC + NaIHS [56 on mechanical ventilation (MV) at baseline] and 195 CC (21 on MV at baseline) are summarized. At baseline, NaIHS-treated patients had basal oxygen saturation of 90.7 ± 0.2% (74.3% were on supplemental oxygen at baseline) and a basal respiratory rate of 22.7 ± 0.3 breath/min. In the CC group, basal oxygen saturation was 92.6 ± 0.4% (52.1% were on oxygen supplementation at baseline) and respiratory rate was 19.3 ± 0.3 breath/min. Despite greater pulmonary compromise at baseline in the NaIHS-treated group, the length of treatment (LOT) was 9.1 ± 0.2 gs with an average length of stay (ALOS) of 11.5 ± 0.3 days, in comparison with an ALOS of 13.3 ± 0.9 days in the CC group. In patients on MV who received NaIHS, the ALOS was lower than in the CC group. In both NaIHS-treated groups, a rapid reversal of deterioration in oxygenation and NEWS2 scores was observed acutely after initiation of NaIHS therapy. No serious adverse events were considered related to ibuprofen therapy. Mortality was lower in both NaIHS groups compared with CC groups. CONCLUSIONS: Treatment of COVID-19 pneumonitis with inhalational nebulized NaIHS was associated with rapid improvement in hypoxia and vital signs, with no serious adverse events attributed to therapy. Nebulized NaIHS s worthy of further study in randomized, placebo-controlled trials (ClinicalTrials.gov: NCT04382768).

[Collateral damage of COVID-19 pandemic in private healthcare centres of Argentina]. / Daño colateral de la pandemia por COVID-19 en centros privados de salud de Argentina.

To contain the coronavirus pandemic (COVID-19), a strict nationwide lockdown has been enforced and the health systems have been reorganized to deal with this entity. During this period, changes in the care of non-infectious diseases have been observed. Our aim was to describe the impact of the COVID-19 pandemic in the care of non-communicable diseases. A structured retrospective survey was carried out in 31 healthcare centers affiliated with the Asociación de Clínicas, Sanatorios y Hospitales Privados de la República Argentina y Cámara de Entidades de Diagnóstico y Tratamiento. We compared data for April 2019 versus April 2020 regarding emergency room consultations, hospital admissions, invasive procedures and treatments, and bed occupancy. In April 2020, we observed a decrease in emergency room visits (75%) and hospitalizations (48%). A 62% decrease in admissions was noted for angina pectoris and acute coronary syndromes and a 46% decrease in admissions for stroke and transient ischemic attack. A meaningful decrease was found in coronary angioplasties (59%) and total percutaneous interventions (65%), and also a decrease in general surgeries (73%), and cardiac surgeries (58%). Although social distancing measures are a key public health strategy to flatten the infection curve, the observed decrease in medical visits and interventions may impact negatively on cardiovascular, cerebrovascular and cancer related morbidity and mortality. A collective effort is required to avoid the unintended consequences and collateral damage of the COVID-19 pandemic.

Para contener la pandemia de COVID-19 se han adoptado medidas nacionales estrictas de aislamiento social y se han reorganizado los sistemas de salud. En este período, se observaron cambios en la atención de enfermedades no infecciosas. El objetivo de este trabajo fue describir las consecuencias de la pandemia de COVID-19 sobre la atención de enfermedades no transmisibles. Se realizó una encuesta estructurada retrospectiva a 31 centros asistenciales de la Asociación de Clínicas, Sanatorios y Hospitales Privados de la República Argentina y Cámara de Entidades de Diagnóstico y Tratamiento. Se compararon indicadores de abril de 2019 versus abril 2020. Se recolectaron datos sobre consultas de emergencia, ingresos hospitalarios, procedimientos invasivos, tratamiento y ocupación de áreas de internación. En ese periodo las consultas a emergencias y las hospitalizaciones disminuyeron en 75% y 48% respectivamente; los ingresos por angina de pecho y síndrome coronario agudo en 62% y los debidos a accidentes cerebrovascular e isquémico transitorio en 46%. Se encontró una disminución de las angioplastias coronarias (59%) e intervenciones percutáneas totales (65%), y un descenso tanto de las cirugías generales (73%) como de las cardíacas centrales (58%). Si bien el aislamiento social obligatorio es una estrategia clave de salud pública para aplanar la curva de propagación de la infección, la marcada disminución porcentual de consultas e intervenciones podría influir negativamente sobre la morbimortalidad cardiovascular, cerebrovascular y oncológica. Se requiere un esfuerzo conjunto para evitar una posible expansión del daño colateral del COVID-19.

