Prominent Longitudinal Strain Reduction of Basal Left Ventricular Segments in Patients With Coronavirus Disease-19.

BACKGROUND: Coronavirus disease-19 (COVID-19) has been associated with overt and subclinical myocardial dysfunction. We observed a recurring pattern of reduced basal left ventricular (LV) longitudinal strain on speckle-tracking echocardiography in hospitalized patients with COVID-19 and subsequently aimed to identify characteristics of affected patients. We hypothesized that patients with COVID-19 with reduced basal LV strain would demonstrate elevated cardiac biomarkers. METHODS AND RESULT: Eighty-one consecutive patients with COVID-19 underwent speckle-tracking echocardiography. Those with poor quality speckle-tracking echocardiography (n = 2) or a known LV ejection fraction of <50% (n = 4) were excluded. Patients with an absolute value basal longitudinal strain of <13.9% (2 standard deviations below normal) were designated as cases (n = 39); those with a basal longitudinal strain of ≥13.9% were designated as controls (n = 36). Demographics and clinical variables were compared. Of 75 included patients (mean age 62 ± 14 years, 41% women), 52% had reduced basal strain. Cases had higher body mass index (median 34.1; interquartile range 26.5-37.9 kg/m2 vs median 26.9, interquartile range, 24.8-30.0 kg/m2, P = .009), and greater proportions of Black (74% vs 36%, P = .0009), hypertensive (79% vs 56%, P = .026), and diabetic patients (44% vs 19%, P = .025) compared with controls. Troponin and N-terminal pro-brain natriuretic peptide levels trended higher in cases, but were not significantly different. CONCLUSIONS: Reduced basal LV strain is common in patients with COVID-19. Patients with hypertension, diabetes, obesity, and Black race were more likely to have reduced basal strain. Further investigation into the significance of this strain pattern is warranted.

Prevalence and Clinical Correlates of Echo-Estimated Right and Left Heart Filling Pressures in Hospitalized Patients With Coronavirus Disease 2019.

OBJECTIVES: The prevalence of elevated right and left heart filling pressures in coronavirus disease 2019 is not well characterized. We aimed to characterize the prevalence of pulmonary hypertension and concurrent elevated left heart filling pressure in hospitalized patients with coronavirus disease 2019. We hypothesized that a significant proportion of coronavirus disease 2019 patients has evidence of pulmonary hypertension associated with elevated left heart filling pressure on transthoracic echocardiography. DESIGN: Retrospective cohort study. SETTING: Academic tertiary-care center. PATIENTS: Hospitalized coronavirus disease 2019 patients who underwent clinical transthoracic echocardiography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The exposure variable of interest was right ventricular systolic pressure, calculated using the American Society of Echocardiography guidelines. Pulmonary hypertension was defined as right ventricular systolic pressure greater than 40 mm Hg. Left heart filling pressure was estimated with Nagueh's method for pulmonary artery occlusion pressure using E/e' ratio, and normal was considered pulmonary artery occlusion pressure less than 16 mm Hg. Clinical characteristics and outcomes were compared between the patients with and without pulmonary hypertension. A total of 73 patients (median age 66 yr [57-75 yr]; 46% women) were included. Median right ventricular systolic pressure was 39 mm Hg (interquartile range, 32-50 mm Hg), and 36 patients (49.3%) had evidence of pulmonary hypertension. Patients with pulmonary hypertension were more likely to require ICU admission (86% vs 65%; p = 0.035) and have acute respiratory distress syndrome (72% vs 49%; p = 0.0053) than those without. In-hospital mortality was 26% for those with pulmonary hypertension compared with 14% for those without (p = 0.19). Patients with pulmonary hypertension had higher median-estimated pulmonary artery occlusion pressure (17.4 mm Hg [12.7-21.3 mm Hg] vs 12.1 mm Hg [10.0-14.1 mm Hg]; p = 0.0008), and elevated left heart filling pressure was present in 59% of those with pulmonary hypertension. CONCLUSIONS: Pulmonary hypertension is common in hospitalized patients with coronavirus disease 2019 and is associated with poor clinical outcomes. Left ventricular filling pressure is elevated in over half of those with pulmonary hypertension and may represent a target to reduce right ventricular afterload and potentially improve outcomes in coronavirus disease 2019.

Cardiovascular Risks and Organ Damage in Secondary Hypertension.

