Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The CAMEO-DAPA Trial.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors reduce risk of hospitalization for heart failure in patients who have heart failure with preserved ejection fraction (HFpEF), but the hemodynamic mechanisms underlying these benefits remain unclear. This study sought to determine whether treatment with dapagliflozin affects pulmonary capillary wedge pressure (PCWP) at rest and during exercise in patients with HFpEF. METHODS: This was a single-center, double-blinded, randomized, placebo-controlled trial testing the effects of 10 mg of dapagliflozin once daily in patients with HFpEF. Patients with New York Heart Association class II or III heart failure, ejection fraction ≥50%, and elevated PCWP during exercise were recruited. Cardiac hemodynamics were measured at rest and during exercise using high-fidelity micromanometers at baseline and after 24 weeks of treatment. The primary end point was a change from baseline in rest and peak exercise PCWPs that incorporated both measurements, and was compared using a mixed-model likelihood ratio test. Key secondary end points included body weight and directly measured blood and plasma volumes. Expired gas analysis was performed evaluate oxygen transport in tandem with arterial lactate sampling. RESULTS: Among 38 patients completing baseline assessments (median age 68 years; 66% women; 71% obese), 37 completed the trial. Treatment with dapagliflozin resulted in reduction in the primary end point of change in PCWP at rest and during exercise at 24 weeks relative to treatment with placebo (likelihood ratio test for overall changes in PCWP; P<0.001), with lower PCWP at rest (estimated treatment difference [ETD], -3.5 mm Hg [95% CI, -6.6 to -0.4]; P=0.029) and maximal exercise (ETD, -5.7 mm Hg [95% CI, -10.8 to -0.7]; P=0.027). Body weight was reduced with dapagliflozin (ETD, -3.5 kg [95% CI, -5.9 to -1.1]; P=0.006), as was plasma volume (ETD, -285 mL [95% CI, -510 to -60]; P=0.014), but there was no significant effect on red blood cell volume. There were no differences in oxygen consumption at 20-W or peak exercise, but dapagliflozin decreased arterial lactate at 20 W (-0.70 ± 0.77 versus 0.37 ± 1.29 mM; P=0.006). CONCLUSIONS: In patients with HFpEF, treatment with dapagliflozin reduces resting and exercise PCWP, along with the favorable effects on plasma volume and body weight. These findings provide new insight into the hemodynamic mechanisms of benefit with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04730947.

The non-invasive assessment of myocardial work by pressure-strain analysis: clinical applications.

Pressure-volume (PV) analysis is the most comprehensive way to describe cardiac function, giving insights into cardiac mechanics and energetics. However, PV analysis still remains a highly invasive and time-consuming method, preventing it from integration into clinical practice. Most of the echocardiographic parameters currently used in the clinical routine to characterize left ventricular (LV) systolic function, such as LV ejection fraction and LV global longitudinal strain, do not take the pressure developed within the LV into account and therefore fall too short in describing LV function as a hydraulic pump. Recently, LV pressure-strain analysis has been introduced as a new technique to assess myocardial work in a non-invasive fashion. This new method showed new insights in comparison to invasive measurements and was validated in different cardiac pathologies, e.g., for the detection of coronary artery disease, cardiac resynchronization therapy (CRT)-response prediction, and different forms of heart failure. Non-invasively assessed myocardial work may play a major role in guiding therapies and estimating prognosis. However, its incremental prognostic validity in comparison to common echocardiographic parameters remains unclear. This review aims to provide an overview of pressure-strain analysis, including its current application in the clinical arena, as well as potential fields of exploitation.

The role of non-invasive devices for the telemonitoring of heart failure patients.

Heart failure (HF) patients represent one of the most prevalent as well as one of the most fragile population encountered in the cardiology and internal medicine departments nowadays. Estimated to account for around 26 million people worldwide, diagnosed patients present a poor prognosis and quality of life with a clinical history accompanied by repeated hospital admissions caused by an exacerbation of their chronic condition. The frequent hospitalizations and the extended hospital stays mean an extremely high economic burden for healthcare institutions. Meanwhile, the number of chronically diseased and elderly patients is continuously rising, and a lack of specialized physicians is evident. To cope with this health emergency, more efficient strategies for patient management, more accurate diagnostic tools, and more efficient preventive plans are needed. In recent years, telemonitoring has been introduced as the potential answer to solve such needs. Different methodologies and devices have been progressively investigated for effective home monitoring of cardiologic patients. Invasive hemodynamic devices, such as CardioMEMS™, have been demonstrated to be reducing hospitalizations and mortality, but their use is however restricted to limited cases. The role of external non-invasive devices for remote patient monitoring, instead, is yet to be clarified. In this review, we summarized the most relevant studies and devices that, by utilizing non-invasive telemonitoring, demonstrated whether beneficial effects in the management of HF patients were effective.

