Tako-Tsubo syndrome in patients with COVID-19: a single centre retrospective case series.

Growing evidence shows that COVID-19 is associated with an increase in Tako-Tsubo syndrome (TTS) incidence. We collected data from patients hospitalized in our multidisciplinary COVID-19 department who had a diagnosis of TTS during the second and third wave of the pandemic in Italy. We reported four cases of TTS associated with COVID-19. No patient had any classical trigger for TTS except for COVID-19. Mean age was 72 years (67-81) and all patients had a SARS-CoV-2-related interstitial pneumonia confirmed by computed tomography. Typical apical ballooning and transitory reduction in left ventricle (LV) systolic function with a complete recovery before discharge were observed in all patients. The mean LV ejection fraction (LVEF) at TTS onset was 42% (40-48%). ECG showed ST-segment elevation in two cases, while an evolution with negative T waves and QTc prolongation was observed in all patients. Three patients underwent coronary angiography. Two patients had Alzheimer's disease. The time interval from hospital admission to TTS onset was 4 (2-6) days, and the time interval from COVID-19 symptom onset to TTS diagnosis was 10 (8-12) days.  COVID-19 may be a trigger for TTS, though TTS pathophysiology in COVID-19 patients remains unclear, likely due to its multifactorial nature.

[ANMCO statement: Uric acid and cardiovascular disease: evidence and therapeutic approach]. / Statement ANMCO: Acido urico e malattie cardiovascolari: evidenze e approccio terapeutico.

Pathophysiologic processes promoted by uric acid, including inflammation and oxidative stress, play a key role in the pathogenesis of several cardiovascular diseases. Furthermore, a number of epidemiological studies have shown an association between uric acid plasma levels and multiple cardiovascular risk factors. This ANMCO statement provides an update on available evidence regarding the association between elevated plasma uric acid levels and cardiovascular disease risk and the safety and efficacy of uric acid lowering agents (allopurinol and febuxostat) used in patients with urate crystal deposits. In addition, it summarizes practical indications for the use of these drugs in at-risk patients or in patients with cardiovascular disease.

[ANMCO Expert opinion: Bempedoic acid place in therapy for hypercholesterolemia management]. / ANMCO Expert opinion: Posizionamento terapeutico dell'acido bempedoico nel trattamento dell'ipercolesterolemia.

Growing evidence supporting the central role of hypercholesterolemia in atherosclerotic disease pathogenesis and progression has led to the development of new therapeutic approaches. Bempedoic acid has recently been approved for marketing following several studies that demonstrated its efficacy and safety. This drug represents a new therapeutic option that, like statins, acts on the enzymatic cascade that is involved in cholesterol synthesis. However, its hepatic selectivity of action reduces the risk of muscle adverse effects. This ANMCO document highlights clinical settings in which bempedoic acid represents a particularly useful therapeutic option. Furthermore, the document discusses the possibilities of use based on both international recommendations and current national regulations. Finally, we report practical guidance on hypercholesterolemia management in light of the available therapeutic armamentarium.

The polypill strategy in cardiovascular disease prevention: It's time for its implementation.

A polypill strategy has been demonstrated to improve treatment adherence in several cardiovascular disease (CVD) settings. However, data on the prognostic impact in the secondary prevention setting have been scarce. The Secondary Prevention of Cardiovascular Disease in the Elderly trial, the results of which have been recently published, has demonstrated a benefit in terms of major adverse CVD event reduction. This finding, in addition to previous evidence, should lead to a broader polypill implementation in CVD prevention.

Impact of Working from Home on Cardiovascular Health: An Emerging Issue with the COVID-19 Pandemic.

Mandatory working from home is one of the consequences of the COVID-19 pandemic for a large number of workers. Transition to working from home may significantly impact lifestyle, psychosocial status, and the overall health of workers. This review summarizes available data about the effects of lockdown measures, particularly working from home, on cardiovascular risk factors including sedentary lifestyle, unhealthy diet pattern, psychological distress, smoking, alcohol misuse, and cardiometabolic parameters. Finally, we suggest countermeasures that can attenuate the negative health impact of working from home. Indeed, timely and tailored interventions implemented by companies in cooperation with the health care system could allow workers to benefit more from some of the advantages associated with working from home.