Daño colateral de la pandemia por COVID-19 en centros privados de salud de Argentina / Collateral damage of COVID-19 pandemic in private healthcare centres of Argentina

Para contener la pandemia de COVID-19 se han adoptado medidas nacionales estrictas de aislamiento social y se han reorganizado los sistemas de salud. En este período, se observaron cambios en la atención de enfermedades no infecciosas. El objetivo de este trabajo fue describir las consecuencias de la pandemia de COVID-19 sobre la atención de enfermedades no transmisibles. Se realizó una encuesta estructurada retrospectiva a 31 centros asistenciales de la Asociación de Clínicas, Sanatorios y Hospitales Privados de la República Argentina y Cámara de Entidades de Diagnóstico y Tratamiento. Se compararon indicadores de abril de 2019 versus abril 2020. Se recolectaron datos sobre consultas de emergencia, ingresos hospitalarios, procedimientos invasivos, tratamiento y ocupación de áreas de internación. En ese periodo las consultas a emergencias y las hospitalizaciones disminuyeron en 75% y 48% respectivamente; los ingresos por angina de pecho y síndrome coronario agudo en 62% y los debidos a accidentes cerebrovascular e isquémico transitorio en 46%. Se encontró una disminución de las angioplastias coronarias (59%) e intervenciones percutáneas totales (65%), y un descenso tanto de las cirugías generales (73%) como de las cardíacas centrales (58%). Si bien el aislamiento social obligatorio es una estrategia clave de salud pública para aplanar la curva de propagación de la infección, la marcada disminución porcentual de consultas e intervenciones podría influir negativamente sobre la morbimortalidad cardiovascular, cerebrovascular y oncológica. Se requiere un esfuerzo conjunto para evitar una posible expansión del daño colateral del COVID-19.

To contain the coronavirus pandemic (COVID-19), a strict nationwide lockdown has been enforced and the health systems have been reorganized to deal with this entity. During this period, changes in the care of non-infectious diseases have been observed. Our aim was to describe the impact of the COVID-19 pandemic in the care of non-communicable diseases. A structured retrospective survey was carried out in 31 healthcare centers affiliated with the Asociación de Clínicas, Sanatorios y Hospitales Privados de la República Argentina y Cámara de Entidades de Diagnóstico y Tratamiento. We compared data for April 2019 versus April 2020 regarding emergency room consultations, hospital admissions, invasive procedures and treatments, and bed occupancy. In April 2020, we observed a decrease in emergency room visits (75%) and hospitalizations (48%). A 62% decrease in admissions was noted for angina pectoris and acute coronary syndromes and a 46% decrease in admissions for stroke and transient ischemic attack. A meaningful decrease was found in coronary angioplasties (59%) and total percutaneous interventions (65%), and also a decrease in general surgeries (73%), and cardiac surgeries (58%). Although social distancing measures are a key public health strategy to flatten the infection curve, the observed decrease in medical visits and interventions may impact negatively on cardiovascular, cerebrovascular and cancer related morbidity and mortality. A collective effort is required to avoid the unintended consequences and collateral damage of the COVID-19 pandemic.

Exaggerated coronary vasoconstriction limits muscle metaboreflex-induced increases in ventricular performance in hypertension.