Secondary hypertension is associated with increased cardiovascular risk and exaggerated target organ damage, not only due to the higher and more sustained blood pressure values often observed in these patients but also because certain forms of hypertension can increase cardiovascular risk and organ damage by the neurohormonal and/or molecular pathways activation they exert. Early identification of secondary forms of hypertension can help mitigate organ damage and prevent cardiovascular complications. Signs and symptoms distinction among types of secondary hypertension is essential in order to prevent complications.

Thrombospondins in the transition from myocardial infarction to heart failure.

The heart's reaction to ischemic injury from a myocardial infarction involves complex cross-talk between the extra-cellular matrix (ECM) and different cell types within the myocardium. The ECM functions not only as a scaffold where myocytes beat synchronously, but an active signaling environment that regulates the important post-MI responses. The thrombospondins are matricellular proteins that modulate cell--ECM interactions, functioning as "sensors" that mediate outside-in and inside-out signaling. Thrombospondins are highly expressed during embryonic stages, and although their levels decrease during adult life, can be re-expressed in high quantities in response to cardiac stress including myocardial infarction and heart failure. Like a Swiss-army knife, the thrombospondins possess many tools: numerous binding domains that allow them to interact with other elements of the ECM, cell surface receptors, and signaling molecules. It is through these that the thrombospondins function. In the present review, we provide basic as well as clinical evidence linking the thrombospondin proteins with the post myocardial infarction response, including inflammation, fibrotic matrix remodeling, angiogenesis, as well as myocyte hypertrophy, apoptosis, and contractile dysfunction in heart failure. We will describe what is known regarding the intracellular signaling pathways that are involved with these responses, paving the road for future studies identifying these proteins as therapeutic targets for cardiac disease.

A Sudden Change of Heart: A Case of Rapidly Reversed Stress Cardiomyopathy in a Critically Ill Patient.

We report the case of a 79-year-old woman who presented to our hospital for elective removal of an infratentorial meningioma and suffered a periprocedural cardiac arrest. Shortly after uncomplicated induction of anesthesia prior to the surgery, the patient became hypotensive and bradycardic, culminating ultimately in a cardiac arrest with pulseless electrical activity. Return of spontaneous circulation occurred within 90 seconds of arrest, but the patient remained dependent on maximal doses of epinephrine and dopamine for hemodynamic support. Echocardiography performed on the day of cardiac arrest revealed a newly depressed left ventricular ejection fraction (LVEF) of 15-20% with an apical ballooning pattern. Left heart catheterization showed no obstructive coronary lesions to explain her depressed ejection fraction. A diagnosis of stress cardiomyopathy (SCM) was made given the echocardiographic findings and absence of concomitant coronary disease. Within the next 24 hours, the patient was liberated from inotropic support, and at 6-month follow-up, her LVEF returned to 55% and she had no heart failure symptoms.

Cardiac troponin I Pro82Ser variant induces diastolic dysfunction, blunts ß-adrenergic response, and impairs myofilament cooperativity.

Troponin I (TnI) variant Pro82Ser (cTnIP82S) was initially considered a disease-causing mutation; however, later studies suggested the contrary. We tested the hypothesis of whether a causal link exists between cTnIP82S and cardiac structural and functional remodeling, such as during aging or chronic pressure overload. A cardiac-specific transgenic (Tg) mouse model of cTnIP82S was created to test this hypothesis. During aging, Tg cTnIP82S displayed diastolic dysfunction, characterized by longer isovolumetric relaxation time, and impaired ejection and relaxation time. In young, Tg mice in vivo pressure-volume loops and intact trabecular preparations revealed normal cardiac contractility at baseline. However, upon ß-adrenergic stimulation, a blunted contractile reserve and no hastening in left ventricle relaxation were evident in vivo, whereas, in isolated muscles, Ca(2+) transient amplitude isoproterenol dose-response was blunted. In addition, when exposed to chronic pressure overload, Tg mice show exacerbated hypertrophy and decreased contractility compared with age-matched non-Tg littermates. At the molecular level, this mutation significantly impairs myofilament cooperative activation. Importantly, this occurs in the absence of alterations in TnI or myosin-binding protein C phosphorylation. The cTnIP82S variant occurs near a region of interactions with troponin T; therefore, structural changes in this region could explain its meaningful effects on myofilament cooperativity. Our data indicate that cTnIP82S mutation modifies age-dependent diastolic dysfunction and impairs overall contractility after ß-adrenergic stimulation or chronic pressure overload. Thus cTnIP82S variant should be regarded as a disease-modifying factor for dysfunction and adverse remodeling with aging and chronic pressure overload.

Brief report: antisynthetase syndrome-associated myocarditis.

