Cardiac Work Efficiency Research Articles

Short-term effects on sacubitril/valsartan therapy on right ventricle work and mechanics in patients with heart failure and reduced ejection fraction

Abstract Introduction In previous studies, sacubitril/valsartan (ARNI) therapy has been shown to have a positive effect on right ventricle (RV) function and on systolic pulmonary artery pressure in addition to improvement of left ventricle (LV) function in patients with heart failure and reduced ejection fraction (HFrEF). Recently, it was shown that a short-term ARNI therapy compared to valsartan-only therapy led to reduced systemic blood pressure and LV mechanical work, contributing to reduced LV myocardial perfusion and oxygen consumption. Purpose This paper aimed to study the effect of short-term ARNI therapy on RV mechanics and work and pulmonary and LV filling pressures compared to valsartan-only therapy in patients with HFrEF. Methods The study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with NYHA class II–III heart failure and LV ejection fraction (LVEF) <= 35 %. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, and cardiac and systemic hemodynamics were quantified using echocardiography and 11C-acetate PET before and after 6 weeks of therapy (on stable dose) in 55 patients. The analyses were done with ANCOVA adjusting for pre-randomization values. Results The RV myocardial resting perfusion (mean difference of 0.056 (95% CI, 0.02 to 0.109) ml/g/min, p = 0.041) and RV myocardial oxygen consumption (0.005 (0.001 to 0.010) 1/min, p = 0.015) were significantly lower in the ARNI group compared with the valsartan-only group. The left atrial end-diastolic volume indexed to body surface area (geometric mean difference of 1.071 (95% CI, 0 to 1.148) ml/m2, p = 0.048) and the ratio of early mitral inflow velocity to medial mitral annular early diastolic velocity (mean difference of 2.467 (95% CI, 0.096 to 4.838), p = 0.042) were also significantly lower in the ARNI group compared with the control group. There was no difference between the groups in peak systolic right ventricle to right atrial pressure gradient. Still, the tricuspid annular plane systolic excursion was significantly higher in the valsartan-only group compared with the ARNI group (0.221 (0.039 to 0.404) cm, p = 0.018). There was no difference in RV free wall strain, fractional area change or systolic excursion velocity between the treatment arms (p> 0.262). Conclusions In addition to our earlier findings, sacubitril when added to valsartan appears to reduce also right ventricle myocardial perfusion and oxygen consumption. There was also a reduction in left atrial end-diastolic volume and in early mitral inflow to medial mitral annular early diastolic velocity in the sacubitril/valsartan group as compared to the valsartan-only group, which suggest decreased LV filling pressure.

Short-term effects of sacubitril/valsartan therapy on myocardial oxygen consumption and energetic efficiency of cardiac work in heart failure with reduced ejection fraction: A randomized controlled study.

We sought to evaluate the mechanism of angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan-only control group in patients with heart failure with reduced ejection fraction (HFrEF). The study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with New York Heart Association class II-III heart failure and left ventricular ejection fraction (LVEF) ≤35%. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, cardiac and systemic haemodynamics were quantified using echocardiography and 11 C-acetate positron emission tomography before and after 6 weeks of therapy (on stable dose) in 55 patients (ARNI group: n = 27, mean age 63 ± 10 years, LVEF 29.2 ± 10.4%; and valsartan-only control group: n = 28, mean age 64 ± 8 years, LVEF 29.0 ± 7.3%; all p = NS). The energetic efficiency of cardiac work remained unchanged in both treatment arms. However, both diastolic (-4.5 mmHg; p = 0.026) and systolic blood pressure (-9.8 mmHg; p = 0.0007), myocardial perfusion (-0.054 ml/g/min; p = 0.045), and left ventricular mechanical work (-296; p = 0.038) decreased significantly in the ARNI group compared to the control group. Although myocardial oxygen consumption decreased in the ARNI group (-5.4%) compared with the run-in period and remained unchanged in the control group (+0.5%), the between-treatment group difference was not significant (p = 0.088). We found no differences in the energetic efficiency of cardiac work between ARNI and valsartan-only groups in HFrEF patients. However, ARNI appears to have haemodynamic and cardiac mechanical effects over valsartan in heart failure patients.

Relationship between cardiac mechanical properties and cardiac magnetic resonance imaging at rest in childhood acute lymphoblastic leukemia survivors.

