Early treatment with a sodium-glucose co-transporter 2 inhibitor in high-risk patients with acute heart failure: Rationale for and design of the EMPA-AHF trial.

AIMS: The aim of the EMPA-AHF trial is to clarify whether early initiation of a sodium-glucose co-transporter 2 inhibitor before clinical stabilization is safe and beneficial for patients with acute heart failure (AHF) who are at a high risk of adverse events. METHODS: The EMPA-AHF trial is a randomized, double-blind, placebo-controlled, multicentre trial examining the efficacy and safety of early initiation of empagliflozin (10 mg once daily). In total, 500 patients admitted for AHF will be randomized 1:1 to either empagliflozin 10 mg daily or placebo at 47 sites in Japan. Study entry requires hospitalization for AHF with dyspnoea, signs of volume overload, elevated natriuretic peptide, and at least one of the following criteria: estimated glomerular filtration rate <60 mL/min/1.73 m2; already taking ≥40 mg of furosemide daily before hospitalization; and urine output of <300 mL within 2 hours after an adequate dose of intravenous furosemide. Patients will be randomized within 12 hours of hospital presentation, with treatment continued up to 90 days. The primary outcome is the clinical benefit of empagliflozin on the win ratio for a hierarchical composite endpoint consisting of death within 90 days, heart failure rehospitalization within 90 days, worsening heart failure during hospitalization, and urine output within 48 hours after treatment initiation. CONCLUSION: The EMPA-AHF trial is the first to evaluate the efficacy and safety of early initiation of empagliflozin in patients with AHF considered to be at high risk under conventional treatment.

Prognostic Value of Neurological Status on Hospital Arrival for Short-Term Outcome in Patients With Cardiovascular Shock　- Sub-analysis of the Japanese Circulation Society Cardiovascular Shock Registry.

BACKGROUND: Consciousness disturbance is one of the major clinical signs associated with shock state, but its prognostic value has not been previously evaluated in cardiovascular shock patients. We aimed to evaluate the prognostic value of neurological status for 30-day mortality in cardiovascular shock patients without out-of-hospital cardiac arrest (OHCA). Methods and Results: Patients with out-of-hospital onset cardiovascular shock were recruited from the Japanese Circulation Society Shock Registry. Neurological status upon hospital arrival was evaluated using the Japan Coma Scale (JCS). Patients were divided into 4 groups according to the JCS: alert, JCS 0; awake, JCS 1-3 (not fully alert but awake without any stimuli); arousable, JCS 10-30 (arousable with stimulation); and coma JCS 100-300 (unarousable). The primary endpoint was 30-day all-cause death. In total, 700 cardiovascular shock patients without OHCA were assessed. The coma group was associated with a higher incidence of 30-day all-cause death compared with other groups (alert, 15.3%; awake, 24.4%; arousable, 36.8%; coma, 48.5%, P<0.001). Similar trends were observed in etiologically divergent subgroups (acute coronary syndrome, non-ischemic arrhythmia, and aortic disease). On multivariate Cox regression analysis, arousable (hazard ratio [HR], 1.82; 95% CI: 1.16-2.85, P=0.009) and coma (HR, 2.72; 95% CI: 1.76-4.22, P<0.001) (reference: alert) independently predicted 30-day mortality. CONCLUSIONS: Neurological status upon hospital arrival was useful to predict 30-day mortality in cardiovascular shock patients without OHCA.

Changes in vascular properties, not ventricular properties, predominantly contribute to baroreflex regulation of arterial pressure.

Baroreflex modulates both the ventricular and vascular properties and stabilizes arterial pressure (AP). However, how changes in those mechanical properties quantitatively impact the dynamic AP regulation remains unknown. We developed a framework of circulatory equilibrium, in which both venous return and cardiac output are expressed as functions of left ventricular (LV) end-systolic elastance (Ees), heart rate (HR), systemic vascular resistance (R), and stressed blood volume (V). We investigated the contribution of each mechanical property using the framework of circulatory equilibrium. In six anesthetized dogs, we vascularly isolated carotid sinuses and randomly changed carotid sinus pressure (CSP), while measuring the LV Ees, aortic flow, right and left atrial pressure, and AP for at least 60 min. We estimated transfer functions from CSP to Ees, HR, R, and V in each dog. We then predicted these parameters in response to changes in CSP from the transfer functions using a data set not used for identifying transfer functions and predicted changes in AP using the equilibrium framework. Predicted APs matched reasonably well with those measured (r2=0.85-0.96, P<0.001). Sensitivity analyses indicated that Ees and HR (ventricular properties) accounted for 14±4 and 4±2%, respectively, whereas R and V (vascular properties) accounted for 32±4 and 39±4%, respectively, of baroreflex-induced AP regulation. We concluded that baroreflex-induced dynamic AP changes can be accurately predicted by the transfer functions from CSP to mechanical properties using our framework of circulatory equilibrium. Changes in the vascular properties, not the ventricular properties, predominantly determine baroreflex-induced AP regulation.