BACKGROUND: The antisynthetase (AS) syndrome is characterized by autoimmune myopathy, interstitial lung disease, cutaneous involvement, arthritis, fever, and antibody specificity. We describe 2 patients with AS syndrome who also developed myocarditis, depressed biventricular function, and congestive heart failure. METHODS AND RESULTS: Both patients were diagnosed with AS syndrome based on clinical manifestations, detection of serum AS antibodies, and myositis confirmation with the use of skeletal muscle magnetic resonance imaging and skeletal muscle biopsy. In addition, myocarditis resulting in heart failure was confirmed with the use of cardiac magnetic resonance imaging and from endomyocardial biopsy findings. After treatment for presumed AS syndrome-associated myocarditis, one patient recovered and the other patient died. CONCLUSIONS: AS syndrome is a rare entity with morbidity and mortality typically attributed to myositis and lung involvement. This is the first report of AS syndrome-associated myocarditis leading to congestive heart failure in 2 patients. Given the potentially fatal consequences, myocarditis should be considered in patients with AS syndrome presenting with heart failure.

Hyperactive adverse mechanical stress responses in dystrophic heart are coupled to transient receptor potential canonical 6 and blocked by cGMP-protein kinase G modulation.

RATIONALE: The heart is exquisitely sensitive to mechanical stimuli to adapt rapidly to physiological demands. In muscle lacking dystrophin, such as Duchenne muscular dystrophy, increased load during contraction triggers pathological responses thought to worsen the disease. The relevant mechanotransducers and therapies to target them remain unclear. OBJECTIVES: We tested the role of transient receptor potential canonical (TRPC) channels TRPC3 and TRPC6 and their modulation by protein kinase G (PKG) in controlling cardiac systolic mechanosensing and determined their pathophysiological relevance in an experimental model of Duchenne muscular dystrophy. METHODS AND RESULTS: Contracting isolated papillary muscles and cardiomyocytes from controls and mice genetically lacking either TRPC3 or TRPC6 were subjected to auxotonic load to induce stress-stimulated contractility (SSC, gradual rise in force and intracellular Ca(2+)). Incubation with cGMP (PKG activator) markedly blunted SSC in controls and Trpc3(-/-); whereas in Trpc6(-/-), the resting SSC response was diminished and cGMP had no effect. In Duchenne muscular dystrophy myocytes (mdx/utrophin deficient), the SSC was excessive and arrhythmogenic. Gene deletion or selective drug blockade of TRPC6 or cGMP/PKG activation reversed this phenotype. Chronic phosphodiesterase 5A inhibition also normalized abnormal mechanosensing while blunting progressive chamber hypertrophy in Duchenne muscular dystrophy mice. CONCLUSIONS: PKG is a potent negative modulator of cardiac systolic mechanosignaling that requires TRPC6 as the target effector. In dystrophic hearts, excess SSC and arrhythmia are coupled to TRPC6 and are ameliorated by its targeted suppression or PKG activation. These results highlight novel therapeutic targets for this disease.

Cardiac amyloidosis presenting with prolonged QT interval and recurrent polymorphic ventricular tachycardia.

Cardiac amyloidosis results in severely symptomatic heart failure that has a poor prognosis because of the development of a restrictive cardiomyopathy. The diagnosis of cardiac amyloidosis is often delayed because of nonspecific signs and symptoms. We report the case of a 66-year-old woman who had been diagnosed with sick sinus syndrome and presented 5 months later with a long QT interval and recurrent polymorphic ventricular tachycardia. The diagnosis of cardiac amyloidosis was confirmed upon analysis of endomyocardial biopsy results. The patient was subsequently diagnosed with and treated for underlying plasma cell myeloma and later died of cardiac arrest. This atypical presentation of cardiac amyloidosis underscores the need to consider it in the differential diagnosis of patients who have ventricular arrhythmias. To our knowledge, the combination of long QT interval and polymorphic ventricular tachycardia has not been previously reported in association with amyloid heart disease.

Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation.