The characterization of cardiac mechanical properties may contribute to better understanding of doxorubicin-induced cardiotoxicity. Our study aims to investigate the relationship between cardiac mechanical properties, T1 and T2 relaxation times and partition coefficient.Fifty childhood acute lymphoblastic leukemia survivors underwent a cardiac magnetic resonance (CMR) at rest on a 3T MRI system and included a standard ECG-gated 3(3)3(3)5 MOLLI sequence for T1 mapping and an ECG-gated T2-prepared TrueFISP sequence for T2 mapping. Partition coefficient, ejection fraction, end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. CircAdapt model was used to study cardiac mechanical performance (left ventricle stiffness (LVS), contractility (LVC) and pressure (Pmin and Pmax), cardiac work efficiency (CWE) and ventricular arterial coupling).In the whole cohort, our results showed that LVC (R2 = 69.2%, r = 0.83), Pmin (R2 = 62.9%, r = 0.79) and Pmax can be predicted by significant CMR parameters, while T1 (R2 = 23.2%, r = 0.48) and partition coefficient (R2 = 13.8%, r = 0.37) can be predicted by significant cardiac mechanical properties. In SR group LVS (R2 = 94.8%, r = 0.97), LVC (R2 = 93.7%, r = 0.96) and Pmin (R2 = 90.6%, r = 0.95) can be predicted by significant cardiac mechanical properties, while in HR + DEX group CWE (R2 = 49.8%, r = 0.70) can be predicted by significant cardiac mechanical properties. Partition coefficient (R2 = 72.6%, r = 0.85) can be predicted by significant CMR parameters in SR group.Early characterization of cardiac mechanical properties from CMR parameters has the potential to early detect doxorubicin-induced cardiotoxicity.

Cardiac Mechanical Performance Assessment at Different Levels of Exercise in Childhood Acute Lymphoblastic Leukemia Survivors.

There is a shortage of relevant studies interested in cardiac mechanical performance. Thus, it is clinically relevant to study the impact of cancer treatments on survivors' cardiac mechanical performance to improve our knowledge. The first objective of this study is to assess survivors' cardiac mechanical performance during a cardiopulmonary exercise test (CPET) using both ventricular-arterial coupling (VAC) and cardiac work efficiency (CWE) from cardiac magnetic resonance (CMR) acquisitions. The second objective is to assess the impact of doxorubicin and dexrazoxane (DEX) treatments. A total of 63 childhood acute lymphoblastic leukemia survivors underwent a CMR at rest on a 3T magnetic resonance imaging system, followed by a CPET on ergocycle. The CircAdapt model was used to study cardiac mechanical performance. At different levels of exercise, arterial elastance, end-systolic elastance, VAC, and CWE were estimated. We observed significant differences between the different levels of exercise for both VAC ( P <0.0001) and CWE parameters ( P =0.001). No significant differences were reported between prognostic risk groups at rest and during the CPET. Nevertheless, we observed that survivors in the SR group had a VAC value slightly lower than heart rate (HR)+DEX and HR groups throughout the CPET. Moreover, survivors in the SR group had a CWE parameter slightly higher than HR+DEX and HR groups throughout the CPET. This study reveals that the combination of CPET, CMR acquisitions and CircAdapt model was sensitive enough to observe slight changes in the assessment of VAC and CWE parameters. Our study contributes to improving survivors' follow-up and detection of cardiac problems induced by doxorubicin-related cardiotoxicity.

Impact of metabolic substrate modification on myocardial efficiency in a rat model of obesity and diabetes

