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.

In-hospital Heart Rate Reduction With Beta Blockers and Ivabradine Early After Recovery in Patients With Acute Decompensated Heart Failure Reduces Short-Term Mortality and Rehospitalization.

Objective: In the past years, heart rate (HR) has emerged as a highly relevant modifiable risk factor for heart failure (HF) patients. However, most of the clinical trials so far evaluated the role of HR in stable chronic HF cohorts. The aim of this multi-center, prospective observational study was to assess the association between HR and therapy with HR modulators (beta blockers, ivabradine, or a combination of ivabradine and beta blockers) at hospital discharge with patients' cardiovascular mortality and re-hospitalization at 6 months in acutely decompensated HF patients. Materials and Methods: We recruited 289 HF patients discharged alive after admission for HF decompensation from 10 centers in northern Italy over 9 months (from April 2017 to January 2018). The primary endpoint was the combination of cardiovascular mortality or re-hospitalizations for HF at 6 months. Results: At 6 months after discharge, 64 patients were readmitted (32%), and 39 patients died (16%). Multivariate analysis showed that HR at discharge ≥ 90 bpm (OR = 8.47; p = 0.016) independently predicted cardiovascular mortality, while therapy with beta blockers at discharge was found to reduce the risk of the composite endpoint. In patients receiving HR modulators the event rates for the composite endpoint, all-cause mortality, and cardiovascular mortality were lower than in patients not receiving HR modulators. Conclusions: Heart rate at discharge ≥90 bpm predicts cardiovascular mortality, while therapy with beta blockers is negatively associated with the composite endpoint of cardiovascular mortality and hospitalization at 6 months in acutely decompensated HF patients. Patients receiving a HR modulation therapy at hospital discharge showed the lowest rate of cardiovascular mortality and re-hospitalization.

Non-invasive CMR-Based Quantification of Myocardial Power and Efficiency Under Stress and Ischemic Conditions in Landrace Pigs.

Background: Myocardial efficiency should be maintained stable under light-to-moderate stress conditions, but ischemia puts the myocardium at risk for impaired functionality. Additionally, the measurement of such efficiency typically requires invasive heart catheterization and exposure to ionizing radiation. In this work, we aimed to non-invasively assess myocardial power and the resulting efficiency during pharmacological stress testing and ischemia induction. Methods: In a cohort of n = 10 healthy Landrace pigs, dobutamine stress testing was performed, followed by verapamil-induced ischemia alongside cardiac magnetic resonance (CMR) imaging. External myocardial power, internal myocardial power, and myocardial efficiency were assessed non-invasively using geometrical and functional parameters from CMR volumetric as well as blood flow and pressure measurements. Results: External myocardial power significantly increased under dobutamine stress [2.3 (1.6-3.1) W/m2 vs. 1.3 (1.1-1.6) W/m2, p = 0.005] and significantly decreased under verapamil-induced ischemia [0.8 (0.5-0.9) W/m2, p = 0.005]. Internal myocardial power [baseline: 5.9 (4.6-8.5) W/m2] was not affected by dobutamine [7.5 (6.9-9.0) W/m2, p = 0.241] nor verapamil [5.8 (4.7-8.8) W/m2, p = 0.878]. Myocardial efficiency did not change from baseline to dobutamine [21% (15-27) vs. 31% (20-44), p = 0.059] but decreased significantly during verapamil-induced ischemia [10% (8-13), p = 0.005]. Conclusion: In healthy Landrace pigs, dobutamine stress increased external myocardial power, whereas myocardial efficiency was maintained stable. On the contrary, verapamil-induced ischemia substantially decreased external myocardial power and myocardial efficiency. Non-invasive CMR was able to quantify these efficiency losses and might be useful for future clinical studies evaluating the effects of therapeutic interventions on myocardial energetics.

The "TIDE"-Algorithm for the Weaning of Patients With Cardiogenic Shock and Temporarily Mechanical Left Ventricular Support With Impella Devices. A Cardiovascular Physiology-Based Approach.