RATIONALE: Stimulation of ß3-adrenoreceptors (ß3-AR) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nNOS) dependent manner. nNOS can be regulated by post-translational modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, the role of phosphorylation of these residues in cardiomyocytes and ß3-AR protective signaling has yet to be explored. OBJECTIVE: We tested the hypothesis that ß3-AR regulation of myocyte stress requires changes in nNOS activation mediated by differential nNOS phosphorylation. METHODS AND RESULTS: Endothelin (ET-1) or norepinephrine induced hypertrophy in rat neonatal ventricular cardiomyocytes (NRVMs) was accompanied by increased ß3-AR gene expression. Co-administration of the ß3-AR agonist BRL-37433 (BRL) reduced cell size and reactive oxygen species (ROS) generation, while augmenting NOS activity. BRL-dependent augmentation of NOS activity and ROS suppression due to NE were blocked by inhibiting nNOS (L-VNIO). BRL augmented nNOS phosphorylation at Ser1412 and dephosphorylation at Ser847. Cells expressing constitutively dephosphorylated Ser1412A or phosphorylated Ser847D nNOS mutants displayed reduced nNOS activity and a lack of BRL modulation. BRL also failed to depress ROS from NE in cells with nNOS-Ser847D. Inhibiting Akt decreased BRL-induced nNOS-Ser1412 phosphorylation and NOS activation, whereas Gi/o blockade blocked BRL-regulation of both post-translational modifications, preventing enhancement of NOS activity and ROS reduction. BRL resulted in near complete dephosphorylation of Ser847 and a moderate rise in Ser1412 phosphorylation in mouse myocardium exposed to chronic pressure-overload. CONCLUSION: ß3-AR regulates myocardial NOS activity and ROS via activation of nNOS involving reciprocal changes in phosphorylation at two regulatory sites. These data identify a novel and potent anti-oxidant and anti-hypertrophic pathway due to nNOS post-translational modification that is coupled to ß3-AR receptor stimulation.

The Anrep effect: 100 years later.

Myocardial stretch elicits a rapid increase in developed force, which is mainly caused by an increase in myofilament calcium sensitivity (Frank-Starling mechanism). Over the ensuing 10-15 min, a second gradual increase in force takes place. This slow force response to stretch is known to be the result of an increase in the calcium transient amplitude and constitutes the in vitro equivalent of the Anrep effect described 100 years ago in the intact heart. In the present review, we will update and discuss what is known about the Anrep effect as the mechanical counterpart of autocrine/paracrine mechanisms involved in its genesis. The chain of events triggered by myocardial stretch comprises 1) release of angiotensin II, 2) release of endothelin, 3) activation of the mineralocorticoid receptor, 4) transactivation of the epidermal growth factor receptor, 5) increased formation of mitochondria reactive oxygen species, 6) activation of redox-sensitive kinases upstream myocardial Na(+)/H(+) exchanger (NHE1), 7) NHE1 activation, 8) increase in intracellular Na(+) concentration, and 9) increase in Ca(2+) transient amplitude through the Na(+)/Ca(2+) exchanger. We will present the experimental evidence supporting each of the signaling steps leading to the Anrep effect and its blunting by silencing NHE1 expression with a specific small hairpin interference RNA injected into the ventricular wall.

Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase.

OBJECTIVES: The aim of this study was to determine whether activation of ß3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload. BACKGROUND: ß3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike ß1- and ß2-ARs, ß3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a "brake" to protect the heart from catecholamine overstimulation. METHODS: C57BL/6J and neuronal NOS (nNOS) knockout mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (ß3 agonist, BRL 0.1 mg/kg/h), or both. RESULTS: Three weeks of BRL treatment in wild-type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide production and superoxide suppression. TAC decreased endothelial NOS (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute nNOS inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOS(-/-) mice. CONCLUSIONS: These results are the first to show in vivo cardioprotective effects of ß3-AR-specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species balance in the failing heart.

Pulmonary capillary wedge pressure augments right ventricular pulsatile loading.

BACKGROUND: Right ventricular failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (R(PA)) and compliance (C(PA)) are consistently and inversely related regardless of age, pulmonary hypertension, or interstitial fibrosis and that this relation may be changed by elevated pulmonary capillary wedge pressure, augmenting right ventricular pulsatile load. METHODS AND RESULTS: Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the R(PA)-C(PA) relationship with pulmonary hypertension, pulmonary fibrosis, patient age, and varying pulmonary capillary wedge pressure. Patients with suspected or documented pulmonary hypertension (n=1009) and normal pulmonary capillary wedge pressure displayed a consistent R(PA)-C(PA) hyperbolic (inverse) dependence, C(PA)=0.564/(0.047+R(PA)), with a near-constant resistance-compliance product (0.48±0.17 seconds). In the same patients, the systemic resistance-compliance product was highly variable. Severe pulmonary fibrosis (n=89) did not change the R(PA)-C(PA) relation. Increasing patient age led to a very small but statistically significant change in the relation. However, elevation of the pulmonary capillary wedge pressure (n=8142) had a larger impact, significantly lowering C(PA) for any R(PA) and negatively correlating with the resistance-compliance product (P<0.0001). CONCLUSIONS: Pulmonary hypertension and pulmonary fibrosis do not significantly change the hyperbolic dependence between R(PA) and C(PA), and patient age has only minimal effects. This fixed relationship helps explain the difficulty of reducing total right ventricular afterload by therapies that have a modest impact on mean R(PA). Higher pulmonary capillary wedge pressure appears to enhance net right ventricular afterload by elevating pulsatile, relative to resistive, load and may contribute to right ventricular dysfunction.

Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle.

RATIONALE: One of the physiological mechanisms by which the heart adapts to a rise in blood pressure is by augmenting myocyte stretch-mediated intracellular calcium, with a subsequent increase in contractility. This slow force response was first described over a century ago and has long been considered compensatory, but its underlying mechanisms and link to chronic adaptations remain uncertain. Because levels of the matricellular protein thrombospondin-4 (TSP4) rapidly rise in hypertension and are elevated in cardiac stress overload and heart failure, we hypothesized that TSP4 is involved in this adaptive mechanism. OBJECTIVE: To determine the mechano-transductive role that TSP4 plays in cardiac regulation to stress. METHODS AND RESULTS: In mice lacking TSP4 (Tsp4⁻/⁻), hearts failed to acutely augment contractility or activate stretch-response pathways (ERK1/2 and Akt) on exposure to acute pressure overload. Sustained pressure overload rapidly led to greater chamber dilation, reduced function, and increased heart mass. Unlike controls, Tsp4⁻/⁻ cardiac trabeculae failed to enhance contractility and cellular calcium after a stretch. However, the contractility response was restored in Tsp4⁻/⁻ muscle incubated with recombinant TSP4. Isolated Tsp4⁻/⁻ myocytes responded normally to stretch, identifying a key role of matrix-myocyte interaction for TSP4 contractile modulation. CONCLUSION: These results identify TSP4 as myocyte-interstitial mechano-signaling molecule central to adaptive cardiac contractile responses to acute stress, which appears to play a crucial role in the transition to chronic cardiac dilatation and failure.

Pressure-volume relation analysis of mouse ventricular function.

Nearly 40 years ago, the Sagawa laboratory spawned a renaissance in the use of instantaneous ventricular pressure-volume (P-V) relations to assess cardiac function. Since then, this analysis has taken hold as the most comprehensive way to quantify ventricular chamber function and energetics and cardiovascular interactions. First studied in large mammalian hearts and later in humans employing a catheter-based method, P-V analysis was translated to small rodents in the late 1990s by the Kass laboratory. Over the past decade, this approach has become a gold standard for comprehensive examination of in vivo cardiac function in mice, facilitating a new era of molecular cardiac physiology. The catheter-based method remains the most widely used approach in mice. In this brief review, we discuss this instrumentation, the theory behind its use, and how volume signals are calibrated and discuss elements of P-V analysis. The goal is to provide a convenient summary of earlier investigations and insights for users whose primary interests lie in genetic/molecular studies rather than in biomedical engineering.

In vivo key role of reactive oxygen species and NHE-1 activation in determining excessive cardiac hypertrophy.

Growing in vitro evidence suggests NHE-1, a known target for reactive oxygen species (ROS), as a key mediator in cardiac hypertrophy (CH). Moreover, NHE-1 inhibition was shown effective in preventing CH and failure; so has been the case for AT1 receptor (AT1R) blockers. Previous experiments indicate that myocardial stretch promotes angiotensin II release and post-translational NHE-1 activation; however, in vivo data supporting this mechanism and its long-term consequences are scanty. In this work, we thought of providing in vivo evidence linking AT1R with ROS and NHE-1 activation in mediating CH. CH was induced in mice by TAC. A group of animals was treated with the AT1R blocker losartan. Cardiac contractility was assessed by echocardiography and pressure-volume loop hemodynamics. After 7 weeks, TAC increased left ventricular (LV) mass by ~45% vs. sham and deteriorated LV systolic function. CH was accompanied by activation of the redox-sensitive kinase p90(RSK) with the consequent increase in NHE-1 phosphorylation. Losartan prevented p90(RSK) and NHE-1 phosphorylation, ameliorated CH and restored cardiac function despite decreased LV wall thickness and similar LV systolic pressures and diastolic dimensions (increased LV wall stress). In conclusion, AT1R blockade prevented excessive oxidative stress, p90(RSK) and NHE-1 phosphorylation, and decreased CH independently of hemodynamic changes. In addition, cardiac performance improved despite a higher work load.