Increases in myocardial oxygen consumption during exercise mainly occur via increases in coronary blood flow (CBF) as cardiac oxygen extraction is high even at rest. However, sympathetic coronary constrictor tone can limit increases in CBF. Increased sympathetic nerve activity (SNA) during exercise likely occurs via the action of and interaction among activation of skeletal muscle afferents, central command, and resetting of the arterial baroreflex. As SNA is heightened even at rest in subjects with hypertension (HTN), we tested whether HTN causes exaggerated coronary vasoconstriction in canines during mild treadmill exercise with muscle metaboreflex activation (MMA; elicited by reducing hindlimb blood flow by ~60%) thereby limiting increases in CBF and ventricular performance. Experiments were repeated after α1-adrenergic blockade (prazosin; 75 µg/kg) and in the same animals following induction of HTN (modified Goldblatt 2K1C model). HTN increased mean arterial pressure from 97.1 ± 2.6 to 132.1 ± 5.6 mmHg at rest and MMA-induced increases in CBF, left ventricular dP/dtmax, and cardiac output were markedly reduced to only 32 ± 13, 26 ± 11, and 28 ± 12% of the changes observed in control. In HTN, α1-adrenergic blockade restored the coronary vasodilation and increased in ventricular function to the levels observed when normotensive. We conclude that exaggerated MMA-induced increases in SNA functionally vasoconstrict the coronary vasculature impairing increases in CBF, which limits oxygen delivery and ventricular performance in HTN. NEW & NOTEWORTHY: We found that metaboreflex-induced increases in coronary blood flow and ventricular contractility are attenuated in hypertension. α1-Adrenergic blockade restored these parameters toward normal levels. These findings indicate that the primary mechanism mediating impaired metaboreflex-induced increases in ventricular function in hypertension is accentuated coronary vasoconstriction.

The pathophysiology of hypertensive acute heart failure.

While acute heart failure (AHF) is often regarded as a single disorder, an evolving understanding recognises the existence of multiple phenotypes with varied pathophysiological alterations. Herein we discuss hypertensive AHF and provide insight into a mechanism where acute fluid redistribution is caused by a disturbance in the ventricular-vascular coupling relationship. In this relationship, acute alterations in vascular elasticity, vasoconstriction and reflected pulse waves lead to increases in cardiac work and contribute to decompensated LV function with associated subendocardial ischaemia and end-organ damage. Chronic predisposing factors (neurohormonal activity, nitric oxide insensitivity, arterial stiffening) and physiological stressors (sympathetic surge, volume overload, physical exertion) that are causally linked to acute symptom onset are discussed. Lastly, we review treatment options including both nitrovasodilators and promising novel therapeutics, and discuss future directions in the management of this phenotypic variant.

Attenuated muscle metaboreflex-induced pressor response during postexercise muscle ischemia in renovascular hypertension.

During dynamic exercise, muscle metaboreflex activation (MMA; induced via partial hindlimb ischemia) markedly increases mean arterial pressure (MAP), and MAP is sustained when the ischemia is maintained following the cessation of exercise (postexercise muscle ischemia, PEMI). We previously reported that the sustained pressor response during PEMI in normal individuals is driven by a sustained increase in cardiac output (CO) with no peripheral vasoconstriction. However, we have recently shown that the rise in CO with MMA is significantly blunted in hypertension (HTN). The mechanisms sustaining the pressor response during PEMI in HTN are unknown. In six chronically instrumented canines, hemodynamic responses were observed during rest, mild exercise (3.2 km/h), MMA, and PEMI in the same animals before and after the induction of HTN [Goldblatt two kidney, one clip (2K1C)]. In controls, MAP, CO and HR increased with MMA (+52 ± 6 mmHg, +2.1 ± 0.3 l/min, and +37 ± 7 beats per minute). After induction of HTN, MAP at rest increased from 97 ± 3 to 130 ± 4 mmHg, and the metaboreflex responses were markedly attenuated (+32 ± 5 mmHg, +0.6 ± 0.2 l/min, and +11 ± 3 bpm). During PEMI in HTN, HR and CO were not sustained, and MAP fell to normal recovery levels. We conclude that the attenuated metaboreflex-induced HR, CO, and MAP responses are not sustained during PEMI in HTN.

Stimulation of the cardiopulmonary baroreflex enhances ventricular contractility in awake dogs: a mathematical analysis study.