Cardiac phase-targeted dynamic load on left ventricle differentially regulates phase-sensitive gene expressions and pathway activation.

The heart has remarkable capacity to adapt to mechanical load and to dramatically change its phenotype. The mechanism underlying such diverse phenotypic adaptations remains unknown. Since systolic overload induces wall thickening, while diastolic overload induces chamber enlargement, we hypothesized that cardiac phase-sensitive mechanisms govern the adaptation. We inserted a balloon into the left ventricle (LV) of a Langendorff perfused rat heart, and controlled LV volume (LVV) using a high performance servo-pump. We created isolated phasic systolic overload (SO) by isovolumic contraction (peak LV pressure >170mmHg) at unstressed diastolic LVV [end-diastolic pressure (EDP)=0mmHg]. We also created pure phasic diastolic overload (DO) by increasing diastolic LVV until EDP >40mmHg and unloading completely in systole. After 3hours under each condition, the myocardium was analyzed using DNA microarray. Gene expressions under SO and DO conditions were compared against unloaded control condition using gene ontology and pathway analysis (n=4 each). SO upregulated proliferation-related genes, whereas DO upregulated fibrosis-related genes (P<10(-5)). Both SO and DO upregulated genes related functionally to cardiac hypertrophy, although the gene profiles were totally different. Upstream regulators confirmed by Western blot indicated that SO activated extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase, and Ca(2+)/calmodulin-dependent protein kinase II (3.2-, 2.0-, and 4.7-fold versus control, P<0.05, n=5), whereas DO activated p38 (2.9-fold, P<0.01), which was consistent with the downstream gene expressions. In conclusion, pure isolated systolic and diastolic overload permits elucidation of cardiac phase-sensitive gene regulation. The genomic responses indicate that mechanisms governing the cardiac phase-sensitive adaptations are different.

Bionic baroreceptor corrects postural hypotension in rats with impaired baroreceptor.

BACKGROUND: Impairment of the arterial baroreflex causes orthostatic hypotension. Arterial baroreceptor sensitivity degrades with age. Thus, an impaired baroreceptor plays a pivotal role in orthostatic hypotension in most elderly patients. There is no effective treatment for orthostatic hypotension. The aims of this investigation were to develop a bionic baroreceptor (BBR) and to verify whether it corrects postural hypotension. METHODS AND RESULTS: The BBR consists of a pressure sensor, a regulator, and a neurostimulator. In 35 Sprague-Dawley rats, we vascularly and neurally isolated the baroreceptor regions and attached electrodes to the aortic depressor nerve for stimulation. To mimic impaired baroreceptors, we maintained intracarotid sinus pressure at 60 mm Hg during activation of the BBR. Native baroreflex was reproduced by matching intracarotid sinus pressure to the instantaneous pulsatile aortic pressure. The encoding rule for translating intracarotid sinus pressure into stimulation of the aortic depressor nerve was identified by a white noise technique and applied to the regulator. The open-loop arterial pressure response to intracarotid sinus pressure (n=7) and upright tilt-induced changes in arterial pressure (n=7) were compared between native baroreceptor and BBR conditions. The intracarotid sinus pressure-arterial pressure relationships were comparable. Compared with the absence of baroreflex, the BBR corrected tilt-induced hypotension as effectively as under native baroreceptor conditions (native, -39±5 mm Hg; BBR, -41±5 mm Hg; absence, -63±5 mm Hg; P<0.05). CONCLUSIONS: The BBR restores the pressure buffering function. Although this research demonstrated feasibility of the BBR, further research is needed to verify its long-term effect and safety in larger animal models and humans.

The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice.