Abstract Background Congenic leptin receptor deficient rat generated by introgression of the Koletsky leptin receptor mutation into BioBreeding Diabetes Resistant rat (BBDR.lepr−/−) is a novel animal model combining obesity, systemic insulin resistance and diabetes. Systemic insulin resistance is associated with reduced myocardial glucose utilization, but its effect on myocardial external efficiency, i.e. the ability of the myocardium to convert energy into external stroke work, remains uncertain. Purpose To characterize cardiac energy metabolism and function in BBDR.lepr−/− rats and to study the effect of dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin in this model. Methods Cardiac phenotype was evaluated in six-month-old male BBDR.lepr−/− rats (n=11) and age-matched male non-diabetic lean control littermates (BBDR.lepr+/− or BBDR.lepr+/+ rats, n=14). Of these, 7 BBDR.lepr−/− rats and 6 controls underwent cardiac ultrasound, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), and [11C]acetate PET in order to evaluate cardiac structure and function as well as glucose and oxidative metabolism. In the remaining rats, fatty acid metabolism was evaluated by [18F]fluorothia-6-heptadecanoic acid ([18F]FTHA) PET/CT. In the linagliptin intervention study, 25 BBDR.lepr−/− male rats were randomly divided into control group (n=11) that received regular chow diet and linagliptin group (n=14) that received linagliptin (10mg/kg/d) mixed in the chow diet for three months. After the intervention, the rats underwent cardiac ultrasound, [18F]FDG PET/CT, and [11C]acetate PET. Results Compared with controls, BBDR.lepr−/− rats showed increased left ventricle (LV) mass (∼40%, p&amp;gt;0.001) and higher systolic blood pressure (∼10%, p=0.02). However, fractional shortening and cardiac output were similar in both groups. Myocardial fractional uptake rate of glucose measured with [18F]FDG PET was significantly reduced (∼86%, p=0.004) (Fig. 1A, E), whereas myocardial fatty acid uptake measured by [18F]FTHA PET was not significantly increased (free fatty acid (FFA) corrected standardized uptake value (SUV) ∼21%, p=0.54) (Fig. 1B) in BBDR.lepr−/− compared to controls. Myocardial oxygen consumption assessed by [11C]acetate PET was similar in both groups (Fig. 1C, E), but LV work per gram of myocardium was reduced (∼28%, p=0.001) resulting in reduced myocardial external efficiency (∼21%, p=0.03) (Fig. 1D) in BBDR.lepr−/− compared to controls. Treatment with linagliptin significantly enhanced myocardial fractional uptake rate of glucose (∼166%, p=0.006) (Fig. 2A, C), but had no effect on efficiency of cardiac work (Fig. 2B). Conclusions Obese and diabetic BBDR.lepr−/− rats demonstrate LV hypertrophy and markedly reduced myocardial glucose utilization associated with impaired myocardial external efficiency despite normal LV systolic function. Enhancement of myocardial glucose uptake by linagliptin did not improve efficiency of cardiac work. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): IMI-SUMMIT

Acute SGLT-2i treatment improves cardiac efficiency during myocardial ischemia independent of Na+/H+ exchanger-1

AimsSodium glucose co-transporter 2 inhibitors (SGLT2i) demonstrate cardioprotective benefits independent of a glucose lowering effect including preservation of cardiac function during a myocardial ischemia. Sodium‑hydrogen exchanger-1 (NHE-1), has been hypothesized to contribute to the cardiac effects of SGLT2i. We characterized the beneficial effects of acute pre-ischemia exposure to SGLT2i and explored the possibility that these effects are explained by NHE-1 inhibition. Methods and resultsSwine were anesthetized and instrumented for invasive hemodynamic measurements. After baseline data collection, swine received a 15–30 min intravenous infusion of vehicle (DMSO), the SGLT2i canagliflozin (~1 mg/kg), or the NHE-1 inhibitor cariporide (~0.03 mg/kg) ending immediately prior to occlusion of the left circumflex artery. Measurements were obtained at baseline, during a 60-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, left anterior descending artery flow, and associated myocardial oxygen consumption were unaffected by acute pre-treatment with canagliflozin or cariporide during ischemia and reperfusion. Acute pre-ischemic treatment with canagliflozin significantly increased diastolic filling and stroke work, producing a rightward shift in the Frank-Starling relationship, and also improved cardiac work efficiency relative to untreated control hearts during ischemia. Effects of NHE-1 inhibition with cariporide were modest and dissimilar. Examination of AP-1 cells transfected with wild-type NHE-1 and iPSC-derived cardiomyocytes confirmed dose-dependent-inhibition of NHE-1 activity by cariporide, while canagliflozin had no significant effect on NHE-1 activity. ConclusionAcute pre-treatment with SGLT2i produces cardioprotective effects during ischemia, including improved work efficiency. These effects are not explained by NHE-1 inhibition. Translational perspectiveSGLT2 inhibitors have been shown to improve cardiac outcomes in patient including reducing myocardial infarction incidence and mortality. The mechanism(s) explaining this effect are not clear. This manuscript demonstrates a protective effect from acute SGLT2i exposure, as short as 15 min, prior to experimental infarction in swine. These effects were independent of NHE1 inhibition. These observations suggest that SGLT2 inhibitors can confer cardioprotective effects on a very short time scale. It is possible that such effects provide an ongoing contribution to ischemic protection even in the setting of chronic treatment.

