Safety of dobutamine stress echocardiography in patients with aortic stenosis

BACKGROUND AND AIM OF THE STUDY: Aortic valve disease is becoming one of the most important cardiac diseases in western society. Low-dose dobutamine stress echocardiography (DSE) is recommended in patients with low-gradient aortic stenosis (AS) and severe left ventricular (LV) dysfunction. DSE is also used in patients with AS and moderately reduced or normal LV function for diagnostic purposes. The study aim was to assess the safety of DSE in the setting of AS and various degrees of LV dysfunction. METHODS: A total of 75 patients with AS who underwent DSE at the authors' center between 1997 and 2001 was reviewed. Group A patients (n = 20) had severely reduced mean LV ejection fraction (LVEF) of 25 +/- 6% and underwent low-dose DSE; group B patients (n = 55) had moderate to normal LV function (LVEF 51 +/- 8%) and underwent high-dose DSE. The mean pressure gradient, valve area and side effects after DSE were evaluated. RESULTS: Serious cardiac arrhythmias occurred in 10 patients. In group A, four patients (20%) developed non-sustained ventricular tachycardia. In group B, two patients (4%) had non-sustained ventricular tachycardia (VT), four (7%) had paroxysmal supraventricular tachycardias, and two (4%) severe symptomatic hypotension. Among the 20 patients with evidence of ischemia on DSE, three developed adverse side effects (no difference compared with patients without ischemia; p = 0.922). Fourteen patients received atropine during DSE, and 1 of these developed non-sustained VT after atropine administration. CONCLUSION: Serious cardiac arrhythmias occur frequently during both low-dose and high-dose DSE in patients with AS. Adverse side effects do not relate to stress-induced ischemia or atropine addition.     

Bilateral aberrant origin of the inferior thyroid artery from the common carotid artery

The thyroid gland is mainly supplied by the superior and inferior thyroid arteries, with the latter being its principal arterial supply in adults. The inferior thyroid artery usually arises from the thyrocervical trunk, and less frequently from the subclavian artery. Rarely, it may originate from the vertebral artery or the common carotid artery. In the present report, we describe a unique case of a 56-year-old patient, undergoing total thyroidectomy and level VI lymph node dissection for papillary thyroid carcinoma, with aberrant origin of both inferior thyroid arteries from the common carotid arteries.     