Myocardial mitochondrial DNA (mtDNA) copy number decreases in heart failure. In post-myocardial infarction mice, increasing mtDNA copy number by overexpressing mitochondrial transcription factor attenuates mtDNA deficiency and ameliorates pathological remodeling thereby markedly improving survival. However, the functional significance of increased mtDNA copy number in hypertensive heart disease remains unknown. We addressed this question using transgenic mice that overexpress Twinkle helicase (Twinkle; Tg), the mtDNA helicase, and examined whether Twinkle overexpression protects the heart from left ventricular (LV) remodeling and failure after pressure overload created by transverse aortic constriction (TAC). Twinkle overexpression increased mtDNA copy number by 2.2 ± 0.1-fold. Heart weight, LV diastolic volume and wall thickness were comparable between Tg and wild type littermates (WT) at 28 days after TAC operation. LV end-diastolic pressure increased in WT after TAC (8.6 ± 2.8 mmHg), and this increase was attenuated in Tg (4.6 ± 2.6 mmHg). Impaired LV fractional shortening after TAC operation was also suppressed in Tg, as measured by echocardiography (WT: 16.2 ± 7.2% vs Tg: 20.7 ± 6.2%). These LV functional improvements were accompanied by a decrease in interstitial fibrosis (WT: 10.6 ± 1.1% vs Tg: 3.0 ± 0.6%). In in vitro studies, overexpressing Twinkle using an adenovirus vector in cultured cardiac fibroblasts significantly suppressed mRNA of collagen 1a, collagen 3a and connective tissue growth factor, and angiotensin II-induced transforming growth factor ß1 expression. The findings suggest that Twinkle overexpression prevents LV function deterioration. In conclusion, Twinkle overexpression increases mtDNA copy number and ameliorates the progression of LV fibrosis and heart failure in a mouse pressure overload model. Increasing mtDNA copy number by Twinkle overexpression could be a novel therapeutic strategy for hypertensive heart disease.

Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes.

The overexpression of mitochondrial transcription factor A (TFAM) attenuates the decrease in mtDNA copy number after myocardial infarction, ameliorates pathological hypertrophy, and markedly improves survival. However, non-transgenic strategy to increase mtDNA for the treatment of pathological hypertrophy remains unknown. We produced recombinant human TFAM protein (rhTFAM). rhTFAM rapidly entered into mitochondria of cultured cardiac myocytes. rhTFAM increased mtDNA and abolished the activation of nuclear factor of activated T cells (NFAT), which is well known to activate pathological hypertrophy. rhTFAM attenuated subsequent morphological hypertrophy of myocytes as well. rhTFAM would be an attractive molecule in attenuating cardiac pathological hypertrophy.

Impact of baroreflex on venous return surface.

BACKGROUND: Although Guyton's concept of venous return (VR) revolutionized circulatory physiology, the pulmonary circulation is invisible in its original framework. Since the pulmonary circulation is critical in left heart failure, we characterized the VR as a surface described by right (P(RA)) and left atrial (P(LA)) pressures and demonstrated that the VR surface was capable of representing mechanics of pulmonary as well as systemic circulation. However how baroreflex impacts the VR surface remains unknown. METHODS/RESULTS: In 8 dogs, we isolated the carotid sinuses and replaced both ventricles with pumps. We varied cardiac output, shifted blood distribution between the systemic and pulmonary circulation at carotid sinus pressures (CSP) of 100 or 140 mmHg. The coefficient of determination of the VR surface ranged 0.96-0.99 indicating how flat the surface is. Increasing CSP decreased maximum VR (233 ± 27 vs. 216 ± 33 ml/kg/min, p<0.05), whereas did not change the slopes of VR along P(RA) or P(LA) axes. CONCLUSIONS: Baroreflex parallel shifts the VR surface, thereby stressed volume, without changing its slopes.

Artificial baroreflex system restores volume tolerance in the absence of native baroreflex.

The arterial baroreflex stabilizes arterial pressure by modulating the mechanical properties of cardiovascular system. We previously demonstrated that the baroreflex impairment makes the circulatory system extremely sensitive to volume overload and predisposes to pulmonary edema irrespective of left ventricular systolic function. To overcome the volume intolerance, we developed an artificial baroreflex system by directly stimulating the carotid sinus nerves in response to changes in arterial pressure. The artificial baroreflex system precisely reproduced the native arterial pressure response and restored physiological volume buffering function. We conclude that the artificial baroreflex system would be an attractive tool in preventing pulmonary edema in patients with impaired baroreflex function.