Inhibition of sodium-glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization.

The goal of the present study was to evaluate the effects of SGLT2i on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in normal, metabolically healthy swine. Lean swine received placebo or canagliflozin (300mg PO) 24h prior to and the morning of an invasive physiologic study protocol. Hemodynamic and cardiac function measurements were obtained at baseline, during a 30-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, coronary flow, and myocardial oxygen consumption were unaffected by canagliflozin treatment. Ventricular volumes remained unchanged in controls throughout the protocol. At the onset of ischemia, canagliflozin produced acute large increases in left ventricular end-diastolic and systolic volumes which returned to baseline with reperfusion. Canagliflozin-mediated increases in end-diastolic volume were directly associated with increases in stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial uptake of glucose, lactate, free fatty acids or ketones, were noted between treatment groups at any time. In separate experiments using a longer 60min coronary occlusion followed by 2h of reperfusion, canagliflozin increased end-diastolic volume and stroke volume and significantly diminished myocardial infarct size relative to control swine. These data demonstrate that SGLT2i with canagliflozin preserves cardiac contractile function and efficiency during regional myocardial ischemia and provides ischemia protection independent of alterations in myocardial substrate utilization.

Role of Cardiac Magnetic Resonance in Heart Failure with Preserved Ejection Fraction

Approximately half of the patients presenting with heart failure have preserved ejection fraction. These patients usually have a combination of underlying etiologies and may profit from individualized treatment. Failure of clinical trials without adequate understanding of the underlying problem highlights the need for an in-depth assessment of this complex clinical syndrome. This review seeks to discuss the role of cardiovascular magnetic resonance imaging (CMR) in improving diagnosis and targeted management of heart failure with preserved ejection fraction (HFpEF). Technical advances in tissue mapping techniques enable a virtual histopathological perspective to detect myocardial disease processes, such as inflammation, infiltration, and fibrosis. Myocardial perfusion imaging enables separation between regional ischemia due to epicardial coronary artery disease (CAD) and microvascular disease. Finally, computation of aortic pulse wave velocity (PWV) provides insight into the effects of the vascular stiffness on the efficiency of cardiac work. A comprehensive CMR protocol enables identification of the underlying pathophysiology in patients with HFpEF, allows identification of important differential diagnoses in patients with specific diseases, and may lead to imaging-guided precision medicine in HFpEF.

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The athlete's heart is a set of morphological and functional characteristics that develop over time due to sports training. These adaptive changes result in increase in cardiac work efficiency and economy. They are manidested as cardiac muscle hypertrophy and dilation, with accompanying angiogenesis and slower heart rate, that are influenced by variable regulatory systems and genetic predisposition. The problem of sudden cardiac death in athletes, which persists despite numerous activities aimed at prevention, creates the need for a better definition of the athlete's heart, especially in terms of its differentiation from certain pathological conditions. This is of particular importance in the context of cardiac electrical activity. Right heart adaptations, hormonal regulatory mechanisms and the effects of nonphysiological adaptations during training, that may lead to pathologic alterations direction, are all relevant in the investigation of adverse cardiac events in athletes. In order to prevent sudden cardiac death in athletes, it is necessary to examine competitive athletes as well as apparently health individuals who recreationally exercise at a high volume. There are guidelines for mass screening and individual examinations, for all age groups and both genders, as well as for public service staff who require intense physical activity during their occupation. Both American and European recommendations require a detailed anamnesis and physical examination, whereas European, apart from that, require initial electrocardiography. The implementation of additional tests is necessary if the existence of any underlying pathophysiologic process is suspected. Checks should be performed before engaging in sports activities, as well as during training and competition periods.