Objectives: Mechanical circulatory support (MCS) is often required to stabilize therapy-refractory cardiogenic shock patients. Left ventricular (LV) unloading by mechanical ventricular support (MVS) via percutaneous devices, such as with Impella® axial pumps, alone or in combination with extracorporeal life support (ECLS, ECMELLA approach), has emerged as a potential clinical breakthrough in the field. While the weaning from MCS is essentially based on the evaluation of circulatory stability of patients, weaning from MVS holds a higher complexity, being dependent on bi-ventricular function and its adaption to load. As a result of this, weaning from MVS is mostly performed in the absence of established algorithms. MVS via Impella is applied in several cardiogenic shock etiologies, such as acute myocardial infarction (support over days) or acute fulminant myocarditis (prolonged support over weeks, PROPELLA). The time point of weaning from Impella in these cohorts of patients remains unclear. We here propose a novel cardiovascular physiology-based weaning algorithm for MVS. Methods: The proposed algorithm is based on the experience gathered at our center undergoing an Impella weaning between 2017 and 2020. Before undertaking a weaning process, patients must had been ECMO-free, afebrile, and euvolemic, with hemodynamic stability guaranteed in the absence of any inotropic support. The algorithm consists of 4 steps according to the acronym TIDE: (i) Transthoracic echocardiography under full Impella-unloading; (ii) Impella rate reduction in single 8-24 h-steps according to patients hemodynamics (blood pressure, heart rate, and ScVO2), including a daily echocardiographic assessment at minimal flow (P2); (iii) Dobutamine stress-echocardiography; (iv) Right heart catheterization at rest and during Exercise-testing via handgrip. We here present clinical and hemodynamic data (including LV conductance data) from paradigmatic weaning protocols of awake patients admitted to our intensive care unit with cardiogenic shock. We discuss the clinical consequences of the TIDE algorithm, leading to either a bridge-to-recovery, or to a bridge-to-permanent LV assist device (LVAD) and/or transplantation. With this protocol we were able to wean 74.2% of the investigated patients successfully. 25.8% showed a permanent weaning failure and became LVAD candidates. Conclusions: The proposed novel cardiovascular physiology-based weaning algorithm is based on the characterization of the extent and sustainment of LV unloading reached during hospitalization in patients with cardiogenic shock undergoing MVS with Impella in our center. Prospective studies are needed to validate the algorithm.

[Coronary physiology in the catheter laboratory]. / Koronarphysiologie im Herzkatheterlabor.

The regulation of coronary flow is mainly located in the resistance vessels of the microcirculation, so that the functional relevance of a coronary stenosis arises from the interaction between the epicardial stenosis and the downstream microcirculation. These complex interactions are precisely detectable by physiological measurements, such as the instantaneous wave-free ratio (iwFR) or the fractional flow reserve (FFR). In contrast, the purely visual assessment of the coronary anatomy could lead to misinterpretation and possibly to incorrect revascularization decisions. Consequently, in the current guidelines on myocardial revascularization of the European Society of Cardiology (ESC) the measurement of iwFR and FFR has a class IA indication in intermediate stenoses with unclear hemodynamic relevance. Despite this clear recommendation, physiological measurements are not yet regularly used in the clinical routine. Besides the purely hemodynamic assessment, novel methods such as co-registration and coronary mapping can be used for virtual planning of percutaneous coronary interventions, especially in vessels with diffuse lesions and serial stenoses. Furthermore, invasive flow measurements are also helpful for risk stratification between conservative and interventional treatment of patients with acute coronary syndrome, where additional factors of flow limitation, such as coronary spasm, thrombus and acute disturbance of the microcirculation play an important role.

Cellular contribution to left and right atrial dysfunction in chronic arterial hypertension in pigs.