From the Cover: Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function

cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN channel CNBD.Hyperpolarization-activated cyclic nucleotide-gated (HCN1–4) channels are the molecular determinants of the h-current (I_h), which regulates critical neuronal properties, including membrane resting potential, dendritic excitability, and intrinsic rhythmicity (1). HCN channels are dually regulated by voltage and by binding of cAMP to the cyclic nucleotide binding domain (CNBD), which is found on the cytoplasmic C-terminal tail of the channel. The CNBD exerts a tonic inhibition on the channel pore, with the opening transition of the channel being allosterically coupled to the conformational changes in the CNBD induced by cAMP binding (2). Thus, the closed-to-open transition of the channel is thought to reflect the transition from the cAMP-free conformation to the cAMP-bound conformation of the CNBD, which stabilize, respectively, the closed and open states of the channel (2, 3). The C-linker, an α-helical folded domain that connects the CNBD to the pore region, conveys the regulation of channel gating from the CNBD to the pore (4–6). As a result of this allosteric mechanism, the binding of cAMP shifts the voltage dependence of the HCN channel opening to more positive potentials and increases maximal I_h at extreme negative voltages, where voltage gating is complete.In addition to cAMP, HCN channels in the brain are regulated by auxiliary proteins, such as TRIP8b, a cytosolic β-subunit of neuronal HCN channels, which inhibits channel activation by antagonizing the effects of cAMP (7–9). We have previously shown that TRIP8b_core, an 80-aa sequence located in the TRIP8b protein core that directly interacts with the C-linker/CNBD region of HCN channels, is necessary and sufficient to prevent all of the effects of cAMP on the channel (10, 11). TRIP8b_core decreases both the sensitivity of the channel to cAMP [half maximal concentration (k_1/2)] and the efficacy of cAMP in inducing channel opening [half activation voltage (V_1/2)]; conversely, cAMP binding inhibits these actions of TRIP8b. These mutually antagonistic effects are well described by a cyclic allosteric model in which TRIP8b binding reduces the affinity of the channel for cAMP, with the affinity of the open state for cAMP being reduced to a greater extent than the cAMP affinity of the closed state (11).A second important action of TRIP8b is to reduce maximal current through HCN channels in the absence of cAMP (11). As a consequence, application of cAMP produces a larger increase in maximal I_h in the presence of TRIP8b than in its absence. The observation that TRIP8b exerts opposing influences on the two major actions of cAMP on HCN channel function, namely, reduces the effect of cAMP to shift the voltage dependence of channel gating but enhances the effect of cAMP to increase maximal current, has important implications for the ability of cAMP to modulate neuronal excitability in vivo. Thus, the relative extent by which neuromodulatory transmitters alter maximal I_h or shift the voltage dependence of HCN channel gating can vary widely among distinct classes of neurons (12–14). The differential expression of TRIP8b may provide a mechanistic explanation for this finding, because in neurons with high levels of TRIP8b expression, cAMP will exert a larger action to enhance maximal current, and a smaller action to alter the voltage dependence of channel gating, compared with neurons in which TRIP8b expression is low. Such fine-tuning broadens the range of physiological actions that cAMP can exert to modulate neuronal firing.In the present study, we address the structural basis for the mutually antagonistic effects of cAMP and TRIP8b on HCN channel function. Although our previous biochemical and electrophysiological data strongly support the hypothesis that TRIP8b and cAMP binding sites do not overlap, direct structural information on the TRIP8b–CNBD complex is required to validate the allosteric antagonism model of interaction between the two ligands. A plausible hypothesis for the antagonistic effect of TRIP8b and cAMP is that each of the two ligands stabilizes the CNBD in a conformation that decreases the affinity for the other. To test this hypothesis, we first generated the 3D structure of the cAMP-free HCN2 channel CNBD using solution NMR spectroscopy and then characterized its interaction with the TRIP8b_core fragment. By comparing the cAMP-free with the available cAMP-bound HCN2 channel CNBD structure (15, 16), we reconstruct the full conformational changes induced by cAMP binding, revealing critical transitions occurring in the P- and C-helices of the CNBD, and further highlighting the role of the N-terminal helical bundle in transducing the movements of the CNBD to the channel pore. We next identify, through NMR titration, site-directed mutagenesis, and biochemical interaction assays, the binding site of TRIP8b_core on the cAMP-free form of the HCN2 channel CNBD. Our results demonstrate that cAMP and TRIP8b do not directly compete for the same binding region and support a model of mutual allosteric inhibition between cAMP and TRIP8b. Finally, our results clarify the mechanism by which TRIP8b antagonizes the effect of cAMP on channel gating: TRIP8b directly interacts with two mobile elements that drive the ligand-induced conformational changes in the CNBD. TRIP8b binding to the CNBD therefore prevents the cAMP-induced transition and stabilizes the channel in the cAMP-free conformation.     

A search for β thalassemia mutations in 4000 year old ancient DNAs of Minoan Cretans

Ancient DNA methodologies can be applied in the investigation of the genetics of extinct populations. A search for beta thalassemia mutations was performed on 49 Minoan individuals from the Bronze Age who were living in the island of Crete approximately 4000 Years Before Present (YBP). Standard precautionary measures were employed in the laboratory to ensure authenticity of the DNA extracted from the ancient bones, resulting in the successful analysis of DNA of 24 Minoans. DNA sequencing focused on the Intervening Sequence 1 (IVS-1) of the beta globin gene and its splicing junctions. 63% of the thalassemia mutations observed among modern Cretans reside in beta IVS-1. None of the Minoan individuals carried one of the IVS-1 mutations known to cause beta thalassemia; however, only one was expected to be observed if the average frequency of beta thalassemia heterozygotes in the Minoan population was the same with that of modern day Cretans (7.6%). One individual contained a C to G substitution in position 91 of the IVS-1, located 40 bp 5' to the intron 1/exon 2 junction. Functional studies indicated that the mutation did not affect mRNA splicing or stability, and most likely represented an innocent single nucleotide polymorphism.     