Do Pathophysiologic Mechanisms Linking Unhealthy Lifestyle to Cardiovascular Disease and Cancer Imply Shared Preventive Measures?　- A Critical Narrative Review.

Growing evidence has shown a bidirectional link between the cardiologic and oncologic fields. Several investigations support the role of unhealthy behaviors as pathogenic factors of both cardiovascular disease and cancer. We report epidemiological and research findings on the pathophysiological mechanisms linking unhealthy lifestyle to cardiovascular disease and cancer. For each unhealthy behavior, we also discuss the role of preventive measures able to affect both cardiovascular disease and cancer occurrence and progression.

Sacubitril/valsartan: preliminary experience in post-acute stabilized patients with reduced ejection fraction heart failure.

INTRODUCTION: We investigated the effectiveness of sacubitril/valsartan by performing laboratory tests and a 6-minute walking test (6-MWT) at 1 and 6 months after treatment initiation. METHODS: We evaluated patients admitted to our Cardiology Department, stabilized after an episode of acute decompensated heart failure (HF), who were considered eligible for sacubitril/valsartan therapy. Therapy was initiated after interrupting angiotensin-converting enzyme (ACE) inhibitors for at least 36 h or after the last dose of an angiotensin receptor blocker (ARB). In naïve patients, we initiated a low dose of sacubitril/valsartan combination following patient stabilization. Before discharge, a 6-MWT was performed to evaluate patient's functional capacity, measuring total walked distance (in meters), oxygen saturation and heart rate at the beginning and at the end of the test; Borg Scale was applied to evaluate the intensity of dyspnoea. After discharge, follow-up visits at 1 and 6 months, 2D-echocardiography, blood tests and 6-MWT were performed to re-evaluate the efficacy of the treatment. RESULTS: A total of 14 patients (85.7% males) were included. Mean age was 66.0 ± 10.3 years. Body mass index (BMI) was 29.9 ± 4.7 kg/m2. There were no differences in creatinine at admission compared with values at 1 and 6 months. Mean left ventricular ejection fraction (LVEF) was 28.7 ± 4.7% at baseline and increased to 33.5 ± 6.6% and 38.0 ± 2.9% at 1 and 6 months, respectively (p = .028). Total distance covered at 6-MWT increased over the study period (baseline: 227.4 ± 62.8 m; 6 months: 257.3 ± 65.2 m, p = .317) although the increase was not statistically significant. CONCLUSIONS: The present experience showed that angiotensin receptor-neprilysin inhibitor (ARNi) might represent a new valuable therapeutic strategy, even at the earlier stages of stabilized acute HF. Therefore, we suggest a clinical practice algorithm, to consider before discharge, which should be validated by further analyses.

Impact of Glycemic Variability on Chromatin Remodeling, Oxidative Stress, and Endothelial Dysfunction in Patients With Type 2 Diabetes and With Target HbA1c Levels.

Intensive glycemic control (IGC) targeting HbA1c fails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D); however, the underlying mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigated whether epigenetic regulation of the adaptor protein p66Shc, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA1c >7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbA1c of ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F2α (8-isoPGF2α), and epigenetic regulation of p66Shc were assessed at baseline and follow-up. Continuous glucose monitoring was performed to determine the mean amplitude of glycemic excursion (MAGE) and postprandial incremental area under the curve (AUCpp). At baseline, patients with T2D showed impaired FMD, increased urinary 8-isoPGF2α, and p66Shc upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF2α, and p66Shc expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66Shc promoter of patients with T2D, and IGC did not change such adverse epigenetic remodeling. Persistent downregulation of methyltransferase DNMT3b and deacetylase SIRT1 may explain the observed p66Shc-related epigenetic changes. MAGE and AUCpp but not HbA1c were independently associated with the altered epigenetic profile on the p66Shc promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA1c levels.