Simultaneous pressure–volume measurements using optical sensors and MRI for left ventricle function assessment during animal experiment

Simultaneous pressure and volume measurements enable the extraction of valuable parameters for left ventricle function assessment. Cardiac MR has proven to be the most accurate method for volume estimation. Nonetheless, measuring pressure simultaneously during MRI acquisitions remains a challenge given the magnetic nature of the widely used pressure transducers. In this study we show the feasibility of simultaneous in vivo pressure–volume acquisitions with MRI using optical pressure sensors. Pressure–volume loops were calculated while inducing three inotropic states in a sheep and functional indices were extracted, using single beat loops, to characterize systolic and diastolic performance. Functional indices evolved as expected in response to positive inotropic stimuli. The end-systolic elastance, representing the contractility index, the diastolic myocardium compliance, and the cardiac work efficiency all increased when inducing inotropic state enhancement. The association of MRI and optical pressure sensors within the left ventricle successfully enabled pressure–volume loop analysis after having respective data simultaneously recorded during the experimentation without the need to move the animal between each inotropic state.

Myocardial blood flow and its transit time, oxygen utilization, and efficiency of highly endurance-trained human heart.

Highly endurance-trained athlete's heart represents the most extreme form of cardiac adaptation to physical stress, but its circulatory alterations remain obscure. In the present study, myocardial blood flow (MBF), blood mean transit time (MTT), oxygen extraction fraction (OEF) and consumption (MVO2), and efficiency of cardiac work were quantified in highly trained male endurance athletes and control subjects at rest and during supine cycling exercise using [(15)O]-labeled radiotracers and positron emission tomography. Heart rate and MBF were lower in athletes both at rest and during exercise. OEF increased in response to exercise in both groups, but was higher in athletes (70 ± 21 vs. 63 ± 11 % at rest and 86 ± 13 vs. 73 ± 10 % during exercise). MTT was longer and vascular resistance higher in athletes both at rest and during exercise, but arterial content of 2,3-diphosphoglycerate (oxygen affinity) was unchanged. MVO2 per gram of myocardium trended (p = 0.08) lower in athletes both at rest and during exercise, while myocardial efficiency of work and MVO2 per beat were not different between groups. Arterial levels of free fatty acids were ~twofold higher in athletes likely leading to higher myocardial fatty acid oxidation and hence oxygen cost, which may have blunted the bradycardia-induced decrease in MVO2. Finally, the observed group differences in MBF, OEF, MTT and vascular resistance remained significant also after they were controlled for differences in MVO2. In conclusion, in highly endurance-trained human heart, increased myocardial blood transition time enables higher oxygen extraction levels with a lower myocardial blood flow and higher vascular resistance. These physiological adaptations to exercise training occur independently of the level of oxygen consumption and together with training-induced bradycardia may serve as mechanisms to increase functional reserve of the human heart.

Carnitine modulates crucial myocardial adenosine triphosphatases and acetylcholinesterase enzyme activities in choline-deprived rats

Choline is an essential nutrient, and choline deficiency has been associated with cardiovascular morbidity. Choline is also the precursor of acetylcholine (cholinergic component of the heart's autonomic nervous system), whose levels are regulated by acetylcholinesterase (AChE). Cardiac contraction-relaxation cycles depend on ion gradients established by pumps like the adenosine triphosphatases (ATPases) Na(+)/K(+)-ATPase and Mg(2+)-ATPase. This study aimed to investigate the impact of dietary choline deprivation on the activity of rat myocardial AChE (cholinergic marker), Na(+)/K(+)-ATPase, and Mg(2+)-ATPase, and the possible effects of carnitine supplementation (carnitine, structurally relevant to choline, is used as an adjunct in treating cardiac diseases). Adult male albino Wistar rats were distributed among 4 groups, and were fed a standard or choline-deficient diet for one month with or without carnitine in their drinking water (0.15% w/v). The enzyme activities were determined spectrophotometrically in the myocardium homogenate. Choline deficiency seems to affect the activity of the aforementioned parameters, but only the combination of choline deprivation and carnitine supplementation increased myocardial Na(+)/K(+)-ATPase activity along with a concomitant decrease in the activities of Mg(2+)-ATPase and AChE. The results suggest that carnitine, in the setting of choline deficiency, modulates cholinergic myocardial neurotransmission and the ATPase activity in favour of cardiac work efficiency.

Myocardial substrate metabolism in obesity.

Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end-stage systolic heart failure. Obesity causes changes in cardiac metabolism, which make ATP production and utilization less efficient, producing functional consequences that are linked to the increased rate of heart failure in this population. As a result of the increases in circulating fatty acids and insulin resistance that accompanies excess fat storage, several of the proteins and genes that are responsible for fatty acid uptake and metabolism are upregulated, and the metabolic machinery responsible for glucose utilization and oxidation are inhibited. The resultant increase in fatty acid metabolism, and the inherent alterations in the proteins of the electron transport chain used to create the gradient needed to drive mitochondrial ATP production, results in a decrease in efficiency of cardiac work and a relative increase in oxygen usage. These changes in cardiac mitochondrial metabolism are potential therapeutic targets for the treatment and prevention of obesity-related heart failure.

Altered ventriculo-arterial coupling during exercise in athletes releasing biomarkers after endurance running

Exercise can lead to release of biomarkers such as cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), a poorly understood phenomenon proposed to especially occur with high-intensity exercise in less trained subjects. We hypothesised that haemodynamic perturbations during exercise are larger in athletes with cTnT release, and studied athletes with detectable cTnT levels after an endurance event (HIGH; n=16; 46±9years) against matched controls whose levels were undetectable (LOW; n=11; 44±7years). Echocardiography was performed at rest and at peak supine bicycle exercise stress. Left ventricular (LV) end-systolic elastance (E (LV) a load-independent measure of LV contractility), effective arterial elastance (E (A) a lumped index of arterial load) and end-systolic meridional wall stress were calculated from cardiac dimensions and brachial blood pressure. Efficiency of cardiac work was judged from the ventriculo-arterial coupling ratio (E (A)/E (LV): optimal range 0.5-1.0). While subgroups had similar values at rest, we found ventriculo-arterial mismatch during exercise in HIGH subjects [0.47 (0.39-0.58) vs. LOW: 0.73 (0.62-0.83); p<0.01] due to unopposed increase in E (LV) (p<0.05). In LOW subjects, a greater increase occurred in E (A) during exercise (+81±67% vs. HIGH: +39±32%; p=0.02) which contributed to a maintained coupling ratio. Subjects with higher baseline NT-proBNP had greater systolic wall stress during exercise (R (2)=0.39; p<0.01) despite no correlation at rest (p=ns). In conclusion, athletes with exercise-induced biomarker release exhibit ventriculo-arterial mismatch during exercise, suggesting non-optimal cardiac work may contribute to this phenomenon.

E0650 The effects of biventricular synchronous pacing on CBF, MVO2 and CWE in dogs

ObjectiveTo compare the effects of biventricular synchronous pacing with different pacing site on coronary Blood flow (CBF), myocardial oxygen consumption (MVO2) and cardiac work efficiency (CWE).MethodsRA-cHisB and RA-RVA sequential pacing,...

Effect of the cardioselective Δ337T thyroid receptor (TR)β1 mutation on cardiac substrate fluxes and work efficiency

Hypothyroidism depresses cardiac work efficiency (CWE) in situ and in isolated rat heart models. The mechanisms are unclear, but may involve thyroid receptor control of substrate metabolism. To test this hypothesis and to avoid confounding systemic factor effects on cardiac metabolism, we studied mice expressing a cardioselective dominant negative TRβ1 mutation, Δ337T. We used a working mouse heart with 13Carbon (30 min infusion) isotopomer analyses by MR spectroscopy to determine function, oxygen consumption, fluxes and fractional contribution (Fc) of acetyl-CoA to the citric acid cycle simultaneously for multiple substrates (1,3-13C-acetoacetate, L-3-13C-lactate, U-13C-free fatty acids and unlabeled glucose). Heart rate, –dP/dt and pressure rate product were reduced in Δ337T (n=4) compared to wild type (WT, n=5). However, Δ337T CWE (103mmHg×ml/μmolO2×min−1g−1) exceeded WT [230 vs 102 (P<0.007)]. No differences in flux for any substrate or for anaplerosis occurred, though Fc for free fatty acids tended to be increased in Δ337T. Shifts in flux among these major substrate pathways do not seem to play a major role in the marked changes in CWE with thyroid receptor dysfunction. These data show that although cardioselective hypothyroidism depresses diastolic function, CWE is increased. Furthermore, thyroid receptor dysfunction can alter CWE at sites of either ATP utilization or respiratory coupling, substrate oxidation pathways playing a less significant part. Supported by NIH HL60666.

Differing mechanisms for dobutamine in enhancement of cardiac work efficiency in normal and failing hearts

Differing mechanisms for dobutamine in enhancement of cardiac work efficiency in normal and failing hearts

Spinal cord stimulation treatment for angina pectoris: more than a placebo?