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF.

BACKGROUND: Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF. METHODS: 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student's t-test, as applicable. RESULTS: Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium-calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition. CONCLUSION: The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.

Volume Balance in Chronic Kidney Disease: Evaluation Methodologies and Innovation Opportunities.

BACKGROUND: Patients affected by chronic kidney disease are at a risk of cardiovascular morbidity and mortality. Body fluids unbalance is one of the main characteristics of this condition, as fluid overload is highly prevalent in patients affected by the cardiorenal syndrome. SUMMARY: We describe the state of the art and new insights into body volume evaluation. The mechanisms behind fluid balance are often complex, mainly because of the interplay of multiple regulatory systems. Consequently, its management may be challenging in clinical practice and even more so out-of-hospital. Availability of novel technologies offer new opportunities to improve the quality of care and patients' outcome. Development and validation of new technologies could provide new tools to reduce costs for the healthcare system, promote personalized medicine, and boost home care. Due to the current COVID-19 pandemic, a proper monitoring of chronic patients suffering from fluid unbalances is extremely relevant. Key Message: We discuss the main mechanisms responsible for fluid overload in different clinical contexts, including hemodialysis, peritoneal dialysis, and heart failure, emphasizing the potential impact provided by the implementation of the new technologies.

Implications of SGLT Inhibition on Redox Signalling in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained (atrial) arrhythmia, a considerable global health burden and often associated with heart failure. Perturbations of redox signalling in cardiomyocytes provide a cellular substrate for the manifestation and maintenance of atrial arrhythmias. Several clinical trials have shown that treatment with sodium-glucose linked transporter inhibitors (SGLTi) improves mortality and hospitalisation in heart failure patients independent of the presence of diabetes. Post hoc analysis of the DECLARE-TIMI 58 trial showed a 19% reduction in AF in patients with diabetes mellitus (hazard ratio, 0.81 (95% confidence interval: 0.68-0.95), n = 17.160) upon treatment with SGLTi, regardless of pre-existing AF or heart failure and independent from blood pressure or renal function. Accordingly, ongoing experimental work suggests that SGLTi not only positively impact heart failure but also counteract cellular ROS production in cardiomyocytes, thereby potentially altering atrial remodelling and reducing AF burden. In this article, we review recent studies investigating the effect of SGLTi on cellular processes closely interlinked with redox balance and their potential effects on the onset and progression of AF. Despite promising insight into SGLTi effect on Ca2+ cycling, Na+ balance, inflammatory and fibrotic signalling, mitochondrial function and energy balance and their potential effect on AF, the data are not yet conclusive and the importance of individual pathways for human AF remains to be established. Lastly, an overview of clinical studies investigating SGLTi in the context of AF is provided.

A transmural gradient of myocardial remodeling in early-stage heart failure with preserved ejection fraction in the pig.

Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction. This study aimed to analyze whether early HFpEF is already associated with ultrastructural alterations and whether they differ quantitatively among the layers of the left ventricular wall. HFpEF was induced in pigs by deoxy-corticosterone acetate (DOCA) treatment along with a high-salt/high lipid diet over 3 months and compared with weight-matched normal pigs (n = 5 each). Samples of the left ventricle were taken and processed for light and electron microscopy. Interstitial fibrosis, subcellular composition of cardiomyocytes and mean cardiomyocyte diameter were evaluated by stereology in subendocardial, midmyocardial and subepicardial regions. DOCA enhanced the mean cardiomyocyte diameter in all locations of the ventricle wall to the same degree. The subcellular composition did not differ between the locations and was not altered by DOCA. The volume fraction of interstitium was smaller in the subendocardium of DOCA group than of control group. Within the interstitium, the volume fraction of collagen fibrils (between cardiomyocytes) was increased in the subendocardial and midmyocardial wall layers of the DOCA group but not in the subepicardial layer. Although the capillary length density and average supply area were not altered in response to DOCA in any of the wall layers, the volume fraction of blood vessels related to the interstitial space was enhanced in the subendocardium of the DOCA group but not in the other wall layers. In conclusion, cardiomyocyte changes due to DOCA were similar in subepicardial, midmyocardial and subendocardial regions but DOCA-induced changes in the interstitium appeared to be more pronounced in the subendocardial ventricular wall layers. This suggests a pivotal role of the subendocardial interstitium in the pathogenesis of HFpEF.