AIMS: Atrial contractile dysfunction contributes to worse prognosis in hypertensive heart disease (HHD), but the role of cardiomyocyte dysfunction in atrial remodelling in HHD is not well understood. We investigated and compared cellular mechanisms of left (LA) and right atrial (RA) contractile dysfunction in pigs with HHD. METHODS AND RESULTS: In vivo electrophysiological and magnetic resonance imaging studies were performed in control and pigs treated with 11-deoxycorticosterone acetate (DOCA)/high-salt/glucose diet (12 weeks) to induce HHD. HHD leads to significant atrial remodelling and loss of contractile function in LA and a similar trend in RA (magnetic resonance imaging). Atrial remodelling was associated with a higher inducibility of atrial fibrillation but unrelated to changes in atrial refractory period or fibrosis (histology). Reduced atrial function in DOCA pigs was related to reduced contraction amplitude of isolated LA (already at baseline) and RA myocytes (at higher frequencies) due to reduced intracellular Ca release (Fura 2-AM, field stimulation). However, Ca regulation differed in LA and RA cardiomyocytes: LA cardiomyocytes showed reduced sarcoplasmic reticulum (SR) [Ca], whereas in RA, SR [Ca] was unchanged and SR Ca2+ -ATPase activity was increased. Sodium-calcium exchanger (NCX) activity was not significantly altered. We used ORM-10103 (3 µM), a specific NCX inhibitor to improve Ca availability in LA and RA cardiomyocytes from DOCA pigs. Partial inhibition of NCX increased Ca2+ transient amplitude and SR Ca in LA, but not RA cells. CONCLUSIONS: In this large animal model of HHD, atrial remodelling in sinus rhythm in vivo was related to differential LA and RA cardiomyocyte dysfunction and Ca signalling. Selective acute inhibition of NCX improved Ca release in diseased LA cardiomyocytes, suggesting a potential therapeutic approach to improve atrial inotropy in HHD.

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.

Thermodilution vs estimated Fick cardiac output measurement in an elderly cohort of patients: A single-centre experience.

AIMS: Patients referred to the cath-lab are an increasingly elderly population. Thermodilution (TD, gold standard) and the estimated Fick method (eFM) are interchangeably used in the clinical routine to measure cardiac output (CO). However, their correlation in an elderly cohort of cardiac patients has not been tested so far. METHODS: A single, clinically-indicated right heart catheterization was performed on each patient with CO estimated by eFM and TD in 155 consecutive patients (75.1±6.8 years, 57.7% male) between April 2015 and August 2017. Whole Body Oxygen Consumption (VO2) was assumed by applying the formulas of LaFarge (LaF), Dehmer (De) and Bergstra (Be). CO was indexed to body surface area (Cardiac Index, CI). RESULTS: CI-TD showed an overall moderate correlation to CI-eFM as assessed by LaF, De or Be (r2 = 0.53, r2 = 0.54, r2 = 0.57, all p < .001, respectively) with large limits of agreement (-0.64 to 1.09, -1.07 to 0.77, -1.38 to 0.53 l/m2/min, respectively). The mean difference of CI between methods was 0.22, -0.15 and -0.42 (all p<0.001 for difference to TD), respectively. A rate of error ≥20% occurred with the equations by LaF, De or Be in 40.6%, 26.5% and 36.1% of patients, respectively. A CI <2.2 l/m2min was present in 42.6% of patients according to TD and in 60.0%, 31.0% and in 16.1% of patients according to eFM by the formulas of LaF, De or Be. CONCLUSION: Although CI-eFM shows an overall reasonable correlation with CI-TD, the predictive value in a single patient is low. CI-eFM cannot replace CI-TD in elderly patients.

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.

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.

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.

Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation.

