‘Superimposed miracles’ An extremely rare case of a septuagenarian with an unrepaired tetralogy of Fallot: a case report

Background Although the life expectancy of patients with tetralogy of Fallot (TOF) is comparable to that of the general population due to advancements in surgical intervention, if untreated, patients with TOF may die during their childhood. However, it has been anecdotally reported that a small number of patients with unrepaired TOF survived into their senescence. Case Summary A 71-year-old man with a history of multiple heart failure admissions was referred to our institute after successful cardiopulmonary arrest resuscitation. Transthoracic echocardiography showed the overriding of the aorta on a large ventricular septal defect and right ventricular hypertrophy, along with severe pulmonary stenosis (PS), all of which indicated unrepaired TOF. Computed tomography revealed a patent Blalock-Taussig shunt, which was constructed at the age of 19 years. Coronary angiography revealed multivessel coronary stenoses. Although radical intracardiac repair was not performed due to his multiple comorbidities, his heart failure symptoms were significantly improved owing to proper medication titration. One year following discharge, the patient was well and enjoyed playing golf. Discussion Specific anatomical, functional and haemodynamic characteristics may be required for the long-term survival of patients with TOF. PS should be initially mild to guarantee pulmonary flow during childhood and adolescence, and gradual PS exacerbation should be paralleled with systemic-to-pulmonary collateral development or an extra-cardiac shunt. Moreover, reduced left ventricular compliance may act as a balancing factor against a right-to-left shunt. The presence of all of these special requirements may have contributed to the unusual survival for this patient.

Diastolic Function and Ambulatory Hypertension in Children With Chronic Kidney Disease

Diastolic dysfunction is one of the earliest cardiac abnormalities in patients with chronic kidney disease. We analyzed echocardiographic markers of left ventricular function from 786 children and adolescents (1658 person-visits) enrolled in the CKiD (Chronic Kidney Disease in Children) cohort, a large prospective observational study of children with chronic kidney disease. Primary outcome was early mitral inflow velocity-to-early mitral annular peak velocity (E/e′) ratio as a marker of left ventricular compliance. Abnormal diastolic function was defined as E/e′>8.0. Those with an abnormal E/e′ ratio were younger, had a lower estimated glomerular filtration rate and hemoglobin, and a higher prevalence of hypertension and left ventricular hypertrophy compared to children with a normal E/e′. In adjusted analysis, a higher E/e′ ratio was independently associated with ambulatory (sustained) hypertension (1.66 [95% CI, 1.15–2.42]). Other significant independent predictors were higher left ventricular mass index Z score, increased body mass index Z score, lower hemoglobin, higher phosphorus level, and younger age. Casual blood pressure was not significantly associated with higher E/e′. These data indicate that ambulatory blood pressure might better identify children with chronic kidney disease at risk for subclinical cardiac dysfunction than clinic blood pressure alone.

Diastolic Dysfunction- Anaesthesiologist’s Dilemma!

Left ventricular systolic dysfunction is well recognized and ably managed by anesthesiologists. Left ventricular diastolic function needs to be reckoned as well, every single time anaesthesia is planned in a patient with cardiac disease. This article emphasizes why one should take cognizance of diastolic dysfunction during perioperative anaesthesia management. Diastolic dysfunction(DD) is the inefficiency of the left ventricle to allow filling at lower atrial pressures.[1] In other words, it is the abnormal relaxation during diastole along with the reduction in left ventricular compliance which culminates into higher filling pressures of the left ventricle.[2] It is associated with comorbid conditions such as hypertension, diabetes and atrial fibrillation. Oftentimes it is asymptomatic at rest but can manifest in stress-induced circumstances such as acute severe hypertension, tachycardia, overzealous fluid administration or arrhythmias especially atrial fibrillation.[3] Various reciprocal changes occur over time within the systolic function due to long-standing diastolic dysfunction. Also, mild to moderate diastolic dysfunction forms an independent predictor for the risk of mortality in addition to the established risk of hypertension, diabetes, coronary artery disease and advanced age.[4] It is also an independent predictor of major adverse cardiac events (MACE). (5) Most of the patients in whom anaesthesia is given for various surgical procedures have comorbidities like hypertension, diabetes, dyslipidemia, atrial fibrillation and ischemic heart disease which endure high risk for DD. They may have associated heart failure with preserved ejection fraction (HFpEF).DD can contribute to postoperative heart failure [6] and is associated with various complications in the postoperative period.[2] The act of administration of anaesthesia, mechanical ventilation and intraoperative events like tachycardia, hypertension, inordinate fluid therapy along with the overall surgic

Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness

The heart is viscoelastic, meaning its compliance is inversely proportional to the speed at which it stretches. During diastolic filling, the left ventricle rapidly expands at rates where viscoelastic forces impact ventricular compliance. In heart disease, myocardial viscoelasticity is often increased and can directly impede diastolic filling to reduce cardiac output. Thus, treatments that reduce myocardial viscoelasticity may provide benefit in heart failure, particularly for patients with diastolic heart failure. Yet, many experimental techniques either cannot or do not characterize myocardial viscoelasticity, and our understanding of the molecular regulators of viscoelasticity and its impact on cardiac performance is lacking. Much of this may stem from a reliance on techniques that either do not interrogate viscoelasticity (i.e., use non-physiological rates of strain) or techniques that compromise elements that contribute to viscoelasticity (i.e., skinned or permeabilized muscle preparations that compromise cytoskeletal integrity). Clinically, cardiac viscoelastic characterization is challenging, requiring the addition of strain-rate modulation during invasive hemodynamics. Despite these challenges, data continues to emerge demonstrating a meaningful contribution of viscoelasticity to cardiac physiology and pathology, and thus innovative approaches to characterize viscoelasticity stand to illuminate fundamental properties of myocardial mechanics and facilitate the development of novel therapeutic strategies.

Sensing and Responding of Cardiomyocytes to Changes of Tissue Stiffness in the Diseased Heart

Cardiomyocytes are permanently exposed to mechanical stimulation due to cardiac contractility. Passive myocardial stiffness is a crucial factor, which defines the physiological ventricular compliance and volume of diastolic filling with blood. Heart diseases often present with increased myocardial stiffness, for instance when fibrotic changes modify the composition of the cardiac extracellular matrix (ECM). Consequently, the ventricle loses its compliance, and the diastolic blood volume is reduced. Recent advances in the field of cardiac mechanobiology revealed that disease-related environmental stiffness changes cause severe alterations in cardiomyocyte cellular behavior and function. Here, we review the molecular mechanotransduction pathways that enable cardiomyocytes to sense stiffness changes and translate those into an altered gene expression. We will also summarize current knowledge about when myocardial stiffness increases in the diseased heart. Sophisticated in vitro studies revealed functional changes, when cardiomyocytes faced a stiffer matrix. Finally, we will highlight recent studies that described modulations of cardiac stiffness and thus myocardial performance in vivo. Mechanobiology research is just at the cusp of systematic investigations related to mechanical changes in the diseased heart but what is known already makes way for new therapeutic approaches in regenerative biology.

Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium

Background: Diastolic dysfunction is a prevalent and therapeutically intractable feature of heart failure (HF). Increasing ventricular compliance can improve diastolic performance, but the viscoelastic forces that resist diastolic filling and become elevated in human HF are poorly defined. Having recently identified posttranslationally detyrosinated microtubules as a source of viscoelasticity in cardiomyocytes, we sought to test whether microtubules contribute meaningful viscoelastic resistance to diastolic stretch in human myocardium. Methods: Experiments were conducted in isolated human cardiomyocytes and trabeculae. First, slow and rapid (diastolic) stretch was applied to intact cardiomyocytes from nonfailing and HF hearts and viscoelasticity was characterized after interventions targeting microtubules. Next, intact left ventricular trabeculae from HF patient hearts were incubated with colchicine or vehicle and subject to pre- and posttreatment mechanical testing, which consisted of a staircase protocol and rapid stretches from slack length to increasing strains. Results: Viscoelasticity was increased during diastolic stretch of HF cardiomyocytes compared with nonfailing counterparts. Reducing either microtubule density or detyrosination reduced myocyte stiffness, particularly at diastolic strain rates, indicating reduced viscous forces. In myocardial tissue, we found microtubule depolymerization reduced myocardial viscoelasticity, with an effect that decreased with increasing strain. Colchicine reduced viscoelasticity at strains below, but not above, 15%, with a 2-fold reduction in energy dissipation upon microtubule depolymerization. Post hoc subgroup analysis revealed that myocardium from patients with HF with reduced ejection fraction were more fibrotic and elastic than myocardium from patients with HF with preserved ejection fraction, which were relatively more viscous. Colchicine reduced viscoelasticity in both HF with preserved ejection fraction and HF with reduced ejection fraction myocardium. Conclusions: Failing cardiomyocytes exhibit elevated viscosity and reducing microtubule density or detyrosination lowers viscoelastic resistance to diastolic stretch in human myocytes and myocardium. In failing myocardium, microtubules elevate stiffness over the typical working range of strains and strain rates, but exhibited diminishing effects with increasing length, consistent with an increasing contribution of the extracellular matrix or myofilament proteins at larger excursions. These studies indicate that a stabilized microtubule network provides a viscous impediment to diastolic stretch, particularly in HF.