Control of ventricular unloading using an electrocardiogram-synchronized pulsatile ventricular assist device under high stroke ratios.

Pulsatile ventricular assist devices (pVADs) yield a blood flow that imitates the pulsatile flow of the heart and, therefore, could diminish the adverse events related to the continuous flow provided by the ventricular assist devices that are commonly used. However, their intrinsic characteristics of larger size and higher weight set a burden to their implantation, that along with the frequent mechanical failures and thrombosis events, reduce the usage of pVADs in the clinical environment. In this study, we investigated the possibility to reduce the pump size by using high pump stroke ratios while maintaining the ability to control the hemodynamics of the cardiovascular system (CVS). In vitro and in vivo experiments were conducted with a custom pVAD implemented on a hybrid mock circulation system and in five sheep, respectively. The actuation of the pVAD was synchronized with the heartbeat. Variations of the pump stroke ratio, time delay between the pump stroke and the heart stroke, as well as duration of the pump systole in respect to the total cardiac cycle duration were used to evaluate the effects of various pump settings on the hemodynamics of the CVS. The results suggest that by varying the operating settings of the pVAD, a pulsatile flow that provides physiological hemodynamic parameters, as well as a control over the hemodynamic parameters, can be achieved. Additionally, by employing high pump stroke ratios, the size of the pVAD can be significantly reduced; however, at those high pump stroke ratios, the effect of the other pump parameters diminishes.

Cardiac power output accurately reflects external cardiac work over a wide range of inotropic states in pigs.

BACKGROUND: Cardiac power output (CPO), derived from the product of cardiac output and mean aortic pressure, is an important yet underexploited parameter for hemodynamic monitoring of critically ill patients in the intensive-care unit (ICU). The conductance catheter-derived pressure-volume loop area reflects left ventricular stroke work (LV SW). Dividing LV SW by time, a measure of LV SW min- 1 is obtained sharing the same unit as CPO (W). We aimed to validate CPO as a marker of LV SW min- 1 under various inotropic states. METHODS: We retrospectively analysed data obtained from experimental studies of the hemodynamic impact of mild hypothermia and hyperthermia on acute heart failure. Fifty-nine anaesthetized and mechanically ventilated closed-chest Landrace pigs (68 ± 1 kg) were instrumented with Swan-Ganz and LV pressure-volume catheters. Data were obtained at body temperatures of 33.0 °C, 38.0 °C and 40.5 °C; before and after: resuscitation, myocardial infarction, endotoxemia, sevoflurane-induced myocardial depression and beta-adrenergic stimulation. We plotted LVSW min- 1 against CPO by linear regression analysis, as well as against the following classical indices of LV function and work: LV ejection fraction (LV EF), rate-pressure product (RPP), triple product (TP), LV maximum pressure (LVPmax) and maximal rate of rise of LVP (LV dP/dtmax). RESULTS: CPO showed the best correlation with LV SW min- 1 (r2 = 0.89; p < 0.05) while LV EF did not correlate at all (r2 = 0.01; p = 0.259). Further parameters correlated moderately with LV SW min- 1 (LVPmax r2 = 0.47, RPP r2 = 0.67; and TP r2 = 0.54). LV dP/dtmax correlated worst with LV SW min- 1 (r2 = 0.28). CONCLUSION: CPO reflects external cardiac work over a wide range of inotropic states. These data further support the use of CPO to monitor inotropic interventions in the ICU.

Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo.

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 µg·kg-1·min-1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20-30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.

The CardioMEMS system in the clinical management of end-stage heart failure patients: three case reports.