The cardiopulmonary baroreflex responds to an increase in central venous pressure (CVP) by decreasing total peripheral resistance and increasing heart rate (HR) in dogs. However, the direction of ventricular contractility change is not well understood. The aim was to elucidate the cardiopulmonary baroreflex control of ventricular contractility during normal physiological conditions via a mathematical analysis. Spontaneous beat-to-beat fluctuations in maximal ventricular elastance (Emax), which is perhaps the best available index of ventricular contractility, CVP, arterial blood pressure (ABP), and HR were measured from awake dogs at rest before and after ß-adrenergic receptor blockade. An autoregressive exogenous input model was employed to jointly identify the three causal transfer functions relating beat-to-beat fluctuations in CVP to Emax (CVP → Emax), which characterizes the cardiopulmonary baroreflex control of ventricular contractility, ABP to Emax, which characterizes the arterial baroreflex control of ventricular contractility, and HR to Emax, which characterizes the force-frequency relation. The CVP → Emax transfer function showed a static gain of 0.037 ± 0.010 ml(-1) (different from zero; P < 0.05) and an overall time constant of 3.2 ± 1.2 s. Hence, Emax would increase and reach steady state in ∼16 s in response to a step increase in CVP, without any change to ABP or HR, due to the cardiopulmonary baroreflex. Following ß-adrenergic receptor blockade, the CVP → Emax transfer function showed a static gain of 0.0007 ± 0.0113 ml(-1) (different from control; P < 0.10). Hence, Emax would change little in steady state in response to a step increase in CVP. Stimulation of the cardiopulmonary baroreflex increases ventricular contractility through ß-adrenergic receptor system mediation.

Point-of-care assessment of platelet reactivity in the emergency department may facilitate rapid rule-out of acute coronary syndromes: a prospective cohort pilot feasibility study.

OBJECTIVE: Accurate, efficient and cost-effective disposition of patients presenting to emergency departments (EDs) with symptoms suggestive of acute coronary syndromes (ACS) is a growing priority. Platelet activation is an early feature in the pathogenesis of ACS; thus, we sought to obtain an insight into whether point-of-care testing of platelet function: (1) may assist in the rule-out of ACS; (2) may provide additional predictive value in identifying patients with non-cardiac symptoms versus ACS-positive patients and (3) is logistically feasible in the ED. DESIGN: Prospective cohort feasibility study. SETTING: Two urban tertiary care sites, one located in the USA and the second in Argentina. PARTICIPANTS: 509 adult patients presenting with symptoms of ACS. MAIN OUTCOME MEASURES: Platelet reactivity was quantified using the Platelet Function Analyzer-100, with closure time (seconds required for blood, aspirated under high shear, to occlude a 150 µm aperture) serving as the primary endpoint. Closure times were categorised as 'normal' or 'prolonged', defined objectively as the 90th centile of the distribution for all participants enrolled in the study. Diagnosis of ACS was made using the standard criteria. The use of antiplatelet agents was not an exclusion criterion. RESULTS: Closure times for the study population ranged from 47 to 300 s, with a 90th centile value of 138 s. The proportion of patients with closure times ≥138 s was significantly higher in patients with non-cardiac symptoms (41/330; 12.4%) versus the ACS-positive cohort (2/105 (1.9%); p=0.0006). The specificity of 'prolonged' closure times (≥138 s) for a diagnosis of non-cardiac symptoms was 98.1%, with a positive predictive value of 95.4%. Multivariate analysis revealed that the closure time provided incremental, independent predictive value in the rule-out of ACS. CONCLUSIONS: Point-of-care assessment of platelet reactivity is feasible in the ED and may facilitate the rapid rule-out of ACS in patients with prolonged closure times.

Attenuated muscle metaboreflex-induced increases in cardiac function in hypertension.