BACKGROUND: Arterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms. OBJECTIVE: We aimed to characterize electrical and structural changes accounting for increased AF stability in a large animal model of rapid atrial pacing (RAP)-induced AF combined with desoxycorticosterone acetate (DOCA)-induced HT. METHODS: Eighteen pigs were instrumented with right atrial endocardial pacemaker leads and custom-made pacemakers to induce AF by continuous RAP (600 beats/min). DOCA pellets were subcutaneously implanted in a subgroup of 9 animals (AF+HT group); the other 9 animals served as controls (AF group). Final experiments included electrophysiology studies, endocardial electroanatomic mapping, and high-density mapping with epicardial multielectrode arrays. In addition, 3-dimensional computational modeling was performed. RESULTS: DOCA implantation led to secondary HT (median [interquartile range] aortic pressure 109.9 [100-137] mm Hg in AF+HT vs 82.2 [79-96] mm Hg in AF; P < .05), increased AF stability (55.6% vs 12.5% of animals with AF episodes lasting >1 hour; P < .05), concentric left ventricular hypertrophy, atrial dilatation (119 ± 31 cm2 in AF+HT vs 78 ± 23 cm2 in AF; P < .05), and fibrosis. Collagen accumulation in the AF+HT group was mainly found in non-intermyocyte areas (1.62 ± 0.38 cm3 in AF+HT vs 0.96 ± 0.3 cm3 in AF; P < .05). Left and right atrial effective refractory periods, action potential durations, endo- and epicardial conduction velocities, and measures of AF complexity were comparable between the 2 groups. A 3-dimensional computational model confirmed an increase in AF stability observed in the in vivo experiments associated with increased atrial size. CONCLUSION: In this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.

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.

Inhalation of peptide-loaded nanoparticles improves heart failure.

Peptides are highly selective and efficacious for the treatment of cardiovascular and other diseases. However, it is currently not possible to administer peptides for cardiac-targeting therapy via a noninvasive procedure, thus representing scientific and technological challenges. We demonstrate that inhalation of small (<50 nm in diameter) biocompatible and biodegradable calcium phosphate nanoparticles (CaPs) allows for rapid translocation of CaPs from the pulmonary tree to the bloodstream and to the myocardium, where their cargo is quickly released. Treatment of a rodent model of diabetic cardiomyopathy by inhalation of CaPs loaded with a therapeutic mimetic peptide that we previously demonstrated to improve myocardial contraction resulted in restoration of cardiac function. Translation to a porcine large animal model provides evidence that inhalation of a peptide-loaded CaP formulation is an effective method of targeted administration to the heart. Together, these results demonstrate that inhalation of biocompatible tailored peptide nanocarriers represents a pioneering approach for the pharmacological treatment of heart failure.

A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function.

Heart Failure with preserved Ejection Fraction (HFpEF) represents a major public health problem. The causative mechanisms are multifactorial and there are no effective treatments for HFpEF, partially attributable to the lack of well-established HFpEF animal models. We established a feline HFpEF model induced by slow-progressive pressure overload. Male domestic short hair cats (n = 20), underwent either sham procedures (n = 8) or aortic constriction (n = 12) with a customized pre-shaped band. Pulmonary function, gas exchange, and invasive hemodynamics were measured at 4-months post-banding. In banded cats, echocardiography at 4-months revealed concentric left ventricular (LV) hypertrophy, left atrial (LA) enlargement and dysfunction, and LV diastolic dysfunction with preserved systolic function, which subsequently led to elevated LV end-diastolic pressures and pulmonary hypertension. Furthermore, LV diastolic dysfunction was associated with increased LV fibrosis, cardiomyocyte hypertrophy, elevated NT-proBNP plasma levels, fluid and protein loss in pulmonary interstitium, impaired lung expansion, and alveolar-capillary membrane thickening. We report for the first time in HFpEF perivascular fluid cuff formation around extra-alveolar vessels with decreased respiratory compliance. Ultimately, these cardiopulmonary abnormalities resulted in impaired oxygenation. Our findings support the idea that this model can be used for testing novel therapeutic strategies to treat the ever growing HFpEF population.

Assessment of cardiac fibrosis: a morphometric method comparison for collagen quantification.