BACKGROUND: Recent clinical trials have shown that pulmonary artery pressure-guided therapy via the CardioMEMS™ system reduces the risk of recurrent hospitalizations in chronic heart failure (HF) patients. The CardioMEMS™ pressure sensor is percutaneously implanted in a branch of the pulmonary artery and allows telemetric pressure monitoring via a receiver. According to the most recent ESC guidelines, this technology has currently a class IIb indication in patients with class III New York Heart Association symptoms and a previous hospitalization for congestive heart failure within the last year, regardless of ejection fraction. Aim of this guided-therapy is multifold, including an early prediction of upcoming decompensation, optimization of patients' therapy and thereby avoidance of hospital admissions. In addition, it can be used during acute decompensation events as a novel tool to direct intra-hospital therapeutic interventions such as inotropes infusion or left ventricular (LV) assist device monitoring, with the aim of achieving an optimal volume status. CASE PRESENTATION: We present a case series of three end-stage HF patients with reduced ejection fraction (HFrEF) who received a CardioMEMS™ device as an aid in their clinical management. The CardioMEMS™ system enabled a closer non-invasive hemodynamic monitoring of these patients and guided the extent of therapeutic interventions. Patients were free from device- or system-related complications. In addition, no pressure-sensor failure was observed. Two patients received a 24-h infusion of the calcium sensitizer levosimendan. One patient showed a refractory acute decompensation and underwent LV assist device (LVAD) implantation as a bridge to cardiac transplantation. Switching a patient with recurrent hospitalizations to the Angiotensin Receptor Neprilysin Inhibitor (ARNI, Sacubitril-Valsartan) on top of the optimal heart failure-therapy improved its subjective condition and hemodynamics, avoiding further hospitalization. CONCLUSIONS: Our case series underlines the potential impact of CardioMEMS™ derived data in the daily clinical management of end-stage HF patients. The new concept to combine CardioMEMS™ in the setting of an outpatient levosimendan program as well as a bridge to LVAD-implantation/heart transplantation looks promising but needs further investigations.

Mild hypothermia (33°C) increases the inducibility of atrial fibrillation: An in vivo large animal model study.

OBJECTIVE: Application of therapeutic mild hypothermia in patients after resuscitation, often accompanied by myocardial infarction, cardiogenic shock, and systemic inflammation may impact on cardiac rhythm. We therefore tested susceptibility to atrial arrhythmias during hyperthermia (HT, 40.5°C), normothermia (NT, 38.0°C), and mild hypothermia (MH, 33.0°C). METHODS: Nine healthy, anesthetized closed-chest landrace pigs were instrumented with a quadripolar stimulation catheter in the high right atrium and a decapolar catheter in the coronary sinus. Twelve-lead surface electrograms were recorded and core body temperature was altered to HT, NT, and MH using external warming or intravascular cooling. Repetitive measurements of effective atrial refractory period (AERP), atrial fibrillation (AF) inducibility, and electrocardiogram (ECG) parameters at different heart rates were performed. RESULTS: During MH, AERP was significantly longer while the inducibility of AF was significantly higher compared to NT and HT (median [range]: HT 18 (0, 80)%; NT 25 (0, 80)%; MH 68 (0, 100)%; P < 0.05 MH vs NT+HT). Mean AF duration did not differ between groups. Arterial potassium levels decreased with falling temperatures (HT: 4.2 ± 0.1 mmol/L; NT: 4.0 ± 0.2 mmol/L; MH: 3.5 ± 0.1 mmol/L; P < 0.001). Surface ECGs during MH showed reduced spontaneous heart rate (HT: 99 ± 13 beats/min; NT: 87 ± 15 beats/min; MH: 66 ± 10 beats/min; P < 0.05), increased PQ, stim-Q, and QT intervals (P < 0.01) but no change in QRS duration or time from peak to end of the T wave interval. CONCLUSION: Our data imply that MH represents an arrhythmic substrate rendering the atria more susceptible to AF although conduction times as well as refractory periods are increased. Further investigations on potential electrophysiological limits of therapeutic cooling in patients are required.

Inotropic Effects of Experimental Hyperthermia and Hypothermia on Left Ventricular Function in Pigs-Comparison With Dobutamine.