Sympathoactivation may be excessive during exercise in subjects with hypertension, leading to increased susceptibility to adverse cardiovascular events, including arrhythmias, infarction, stroke, and sudden cardiac death. The muscle metaboreflex is a powerful cardiovascular reflex capable of eliciting marked increases in sympathetic activity during exercise. We used conscious, chronically instrumented dogs trained to run on a motor-driven treadmill to investigate the effects of hypertension on the mechanisms of the muscle metaboreflex. Experiments were performed before and 30.9 ± 4.2 days after induction of hypertension, which was induced via partial, unilateral renal artery occlusion. After induction of hypertension, resting mean arterial pressure was significantly elevated from 98.2 ± 2.6 to 141.9 ± 7.4 mmHg. The hypertension was caused by elevated total peripheral resistance. Although cardiac output was not significantly different at rest or during exercise after induction of hypertension, the rise in cardiac output with muscle metaboreflex activation was significantly reduced in hypertension. Metaboreflex-induced increases in left ventricular function were also depressed. These attenuated cardiac responses caused a smaller metaboreflex-induced rise in mean arterial pressure. We conclude that the ability of the muscle metaboreflex to elicit increases in cardiac function is impaired in hypertension, which may contribute to exercise intolerance.

Altered calsequestrin glycan processing is common to diverse models of canine heart failure.

Calsequestrin-2 (CSQ2) is a resident glycoprotein of junctional sarcoplasmic reticulum that functions in the regulation of SR Ca(2+) release. CSQ2 is biosynthesized in rough ER around cardiomyocyte nuclei and then traffics transversely across SR subcompartments. During biosynthesis, CSQ2 undergoes N-linked glycosylation and phosphorylation by protein kinase CK2. In mammalian heart, CSQ2 molecules subsequently undergo extensive mannose trimming by ER mannosidase(s), a posttranslational process that often regulates protein breakdown. We analyzed the intact purified CSQ2 from mongrel canine heart tissue by electrospray mass spectrometry. The average molecular mass of CSQ2 in normal mongrel dogs was 46,306 ± 41 Da, corresponding to glycan trimming of 3-5 mannoses, depending upon the phosphate content. We tested whether CSQ2 glycan structures would be altered in heart tissue from mongrel dogs induced into heart failure (HF) by two very different experimental treatments, rapid ventricular pacing or repeated coronary microembolizations. Similarly dramatic changes in mannose trimming were found in both types of induced HF, despite the different cardiomyopathies producing the failure. Unique to all samples analyzed from HF dog hearts, 20-40 % of all CSQ2 contained glycans that had minimal mannose trimming (Man9,8). Analyses of tissue samples showed decreases in CSQ2 protein levels per unit levels of mRNA for tachypaced heart tissue, also indicative of altered turnover. Quantitative immunofluorescence microscopy of frozen tissue sections suggested that no changes in CSQ2 levels occurred across the width of the cell. We conclude that altered processing of CSQ2 may be an adaptive response to the myocardium under stresses that are capable of inducing heart failure.

Role of cardiac output versus peripheral vasoconstriction in mediating muscle metaboreflex pressor responses: dynamic exercise versus postexercise muscle ischemia.

Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in normal individuals increases mean arterial pressure (MAP) via increases in cardiac output (CO) with little peripheral vasoconstriction. The rise in CO occurs primarily via increases in heart rate (HR) with maintained or slightly increased stroke volume. When the reflex is sustained during recovery (postexercise muscle ischemia, PEMI), HR declines yet MAP remains elevated. The role of CO in mediating the pressor response during PEMI is controversial. In seven chronically instrumented canines, steady-state values with MMA during mild exercise (3.2 km/h) were observed by reducing hindlimb blood flow by ~60% for 3-5 min. MMA during exercise was followed by 60 s of PEMI. Control experiments consisted of normal exercise and recovery. MMA during exercise increased MAP, HR, and CO by 55.3 ± 4.9 mmHg, 42.5 ± 6.9 beats/min, and 2.5 ± 0.4 l/min, respectively. During sustained MMA via PEMI, MAP remained elevated and CO remained well above the normal recovery levels. Neither MMA during dynamic exercise nor during PEMI significantly affected peripheral vascular conductance. We conclude that the sustained increase in MAP during PEMI is driven by a sustained increase in CO not peripheral vasoconstriction.