Fibrotic remodeling of the heart is a frequent condition linked to various diseases and cardiac dysfunction. Collagen quantification is an important objective in cardiac fibrosis research; however, a variety of different histological methods are currently used that may differ in accuracy. Here, frequently applied collagen quantification techniques were compared. A porcine model of early stage heart failure with preserved ejection fraction was used as an example. Semiautomated threshold analyses were imprecise, mainly due to inclusion of noncollagen structures or failure to detect certain collagen deposits. In contrast, collagen assessment by automated image analysis and light microscopy (LM)-stereology was more sensitive. Depending on the quantification method, the amount of estimated collagen varied and influenced intergroup comparisons. PicroSirius Red, Masson's trichrome, and Azan staining protocols yielded similar results, whereas the measured collagen area increased with increasing section thickness. Whereas none of the LM-based methods showed significant differences between the groups, electron microscopy (EM)-stereology revealed a significant collagen increase between cardiomyocytes in the experimental group, but not at other localizations. In conclusion, in contrast to the staining protocol, section thickness and the quantification method being used directly influence the estimated collagen content and thus, possibly, intergroup comparisons. EM in combination with stereology is a precise and sensitive method for collagen quantification if certain prerequisites are considered. For subtle fibrotic alterations, consideration of collagen localization may be necessary. Among LM methods, LM-stereology and automated image analysis are appropriate to quantify fibrotic changes, the latter depending on careful control of algorithm and comparable section staining.NEW & NOTEWORTHY Direct comparison of frequently applied histological fibrosis assessment techniques revealed a distinct relation of measured collagen and utilized quantification method as well as section thickness. Besides electron microscopy-stereology, which was precise and sensitive, light microscopy-stereology and automated image analysis proved to be appropriate for collagen quantification. Moreover, consideration of collagen localization might be important in revealing minor fibrotic changes.

Postprocedural radial artery occlusion rate using a sheathless guiding catheter for left ventricular endomyocardial biopsy performed by transradial approach.

BACKGROUND: For coronary interventions the arterial access via the radial artery is associated with fewer vascular access site complications, and has been shown to reduce major bleeding when compared to the femoral approach. But the endomyocardial biopsy (EMB) approach is usually done by a transfemoral or cervical access known to be associated with an increased risk of artery puncture and its potential complications (i.e., false aneurysm, artery-venous fistula) and needs post-procedural immobilization. A transradial approach for EMBs is not standardized. The aim of our study is to validate safety and efficacy of the transradial access approach for left ventricular EMB, and to define patients eligible for a safe and successful procedure. METHODS AND RESULTS: We evaluated the transradial access using a 7.5 F sheathless multipurpose guiding catheter to obtain EMBs from the left ventricle (LV). 18 patients were included. The transradial success rate was 100% (18/18). There were no periprocedural cardiac complications. Immediate post-procedural ambulation could be achieved in all patients. Although radial artery pulse was confirmed by ultrasonic vascular Doppler after removal of the guide in 100% (18/18) of the patients, 50% (9/18) of the patients showed occlusion of the radial artery RAO) by duplex sonography proximal to the access site. 33% (3/9) of the patients in the RAO group and 11,1% (1/9) of the patients in the patent radial artery (RAP) group, respectively, experienced mild pain after the procedure in the right lower arm. Colour Doppler ultrasonography of the right radial artery performed 24 h after the procedure revealed radial occlusion in 50% (9/18) of the patients. The diameter of the radial artery was significantly smaller in the RAO group (p = 0,034), peak systolic velocity (PSV) of the right ulnar artery was significantly higher in the RAO group (p = 0.012). Peak systolic velocity of the opposite radial artery was significantly lower in the RAO group (p = 0,045). Gender, sex, diabetes, radial artery inner diameter ≤2.5 mm and lower peak systolic velocity of < 50 cm/s are predictors of RAO. CONCLUSION: The present study demonstrates the safety and efficacy of a transradial access for EMB using a highly hydrophilic sheathless guiding catheter.

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).