OBJECTIVES: The results from the recent Targeted Temperature Management trial raised the question whether cooling or merely the avoidance of fever mediates better neurologic outcome in resuscitated patients. As temperature per se is a major determinant of cardiac function, we characterized the effects of hyperthermia (40.5°C), normothermia (38.0°C), and mild hypothermia (33.0°C) on left ventricular contractile function in healthy pigs and compared them with dobutamine infusion. DESIGN: Animal study. SETTING: Large animal facility, Medical University of Graz, Graz, Austria. SUBJECTS: Nine anesthetized and mechanically ventilated closed-chest Landrace pigs (67 ± 2 kg). INTERVENTIONS: Core body temperature was controlled using an intravascular device. At each temperature step, IV dobutamine was titrated to double maximum left ventricular dP/dt (1.8 ± 0.1 µg/kg/min at normothermia). Left ventricular pressure-volume relationships were assessed during short aortic occlusions. Left ventricular contractility was assessed by the calculated left ventricular end-systolic volume at an end-systolic left ventricular pressure of 100 mm Hg. MEASUREMENTS AND MAIN RESULTS: Heart rate (98 ± 4 vs 89 ± 4 vs 65 ± 2 beats/min; all p < 0.05) and cardiac output (6.7 ± 0.3 vs 6.1 ± 0.3 vs 4.4 ± 0.2 L/min) decreased with cooling from hyperthermia to normothermia and mild hypothermia, whereas left ventricular contractility increased (left ventricular end-systolic volume at a pressure of 100 mm Hg: 74 ± 5 mL at hyperthermia, 52 ± 4 mL at normothermia, and 41 ± 3 mL at mild hypothermia; all p < 0.05). The effect of cooling on left ventricular end-systolic volume at a pressure of 100 mm Hg (hyperthermia to normothermia: -28% ± 3% and normothermia to mild hypothermia: -20% ± 5%) was of comparable effect size as dobutamine at a given temperature (hyperthermia: -28% ± 4%, normothermia: -27% ± 6%, and mild hypothermia: -27% ± 9%). CONCLUSIONS: Cooling from hyperthermia to normothermia and from normothermia to mild hypothermia increased left ventricular contractility to a similar degree as a significant dose of dobutamine in the normal porcine heart. These data indicate that cooling can reduce the need for positive inotropes and that lower rather than higher temperatures are appropriate for the resuscitated failing heart.

Early-stage heart failure with preserved ejection fraction in the pig: a cardiovascular magnetic resonance study.

BACKGROUND: The hypertensive deoxy-corticosterone acetate (DOCA)-salt-treated pig (hereafter, DOCA pig) was recently introduced as large animal model for early-stage heart failure with preserved ejection fraction (HFpEF). The aim of the present study was to evaluate cardiovascular magnetic resonance (CMR) of DOCA pigs and weight-matched control pigs to characterize ventricular, atrial and myocardial structure and function of this phenotype model. METHODS: Five anesthetized DOCA and seven control pigs underwent 3 T CMR at rest and during dobutamine stress. Left ventricular/atrial (LV/LA) function and myocardial mass (LVMM), strains and torsion were evaluated from (tagged) cine imaging. 4D phase-contrast measurements were used to assess blood flow and peak velocities, including transmitral early-diastolic (E) and myocardial tissue (E') velocities and coronary sinus blood flow. Myocardial perfusion reserve was estimated from stress-to-rest time-averaged coronary sinus flow. Global native myocardial T1 times were derived from prototype modified Look-Locker inversion-recovery (MOLLI) short-axis T1 maps. After in-vivo measurements, transmural biopsies were collected for stereological evaluation including the volume fractions of interstitium (VV(int/LV)) and collagen (VV(coll/LV)). Rest, stress, and stress-to-rest differences of cardiac and myocardial parameters in DOCA and control animals were compared by t-test. RESULTS: In DOCA pigs LVMM (p < 0.001) and LV wall-thickness (end-systole/end-diastole, p = 0.003/p = 0.007) were elevated. During stress, increase of LV ejection-fraction and decrease of end-systolic volume accounted for normal contractility reserves in DOCA and control pigs. Rest-to-stress differences of cardiac index (p = 0.040) and end-diastolic volume (p = 0.042) were documented. Maximal (p = 0.042) and minimal (p = 0.012) LA volumes in DOCA pigs were elevated at rest; total LA ejection-fraction decreased during stress (p = 0.006). E' was lower in DOCA pigs, corresponding to higher E/E' at rest (p = 0.013) and stress (p = 0.026). Myocardial perfusion reserve was reduced in DOCA pigs (p = 0.031). T1-times and VV(int/LV) did not differ between groups, whereas VV(coll/LV) levels were higher in DOCA pigs (p = 0.044). CONCLUSIONS: LA enlargement, E' and E/E' were the markers that showed the most pronounced differences between DOCA and control pigs at rest. Inadequate increase of myocardial perfusion reserve during stress might represent a metrics for early-stage HFpEF. Myocardial T1 mapping could not detect elevated levels of myocardial collagen in this model. TRIAL REGISTRATION: The study was approved by the local Bioethics Committee of Vienna, Austria (BMWF-66.010/0091-II/3b/2013).