Exposure to second-hand smoke and reproductive outcomes depending on maternal asthma

Tobacco consumption and exposure to second-hand smoke (SHS) are associated with reduced birth weight. One issue that has not been clarified previously is that of the potential higher risk of this outcome in mothers with asthma. We assessed the role of prenatal maternal tobacco use and SHS on reproductive outcomes and assessed the interaction with maternal history of asthma. Data was collected from the INMA study, a maternal birth cohort selected from the general population established in Spain in 2002. We measured cotinine at the 32nd week of pregnancy in 2,219 females. Diagnosed maternal asthma was self-reported during pregnancy. 35% of mothers reported not being exposed to smoking or SHS during pregnancy. Active smoking (i.e. self-reported or cotinine >50 ng·mL(-1)) was related to a 134 g decrease in birth weight and a relative risk of 1.8 for small for gestational age and fetal growth restriction. These results were not modified by maternal asthma. Maternal asthma had a similar frequency in all exposure groups. Non SHS-exposed females had the lowest prevalence of asthma. SHS (i.e. cotinine 20-50 ng·mL(-1)) decreased birth weight by 32 g among those without maternal asthma, but these differences were not statistically significant (95% CI -88.76-24.76). Maternal asthma did not promote these effects. Maternal history of asthma did not modify the effects of smoking on reproductive outcomes in a cohort sampled from the general population.     

Tarlov cysts: long-term follow-up after microsurgical inverted plication and sacroplasty

Purpose

Surgical treatment of Tarlov cysts is still a matter of debate. Published literature thus far includes mainly small case series with retrospective evaluation and short-term follow-up. We present a novel microsurgical technique that combines the decompression of the nerve fibers with the prevention of recurrence. The long-term follow-up is provided.

Methods

The indication for surgery was incapacitating pain refractory to medical therapy for at least 6 months. The surgical technique consisted in microsurgical opening of the cyst, relief of CSF followed by secured inverted plication of the cyst wall, packing of remnant space with fat graft, and sacroplasty. Pain and neurological deficits were evaluated according to a modified Barrow National Institute score (BNI score, 0–5) and the Departmental Neuro Score (DNS score, 0–20).

Results

A total of 13 patients (9 women, 4 men) were operated and followed up to 14 years (mean FU 5.3 years). Mean age at surgery was 51.8 (±14) years. Pain and neurological deficits improved significantly in 11/13 patients (BNI score pre-OP 5 vs 3.1 ± 1.2 at 1-year-FU, and 2.8 ± 1.2 at last follow-up visit; DNS score pre-OP 5.5 ± 1.5 vs 2.8 ± 2.1 at 1-year follow-up, and 2.6 ± 2.2 at last follow-up visit. Two patients needed revision surgery due to reoccurrence of the cyst. One patient suffered deterioration of preexisting neurological deficit.

Conclusions

The inverted plication technique combined with sacroplasty is a promising technique. It improves pain and neurological deficits on the long term in the majority of patients with symptomatic Tarlov cysts.

     

Cardiovascular safety of oncologic agents: A double-edged sword even in the era of targeted therapies – part 1

Introduction: Patients with cancer are subject to the cardiotoxic effects of cancer therapy and as more patients survive cancer due to improved treatment they are exposed to various forms of cardiovascular (CV) disease as they age, and vice-versa. Such an interplay of age with both malignancy and CV disease may contribute to increased morbidity and mortality.