Local equilibrium in bird flocks.

The correlated motion of flocks is an instance of global order emerging from local interactions. An essential difference with analogous ferromagnetic systems is that flocks are active: animals move relative to each other, dynamically rearranging their interaction network. The effect of this off-equilibrium element is well studied theoretically, but its impact on actual biological groups deserves more experimental attention. Here, we introduce a novel dynamical inference technique, based on the principle of maximum entropy, which accodomates network rearrangements and overcomes the problem of slow experimental sampling rates. We use this method to infer the strength and range of alignment forces from data of starling flocks. We find that local bird alignment happens on a much faster timescale than neighbour rearrangement. Accordingly, equilibrium inference, which assumes a fixed interaction network, gives results consistent with dynamical inference. We conclude that bird orientations are in a state of local quasi-equilibrium over the interaction length scale, providing firm ground for the applicability of statistical physics in certain active systems.

Clinical Implications of Switching Lipid Lowering Treatment from Rosuvastatin to Other Agents in Primary Care.

INTRODUCTION: Switching from any statin to another non-equipotent lipid lowering treatment (LLT) may cause a low-density lipoprotein cholesterol increase and has been associated with a higher probability of negative cardiovascular outcomes. The aim of the study was to assess the impact of switching from rosuvastatin to any other LLT on clinical outcomes in primary care. METHODS: This was a retrospective analysis based on data from IMS Health Longitudinal Patient Database, which is a general practice database including information of more than 1.0 million patients representative of the Italian population by age, and medical conditions. Patients that started on rosuvastatin (10-40 mg/day) between January 2011 and December 2013 were considered. The date of the first prescription was defined as the index date (ID). The observation period lasted from the ID to September 2015 or until LLT discontinuation, or the occurrence of an acute myocardial infarction (AMI), or death. RESULTS: The primary end point of the study was the occurrence of an AMI during the observation period. The final study population included 10,368 patients. During the observation period, 2452 (23.6%) patients were switched from rosuvastatin to another LLT. The majority of patients (55.6%) were switched to atorvastatin, followed by simvastatin (24.9%), simvastatin/ezetimibe combination (10.0%) and other statins (9.5%). Female gender (HR, hazard ratio, 1.10, 95% CI, confidence interval, 1.02-1.19, p = 0.04) and the presence of chronic kidney disease (HR 1.47, 95% CI 1.16-1.86, p = 0.05) were associated with a higher probability of switch. During the observation period, 113 patients experienced an AMI (incidence of 6.7 AMI/1000 patient-years). Multivariate analysis with Cox proportional hazards method, including switching as a time-dependent covariate, demonstrated that changing from rosuvastatin to another LLT was an independent predictor of AMI (HR 2.2, 95% CI 1.4-3.5, p = 0.001). CONCLUSION: We conclude that switching from rosuvastatin to another non-equipotent LLT may impart an increased risk of AMI and should be avoided. FUNDING: AstraZeneca SpA.

GReTA-A Novel Global and Recursive Tracking Algorithm in Three Dimensions.

Tracking multiple moving targets allows quantitative measure of the dynamic behavior in systems as diverse as animal groups in biology, turbulence in fluid dynamics and crowd and traffic control. In three dimensions, tracking several targets becomes increasingly hard since optical occlusions are very likely, i.e., two featureless targets frequently overlap for several frames. Occlusions are particularly frequent in biological groups such as bird flocks, fish schools, and insect swarms, a fact that has severely limited collective animal behavior field studies in the past. This paper presents a 3D tracking method that is robust in the case of severe occlusions. To ensure robustness, we adopt a global optimization approach that works on all objects and frames at once. To achieve practicality and scalability, we employ a divide and conquer formulation, thanks to which the computational complexity of the problem is reduced by orders of magnitude. We tested our algorithm with synthetic data, with experimental data of bird flocks and insect swarms and with public benchmark datasets, and show that our system yields high quality trajectories for hundreds of moving targets with severe overlap. The results obtained on very heterogeneous data show the potential applicability of our method to the most diverse experimental situations.