Background. The effects of thoracolumbal spinal cord stimulation (SCS) are confined to restricted microcirculatory areas. This limitation is generally attributed to a predominantly segmental mode of action on the autonomic nervous system. The goal of this study was to determine whether SCS applied close to supraspinal autonomic centers would induce generalized hemodynamic changes that could explain its alleged antianginal properties. Methods. Invasive hemodynamic tests were performed in 15 anesthetized Göttingen minipigs submitted to iterative cervical SCS of various duration and intensity. Results. Hemodynamic changes exceeding 10% were observed in 59 of 68 SCS sessions (87%). Their extent and time to peak varied with SCS intensity. At 2, 5, and 10 V, significant ( t test p < 0.05) peak changes occurred in cardiac output (+34%, +29%, and +28%, respectively), stroke volume (+19%, +16%, +15%), mean pressure (+9%, +27%, +40%), heart rate (+14%, +23%, +14%), systemic (−17%, NS, NS), and pulmonary vascular (25%, NS, NS) resistances. Strikingly, at 2 V, the increase in cardiac output (+34%) was higher than the synchronous rise in rate pressure product (+22%), indicating efficient cardiac work. At 10 V, however, the cardiac work was inefficient (rate pressure product + 53%/cardiac output + 28%). Conclusions. Low-voltage cervical neuromodulation reduces the postcharge and improves cardiac work efficiency. The resulting reduction in oxygen myocardial demand may account for decreased anginal pain.

Prospective studies on left ventricular geometric patterns and exercise tolerance in unmedicated men with borderline and mild hypertension.

This study was designed and conducted to assess the clinical significance of left ventricular geometric patterns and physical fitness in subjects with untreated borderline and mild hypertension. Symptom-limited maximal treadmill stress testings and echocardiographic examinations were administered to 192 previously unmedicated men. Left ventricular geometric patterns were determined by the combined criteria of left ventricular mass index and relative wall thickness. Subjects whose left ventricular mass index was < 125 g/m2 were followed up for more than 3 years. Normalized treadmill time was lower and pressure rate products at peak exercise were higher in patients with concentric hypertrophy than in those with normal geometry. Of the 77 patients who revealed left ventricular mass index at baseline < 125 g/m2 and who were successfully followed without medication for more than 3 years, 18 demonstrated concentric hypertrophy at the final follow-up examination. During the follow-up period, these 18 patients had significant further augmentation of concentric geometric features, significant decreases in both cardiac output and normalized treadmill time, and significant increases in casual blood pressure and total peripheral resistance compared with those at baseline. Patients with concentric hypertrophy exhibited slightly but significantly impaired levels of physical fitness and cardiac work efficiency, and the progression of concentric hypertrophy demonstrated further impairments of these conditions. Therefore, not only lowering blood pressure, but also improving left ventricular hypertrophy, cardiovascular hemodynamics, and physical fitness might be required in patients with concentric hypertrophy.

Influences of ventricular pacing on hemodynamics, myocardial metabolism, and cardiac work efficiency: potential risks of rate-responsive ventricular pacing.

The influences of ventricular pacing at a rate of 70 beats/min (bpm) on the systemic and coronary hemodynamics, myocardial metabolism, and cardiac work efficiency were evaluated in five patients with bradycardia. The results were compared to those obtained in six normal subjects at rest. In order to elucidate the effects of a relatively high rate of ventricular pacing, cardiovascular and metabolic variables were also obtained at 120 bpm in the normal subjects. It was observed that the patients eventually benefited from ventricular pacing at a rate of 70 bpm and improved in systemic hemodynamics. Although coronary hemodynamics and myocardial metabolism were accelerated, the cardiac work efficiency was not improved. A pacing rate of 120 bpm in the normal subjects did not appear to accelerate systemic hemodynamics, but adverse accelerations of coronary hemodynamics and myocardial metabolism were observed, and the cardiac work efficiency was remarkably reduced as a result. Our observations indicated that the coronary reserve capacity was very important for ventricular pacing, and suggested that an undue increment of the pacing rate not only might be meaningless but also might induce ischemic angina. Therefore, we should be cautious in using a rate-responsive pacing mode, particularly in determination of the upper limit of pacing rates, although many benefits with this pacing mode have recently been advocated.