Areas covered: This two-part review considers the effects of cancer drug treatment on the CV system. In Part I, the various types of CV and cardiometabolic toxicity of anti-cancer drugs and the possible mechanisms involved are discussed. Also, among the specific oncologic agents, the CV effects of the classical agents and of the large molecule immunological agents (monoclonal antibodies, including immune checkpoint inhibitors) are detailed.

Expert opinion: Oncologic agents produce a variety of CV adverse effects, including cardiomyopathy and heart failure, peri-myocarditis, coronary artery disease, peripheral vascular disease, hypertension (HTN), cardiac arrhythmias, valvular heart disease, and pulmonary HTN. Both the oncologist and the cardiologist need to be aware of such adverse effects and of the specific agents that produce them. They need to join forces to prevent, anticipate, recognize, and manage such complications.     

Cardiovascular safety of oncologic agents: a double-edged sword even in the era of targeted therapies – Part 2

Introduction: Patients with cancer are subject to the cardiotoxic effects of cancer therapy. Improved cancer treatments lead to more cancer-survivors, who though are exposed to various forms of cardiovascular (CV) disease (CVD) as they age. Aging patients are at increased risk of developing both malignancy and CVD or they may have survived some form of CVD as a result of effective CV treatments. Furthermore, patients with CVD may develop cancer and require treatment (and vice versa), all contributing to increased morbidity and mortality. The prevalence of both malignancy and CVD will increase due to the trend toward a longer lifespan.

Areas covered: In part 2 of this review, the discussion of the CV effects of specific oncology drugs is completed with inclusion of additional immunological agents, current hormonal and other agents. Early detection and monitoring of cardiotoxicity, use of biomarkers and other imaging and diagnostic methods and prevention and treatment options are also discussed.

Expert opinion: As outlined in part 1 of this review, oncologists need to be aware of the CV adverse-effects of their treatments and make careful and expectant clinical decisions, especially in patients with preexisting CVD or CV risk factors. Similarly, cardiologists should consider a detailed previous history of treatment for malignant disease, including prior chemotherapy exposure, dose(s) received, and/or combined modality therapy with chest radiotherapy. Both specialists should collaborate in order to minimize the impact of these two ubiquitous diseases (cancer and CVD) and mitigate the adverse effects of treatment modalities.     

End-inspiratory occlusion maneuver during transesophageal echocardiography for patent foramen ovale detection in intensive care unit patients

Objective Mechanically ventilated patients in the intensive care unit cannot cooperate to perform the Valsalva maneuver during echocardiography for detection of patent foramen ovale. We evaluated the effectiveness of the end-inspiratory occlusion maneuver to enhance detection of patent foramen ovale in this patient population. Design Prospective interventional study. Setting The 40-bed intensive care unit of a university hospital. Patients and participants Twenty five sedated and mechanically ventilated intensive care unit patients referred by their attending physician for bedside transesophageal echocardiography and agitated saline contrast study for detection of patent foramen ovale. Intervention Agitated saline contrast study with end-inspiratory occlusion maneuver. Measurements and results All patients underwent a complete transesophageal echocardiographic study without any complications. Reduction in right atrial cross-sectional area (from 15.80 ± 6.08 cm² to 12.40 ± 4.63 cm²; p < 0.001) and interatrial septum deviation during the maneuver were recorded in all patients. Microbubbles imaged in the left atrium within three cardiac cycles after injection of agitated saline diagnosed patent foramen ovale in three patients. When end-inspiratory occlusion maneuver was added, patent foramen ovale was diagnosed in seven patients (McNemar χ² = 9.33, p = 0.0023). Conclusions The end-inspiratory occlusion maneuver enhances the sensitivity of transesophageal echocardiography with agitated saline contrast study for diagnosing intermittent patent foramen ovale in critically ill mechanically ventilated patients. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.