Short-range interactions versus long-range correlations in bird flocks.

Bird flocks are a paradigmatic example of collective motion. One of the prominent traits of flocking is the presence of long range velocity correlations between individuals, which allow them to influence each other over the large scales, keeping a high level of group coordination. A crucial question is to understand what is the mutual interaction between birds generating such nontrivial correlations. Here we use the maximum entropy (ME) approach to infer from experimental data of natural flocks the effective interactions between individuals. Compared to previous studies, we make a significant step forward as we retrieve the full functional dependence of the interaction on distance, and find that it decays exponentially over a range of a few individuals. The fact that ME gives a short-range interaction even though its experimental input is the long-range correlation function, shows that the method is able to discriminate the relevant information encoded in such correlations and single out a minimal number of effective parameters. Finally, we show how the method can be used to capture the degree of anisotropy of mutual interactions.

Emergence of collective changes in travel direction of starling flocks from individual birds' fluctuations.

One of the most impressive features of moving animal groups is their ability to perform sudden coherent changes in travel direction. While this collective decision can be a response to an external alarm cue, directional switching can also emerge from the intrinsic fluctuations in individual behaviour. However, the cause and the mechanism by which such collective changes of direction occur are not fully understood yet. Here, we present an experimental study of spontaneous collective turns in natural flocks of starlings. We employ a recently developed tracking algorithm to reconstruct three-dimensional trajectories of each individual bird in the flock for the whole duration of a turning event. Our approach enables us to analyse changes in the individual behaviour of every group member and reveal the emergent dynamics of turning. We show that spontaneous turns start from individuals located at the elongated tips of the flocks, and then propagate through the group. We find that birds on the tips deviate from the mean direction of motion much more frequently than other individuals, indicating that persistent localized fluctuations are the crucial ingredient for triggering a collective directional change. Finally, we quantitatively verify that birds follow equal-radius paths during turning, the effects of which are a change of the flock's orientation and a redistribution of individual locations in the group.

Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND: Cellular studies showed that histone methyltransferase Set7 mediates high glucose-induced inflammation via epigenetic regulation of the transcription factor NF-kB. However, the link between Set7 and vascular dysfunction in patients with diabetes mellitus remains unknown. This study was designed to investigate whether Set7 contributes to vascular dysfunction in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Set7-driven epigenetic changes on NF-kB p65 promoter and expression of NF-kB-dependent genes, cyclooxygenase 2 and inducible endothelial nitric oxide synthase, were assessed in peripheral blood mononuclear cells isolated from 68 subjects (44 patients with T2DM and 24 age-matched controls). Brachial artery flow-mediated dilation, 24-hour urinary levels of 8-isoprostaglandin F2α, and plasma adhesion molecules, intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1, were also determined. Experiments in human aortic endothelial cells exposed to high glucose were performed to elucidate the mechanisms of Set7-driven inflammation and oxidative stress. Set7 expression increased in peripheral blood mononuclear cells from patients with T2DM when compared with controls. Patients with T2DM showed Set7-dependent monomethylation of lysine 4 of histone 3 on NF-kB p65 promoter. This epigenetic signature was associated with upregulation of NF-kB, subsequent transcription of oxidant/inflammatory genes, and increased plasma levels of intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Interestingly, we found that Set7 expression significantly correlated with oxidative marker 8-isoprostaglandin F2α (r=0.38; P=0.01) and flow-mediated dilation (r=-0.34; P=0.04). In human aortic endothelial cells, silencing of Set7 prevented monomethylation of lysine 4 of histone 3 and abolished NF-kB-dependent oxidant and inflammatory signaling. CONCLUSIONS: Set7-induced epigenetic changes contribute to vascular dysfunction in patients with T2DM. Targeting this chromatin-modifying enzyme may represent a novel therapeutic approach to prevent atherosclerotic vascular disease in this setting.

Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes.