Platelet-derived growth factor-AB improves scar mechanics and vascularity after myocardial infarction

Therapies that target scar formation after myocardial infarction (MI) could prevent ensuing heart failure or death from ventricular arrhythmias. We have previously shown that recombinant human platelet-derived growth factor-AB (rhPDGF-AB) improves cardiac function in a rodent model of MI. To progress clinical translation, we evaluated rhPDGF-AB treatment in a clinically relevant porcine model of myocardial ischemia-reperfusion. Thirty-six pigs were randomized to sham procedure or balloon occlusion of the proximal left anterior descending coronary artery with 7-day intravenous infusion of rhPDGF-AB or vehicle. One month after MI, rhPDGF-AB improved survival by 40% compared with vehicle, and cardiac magnetic resonance imaging showed left ventricular (LV) ejection fraction improved by 11.5%, driven by reduced LV end-systolic volumes. Pressure volume loop analyses revealed improved myocardial contractility and energetics after rhPDGF-AB treatment with minimal effect on ventricular compliance. rhPDGF-AB enhanced angiogenesis and increased scar anisotropy (high fiber alignment) without affecting overall scar size or stiffness. rhPDGF-AB reduced inducible ventricular tachycardia by decreasing heterogeneity of the ventricular scar that provides a substrate for reentrant circuits. In summary, we demonstrated that rhPDGF-AB promotes post-MI cardiac wound repair by altering the mechanics of the infarct scar, resulting in robust cardiac functional improvement, decreased ventricular arrhythmias, and improved survival. Our findings suggest a strong translational potential for rhPDGF-AB as an adjunct to current MI treatment and possibly to modulate scar in other organs.

P4718Inadequate response of pulmonary artery pressure after percutaneous mitral valvuloplasty: determinant factors and prognostic impact

Introduction Pulmonary hypertension (HP) has long been known to be a marker of poor outcome in patients with mitral stenosis (MS). Percutaneous mitral valvuloplasty (PMV) is currently the treatment of choice for MS, which results in improvement in HP. However, despite the successful valve opening, the regression of PH may be incomplete. This has been attributed to irreversible morphologic changes within the pulmonary vasculature. Purpose To assess the clinical, echocardiographic and hemodynamic parameters associated with an inadequate response of the pulmonary artery pressure (PAP) immediately after a successful PMV, and also the impact of residual PH on long-term outcome in these patients. Methods 181 patients undergoing PMV for rheumatic MS were enrolled. Invasive hemodynamic and echocardiographic measures were examined in all patients. Inadequate response of PAP was defined as the mean pulmonary artery pressure (mPAP) values unchanged at the end of the procedure. Long-term outcome was a composite endpoint of death, mitral valve replacement, repeat PMV, new onset of atrial fibrillation (AF), or stroke. Results The mean age was 44.1±12.6 years, and 157 patients were women (86.7%). In the overall population, mPAP decreased from 33.4±13.1 mmHg pre to 27.6±9.8 mmHg post (p<0.001), as mitral valve increased from 0.96±0.2 cm2 pre to 1.68±0.2 cm2 post (p<0.001) PMV. Following PMV, 10 patients developed severe mitral regurgitation and were excluded from the analysis. Of the 171 patients analyzed, 52 (30%) did not present reduction of mPAP immediately after the PMV. Transmitral pressure gradients were significantly greater and mitral valve area was smaller in those patients with unchanged mPAP after PMV than in those whose PAP had decreased. Systolic, diastolic and mPAP pressures as well as left atrial pressure were higher in those patients who had improvement in pulmonary pressures after PMV. Multivariate analysis revealed the following independent predictors of unchanged mPAP: AF (Odds ratio [OR] 2.7, 95% [confidence interval] CI 1.1 to 6.4), mitral valve area (OR 1.3, 95% CI 1.1 to 1.5), maximum mitral valve leaflets displacement (OR 0.8, 95% CI 0.7 to 0.9), and left ventricular compliance after PMV (OR 0.8, 95% CI 0.6 to 0.9). During a mean follow-up of 28 months, the endpoint was reached in 48 patients (26%). The pulmonary pressure response to PMV was not predictor of long-term events. Conclusions In a large cohort of patients with MS undergoing PMV, mean pulmonary artery pressure values do not reduce immediately after the procedure in 30% of the cases, despite adequate opening of the valve. The factors associated with inadequate PAP response following PMV were presence of AF, larger mitral valve area, reduced valve leaflets mobility and post procedural low left ventricular compliance. The early non-reduction of mPAP after PMV is not associated with adverse outcome.