Muscle metaboreflex-induced coronary vasoconstriction limits ventricular contractility during dynamic exercise in heart failure.

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after α1-adrenergic blockade (prazosin 20-50 µg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after α1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility.

Dynamic cardiac output regulation at rest, during exercise, and muscle metaboreflex activation: impact of congestive heart failure.

We tested whether mild and moderate dynamic exercise and muscle metaboreflex activation (MMA) affect dynamic baroreflex control of heart rate (HR) and cardiac output (CO), and the influence of stroke volume (SV) fluctuations on CO regulation in normal (N) and pacing-induced heart failure (HF) dogs by employing transfer function analyses of the relationships between spontaneous changes in left ventricular systolic pressure (LVSP) and HR, LVSP and CO, HR and CO, and SV and CO at low and high frequencies (Lo-F, 0.04-0.15 Hz; Hi-F, 0.15-0.6 Hz). In N dogs, both workloads significantly decreased the gains for LVSP-HR and LVSP-CO in Hi-F, whereas only moderate exercise also reduced the LVSP-CO gain in Lo-F. MMA during mild exercise further decreased the gains for LVSP-HR in both frequencies and for LVSP-CO in Lo-F. MMA during moderate exercise further reduced LVSP-HR gain in Lo-F. Coherence for HR-CO in Hi-F was decreased by exercise and MMA, whereas that in Lo-F was sustained at a high level (>0.8) in all settings. HF significantly decreased dynamic HR and CO regulation in all situations. In HF, the coherence for HR-CO in Lo-F decreased significantly in all settings; the coherence for SV-CO in Lo-F was significantly higher. We conclude that dynamic exercise and MMA reduces dynamic baroreflex control of HR and CO, and these are substantially impaired in HF. In N conditions, HR modulation plays a major role in CO regulation. In HF, influence of HR modulation wanes, and fluctuations of SV dominate in CO variations.

Acute induction of autophagy as a novel strategy for cardioprotection: getting to the heart of the matter.

There is no question that necrosis and apoptosis contribute to cardiomyocyte death in the setting of myocardial ischemia-reperfusion. Indeed, considerable effort and resources have been invested in the development of novel therapies aimed at attenuating necrotic and apoptotic cell death, with the ultimate goal of applying these strategies to reduce infarct size and improve outcome in patients suffering acute myocardial infarction (MI) or 'heart attack'. However, an issue that remains controversial is the role of autophagy in determining the fate of ischemic-reperfused cardiomyocytes: i.e., is induction of autophagy detrimental or protective? Recent data from our group obtained in the clinically relevant, in vivo swine model of acute MI provides novel evidence of a positive association between pharmacological upregulation of autophagy (achieved by administration of chloramphenicol succinate (CAPS)) and increased resistance to myocardial ischemia-reperfusion injury.

Identification of sources of low frequency variability of arterial blood pressure: cardiac output acts as a buffer and not as a source.

Arterial blood pressure (ABP) short term variability is due to beat-by-beat fluctuations in cardiac output (CO) and total peripheral resistance (TPR), which have distinct effects at low and high frequencies. In particular, it was shown that CO is able to buffer TPR slow oscillations in the LF band, but it has not been addressed if CO can contribute to oscillations of ABP in this band. In this paper, we propose a model for the identification of ABP variability sources, in order to show evidence that CO fluctuations are not a source of ABP LF oscillations, but they only buffer ABP variability of vasomotor origin.

Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury.

BACKGROUND: Emerging evidence suggests that "adaptive" induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction. METHODS AND RESULTS: Anesthetized pigs underwent 45 minutes of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS) (an agent that purportedly upregulates autophagy; 20 mg/kg) or saline at 10 minutes before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 minutes following CAPS treatment and assayed (by immunoblotting) for 2 proteins involved in autophagosome formation: Beclin-1 and microtubule-associated protein light chain 3-II. To investigate whether the efficacy of CAPS was maintained with "delayed" treatment, additional pigs received CAPS (20 mg/kg) at 30 minutes after occlusion. Expression of Beclin-1 and microtubule-associated protein light chain 3-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5 and 41±4%, respectively, in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline controls (P<0.01 and P<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins. CONCLUSIONS: Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection.