AIM: Diabetes is a major driver of cardiovascular disease, but the underlying mechanisms remain elusive. Prolyl-isomerase Pin1 recognizes specific peptide bonds and modulates function of proteins altering cellular homoeostasis. The present study investigates Pin1 role in diabetes-induced vascular disease. METHODS AND RESULTS: In human aortic endothelial cells (HAECs) exposed to high glucose, up-regulation of Pin1-induced mitochondrial translocation of pro-oxidant adaptor p66(Shc) and subsequent organelle disruption. In this setting, Pin1 recognizes Ser-116 inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) leading to eNOS-caveolin-1 interaction and reduced NO availability. Pin1 also mediates hyperglycaemia-induced nuclear translocation of NF-κB p65, triggering VCAM-1, ICAM-1, and MCP-1 expression. Indeed, gene silencing of Pin1 in HAECs suppressed p66(Shc)-dependent ROS production, restored NO release and blunted NF-kB p65 nuclear translocation. Consistently, diabetic Pin1(-/-) mice were protected against mitochondrial oxidative stress, endothelial dysfunction, and vascular inflammation. Increased expression and activity of Pin1 were also found in peripheral blood monocytes isolated from diabetic patients when compared with age-matched healthy controls. Interestingly, enough, Pin1 up-regulation was associated with impaired flow-mediated dilation, increased urinary 8-iso-prostaglandin F2α and plasma levels of adhesion molecules. CONCLUSIONS: Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kB-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes.

Finite-size scaling as a way to probe near-criticality in natural swarms.

Collective behavior in biological systems is often accompanied by strong correlations. The question has therefore arisen of whether correlation is amplified by the vicinity to some critical point in the parameters space. Biological systems, though, are typically quite far from the thermodynamic limit, so that the value of the control parameter at which correlation and susceptibility peak depend on size. Hence, a system would need to readjust its control parameter according to its size in order to be maximally correlated. This readjustment, though, has never been observed experimentally. By gathering three-dimensional data on swarms of midges in the field we find that swarms tune their control parameter and size so as to maintain a scaling behavior of the correlation function. As a consequence, correlation length and susceptibility scale with the system's size and swarms exhibit a near-maximal degree of correlation at all sizes.

Information transfer and behavioural inertia in starling flocks.

Collective decision-making in biological systems requires all individuals in the group to go through a behavioural change of state. During this transition fast and robust transfer of information is essential to prevent cohesion loss. The mechanism by which natural groups achieve such robustness, though, is not clear. Here we present an experimental study of starling flocks performing collective turns. We find that information about direction changes propagates across the flock with a linear dispersion law and negligible attenuation, hence minimizing group decoherence. These results contrast starkly with current models of collective motion, which predict diffusive transport of information. Building on spontaneous symmetry breaking and conservation laws arguments, we formulate a new theory that correctly reproduces linear and undamped propagation. Essential to the new framework is the inclusion of the birds' behavioural inertia. The new theory not only explains the data, but also predicts that information transfer must be faster the stronger the group's orientational order, a prediction accurately verified by the data. Our results suggest that swift decision-making may be the adaptive drive for the strong behavioural polarization observed in many living groups.

Collective behaviour without collective order in wild swarms of midges.

Collective behaviour is a widespread phenomenon in biology, cutting through a huge span of scales, from cell colonies up to bird flocks and fish schools. The most prominent trait of collective behaviour is the emergence of global order: individuals synchronize their states, giving the stunning impression that the group behaves as one. In many biological systems, though, it is unclear whether global order is present. A paradigmatic case is that of insect swarms, whose erratic movements seem to suggest that group formation is a mere epiphenomenon of the independent interaction of each individual with an external landmark. In these cases, whether or not the group behaves truly collectively is debated. Here, we experimentally study swarms of midges in the field and measure how much the change of direction of one midge affects that of other individuals. We discover that, despite the lack of collective order, swarms display very strong correlations, totally incompatible with models of non-interacting particles. We find that correlation increases sharply with the swarm's density, indicating that the interaction between midges is based on a metric perception mechanism. By means of numerical simulations we demonstrate that such growing correlation is typical of a system close to an ordering transition. Our findings suggest that correlation, rather than order, is the true hallmark of collective behaviour in biological systems.