A porcine model of early atrial fibrillation using a custom-built, radio transmission-controlled pacemaker.

Mechanisms underlying atrial remodeling toward atrial fibrillation (AF) are incompletely understood. We induced AF in 16 pigs by 6weeks of rapid atrial pacing (RAP, 600bpm) using a custom-built, telemetrically controlled pacemaker. AF evolution was monitored three times per week telemetrically in unstressed, conscious animals. We established a dose-response relationship between RAP duration and occurrence of sustained AF >60minutes. Left atrial (LA) dilatation was present already at 2weeks of RAP. There was no evidence of left ventricular heart failure after 6weeks of RAP. As a proof-of-principle, arterial hypertension was induced in 5/16 animals by implanting desoxycorticosterone acetate (DOCA, an aldosterone-analog) subcutaneously to accelerate atrial remodeling. RAP+DOCA resulted in increased AF stability with earlier onset of sustained AF and accelerated anatomical atrial remodeling with more pronounced LA dilatation. This novel porcine model can serve to characterize effects of maladaptive stimuli or protective interventions specifically during early AF.

A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs (n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls (n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.

Prediction of Left Ventricle Pressure Indices Via a Machine Learning Approach Combining ECG, Pulse Oximetry, and Cardiac Sounds: a Preclinical Feasibility Study.

Heart failure (HF) is defined as the inability of the heart to meet body oxygen demand requiring an elevation in left ventricular filling pressures (LVP) to compensate. LVP increase can be assessed in the cardiac catheterization laboratory, but this procedure is invasive and time-consuming to the extent that physicians rather rely on non-invasive diagnostic tools. In this work, we assess the feasibility to develop a novel machine-learning (ML) approach to predict clinically relevant LVP indices. Synchronized invasive (pressure-volume tracings) and non-invasive signals (ECG, pulse oximetry, and cardiac sounds) were collected from anesthetized, closed-chest Göttingen minipigs. Animals were either healthy or had HF with reduced ejection fraction and circa 500 heartbeats were included in the analysis for each animal. The ML algorithm showed excellent prediction of LVP indices estimating, for instance, the end-diastolic pressure with a R2 of 0.955. This novel ML algorithm could assist clinicians in the care of HF patients.

Clinical phenogroup diversity and multiplicity: Impact on mechanisms of exercise intolerance in heart failure with preserved ejection fraction.

AIMS: We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits. METHODS AND RESULTS: Individuals with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow-up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously-proposed, non-exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p < 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08-2.79 for 0-1 vs. ≥2 phenogroup traits present). CONCLUSIONS: Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non-cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome.

Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure.

BACKGROUND: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. OBJECTIVES: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. METHODS: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. RESULTS: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. CONCLUSIONS: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.

Diagnostic and prognostic value of low QRS voltages in cardiac AL amyloidosis.

BACKGROUND: In cardiac AL amyloidosis, myocardial infiltration is typically associated with "low QRS voltages" at the 12-lead electrocardiogram (ECG). Although considered as one of the hallmarks of the disease, its reported prevalence varies from 45% to 70%, mainly because of nonhomogeneous definitions. METHODS: To identify the "low QRS voltage" parameter having the best diagnostic value in identifying cardiac amyloidosis, and to assess its possible prognostic role, ECG and echocardiographic data were collected at diagnosis in 337 consecutive never-treated AL patients (233 with, 104 without cardiac involvement). Prognosis was assessed after a median follow-up of 14.5 months. RESULTS: "Low QRS voltage" prevalence varied from 84.12% when using Sokolow-Lyon index ≤15 mm to 27.04% with the definition of low total voltages (QRS amplitude ≤5 mm in each peripheral and ≤10 mm in each precordial lead), the widely used definition of low peripheral voltages (≤5 mm in each peripheral lead) being able to identify 66.52% cardiac AL patients. The presence of "low peripheral voltages" was associated with a more severe cardiac involvement, and was able to differentiate Mayo stage II patients' survival (i.e., AL patients with intermediate prognosis). According to receiver operator characteristic (ROC) curve analysis, sensitivity and specificity were 58.72% and 80.00%, for a peripheral QRS amplitude ≤24.5 mm (the sum of QRS in all the 6 peripheral leads), and 76.26% and 65.00% for a Sokolow-Lyon index ≤11 mm. CONCLUSIONS: In cardiac AL amyloidosis the prevalence of low QRS voltages is highly dependent on the method used for defining this ECG alteration.