Dynamic control of maximal ventricular elastance via the baroreflex and force-frequency relation in awake dogs before and after pacing-induced heart failure.

We investigated to what extent maximal ventricular elastance (E(max)) is dynamically controlled by the arterial baroreflex and force-frequency relation in conscious dogs and to what extent these mechanisms are attenuated after the induction of heart failure (HF). We mathematically analyzed spontaneous beat-to-beat hemodynamic variability. First, we estimated E(max) for each beat during a baseline period using the ventricular unstressed volume determined with the traditional multiple beat method during vena cava occlusion. We then jointly identified the transfer functions (system gain value and time delay per frequency) relating beat-to-beat fluctuations in arterial blood pressure (ABP) to E(max) (ABP-->E(max)) and beat-to-beat fluctuations in heart rate (HR) to E(max) (HR-->E(max)) to characterize the dynamic properties of the arterial baroreflex and force-frequency relation, respectively. During the control condition, the ABP-->E(max) transfer function revealed that ABP perturbations caused opposite direction E(max) changes with a gain value of -0.023 +/- 0.012 ml(-1), whereas the HR-->E(max) transfer function indicated that HR alterations caused same direction E(max) changes with a gain value of 0.013 +/- 0.005 mmHg.ml(-1).(beats/min)(-1). Both transfer functions behaved as low-pass filters. However, the ABP-->E(max) transfer function was more sluggish than the HR-->E(max) transfer function with overall time constants (indicator of full system response time to a sudden input change) of 11.2 +/- 2.8 and 1.7 +/- 0.5 s (P < 0.05), respectively. During the HF condition, the ABP-->E(max) and HR-->E(max) transfer functions were markedly depressed with gain values reduced to -0.0002 +/- 0.007 ml(-1) and -0.001 +/- 0.004 mmHg.ml(-1).(beats/min)(-1) (P < 0.1). E(max) is rapidly and significantly controlled at rest, but this modulation is virtually abolished in HF.

Muscle metaboreflex-induced coronary vasoconstriction functionally limits increases in ventricular contractility.

Muscle metaboreflex activation during dynamic exercise induces a substantial increase in cardiac work and oxygen demand via a significant increase in heart rate, ventricular contractility, and afterload. This increase in cardiac work should cause coronary metabolic vasodilation. However, little if any coronary vasodilation is observed due to concomitant sympathetically induced coronary vasoconstriction. The purpose of the present study is to determine whether the restraint of coronary vasodilation functionally limits increases in left ventricular contractility. Using chronically instrumented, conscious dogs (n = 9), we measured mean arterial pressure, cardiac output, and circumflex blood flow and calculated coronary vascular conductance, maximal derivative of ventricular pressure (dp/dt(max)), and preload recruitable stroke work (PRSW) at rest and during mild exercise (2 mph) before and during activation of the muscle metaboreflex. Experiments were repeated after systemic alpha(1)-adrenergic blockade ( approximately 50 microg/kg prazosin). During prazosin administration, we observed significantly greater increases in coronary vascular conductance (0.64 + or - 0.06 vs. 0.46 + or - 0.03 ml x min(-1) x mmHg(-1); P < 0.05), circumflex blood flow (77.9 + or - 6.6 vs. 63.0 + or - 4.5 ml/min; P < 0.05), cardiac output (7.38 + or - 0.52 vs. 6.02 + or - 0.42 l/min; P < 0.05), dP/dt(max) (5,449 + or - 339 vs. 3,888 + or - 243 mmHg/s; P < 0.05), and PRSW (160.1 + or - 10.3 vs. 183.8 + or - 9.2 erg.10(3)/ml; P < 0.05) with metaboreflex activation vs. those seen in control experiments. We conclude that the sympathetic restraint of coronary vasodilation functionally limits further reflex increases in left ventricular contractility.