C2238 atrial natriuretic peptide molecular variant is associated with endothelial damage and dysfunction through natriuretic peptide receptor C signaling.

RATIONALE: C2238 atrial natriuretic peptide (ANP) minor allele (substitution of thymidine with cytosine in position 2238) associates with increased risk of cardiovascular events. OBJECTIVE: We investigated the mechanisms underlying the vascular effects of C2238-αANP. METHODS AND RESULTS: In vitro, human umbilical vein endothelial cell were exposed to either wild-type (T2238)- or mutant (C2238)-αANP. Cell survival and apoptosis were tested by Trypan blue, annexin V, and cleaved caspase-3 assays. C2238-αANP significantly reduced human umbilical vein endothelial cell survival and increased apoptosis. In addition, C2238-αANP reduced endothelial tube formation, as assessed by matrigel. C2238-αANP did not differentially modulate natriuretic peptide receptor (NPR)-A/B activity with respect to T2238-αANP, as evaluated by intracellular cGMP levels. In contrast, C2238-αANP, but not T2238-αANP, markedly reduced intracellular cAMP levels in an NPR-C-dependent manner. Accordingly, C2238-αANP showed higher affinity binding to NPR-C, than T2238-αANP. Either NPR-C inhibition by antisense oligonucleotide or NPR-C gene silencing by small interfering RNA rescued survival and tube formation of human umbilical vein endothelial cell exposed to C2238-αANP. Similar data were obtained in human aortic endothelial cell with NPR-C knockdown. NPR-C activation by C2238-αANP inhibited the protein kinase A/Akt1 pathway and increased reactive oxygen species. Adenovirus-mediated Akt1 reactivation rescued the detrimental effects of C2238-αANP. Overall, these data indicate that C2238-αANP affects endothelial cell integrity through NPR-C-dependent inhibition of the cAMP/protein kinase A/Akt1 pathway and increased reactive oxygen species production. Accordingly, C2238-αANP caused impairment of acetylcholine-dependent vasorelaxation ex vivo, which was rescued by NPR-C pharmacological inhibition. Finally, subjects carrying C2238 minor allele showed early endothelial dysfunction, which highlights the clinical relevance of our results. CONCLUSIONS: C2238-αANP reduces endothelial cell survival and impairs endothelial function through NPR-C signaling. NPR-C targeting represents a potential strategy to reduce cardiovascular risk in C2238 minor-allele carriers.

Relation between right and left ventricular function in patients undergoing chronic dialysis.

AIMS: Occurrence of heart failure during dialysis treatment is associated with high mortality. However, mechanisms underlying left ventricular dysfunction (LVD) in these patients are still elusive. In patients undergoing haemodialysis, arteriovenous fistula (AVF) is associated with right ventricular dysfunction (RVD) and a further impairment is observed when AVF is brachial rather than radial. However, it is not known whether AVF-induced RVD is associated with an impaired left ventricular function. We studied the relation between right and left ventricular function in 120 patients undergoing either haemodialysis or peritoneal dialysis and 100 healthy age-matched controls. METHODS: Echocardiography including tissue Doppler imaging (TDI) was performed for both ventricles. Average myocardial performance index (MPI) of the right ventricle (RV MPI) was obtained with a multisegmental approach by using TDI. RESULTS: RVD was higher in haemodialysis than peritoneal dialysis patients and a further increase was observed in haemodialysis patients with brachial access. Interestingly, RV MPI inversely correlated with indices of both left ventricular contraction and relaxation and the association was even stronger in haemodialysis patients, particularly in those with brachial AVF. Of note, dialysis patients in the upper tertile of RV MPI showed the larger impairment of left ventricular function. Regression analyses showed that RV MPI was independently associated with reduced left ventricular function. By contrast, LVD did not significantly affect right ventricular performance in this setting. CONCLUSION: AVF-induced RVD may contribute to LVD in dialysis patients. AVF plays a pivotal role in triggering LVD via right-to-left ventricular interdependence.