Hypertrophic Cardiomyopathy.

PURPOSE OF REVIEW: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac condition with potential for severe complications including sudden cardiac death. Early diagnosis allows appropriate risk stratification and prompt intervention to minimise the potential for adverse outcomes. The implications of poorly coordinated screening are significant, either missing relatives at high-risk or burdening low-risk individuals with a diagnosis associated with reduced life expectancy. We aim to guide clinicians through the diagnostic pathway through to novel treatment options. Several conditions mimic the condition, and we discuss the phenocopies and how to differentiate from HCM. RECENT FINDINGS: We summarise the latest developments informing clinical decision making in the modern era of myosin inhibitors and future gene editing therapies. Early identification will enable prompt referral to specialist centres. A diagnostic flowchart is included, to guide the general cardiology and heart failure clinician in important decision making regarding the care of the HCM patient and importantly their relatives at risk. We have highlighted the importance of screening because genotype-positive/phenotype-negative patients are likely to have the most to gain from novel therapies.

Impact of the cough stimulation system on the care burden and life quality of caregivers of tetraplegics.

OBJECTIVES: To determine caregiver burden and quality of life of primary family caregivers of participants with cervical SCI before and after use of the cough stimulation system (CSS). DESIGN: Prospective assessment at four timepoints via questionnaire responses. SETTING: Out-patient hospital, United States. PARTICIPANTS: 15 primary family caregivers of participants with cervical SCI completed questionnaires including a respiratory care burden index (n = 15) and a commonly employed caregiver burden inventory (n = 9), before and at the 6-month, 1-year and 2-year timepoints following use of the CSS. RESULTS: SCI participants had significant clinical improvements in terms of restoration of an effective cough and ability to manage airway secretions with use of the CSS. Restoration of expiratory muscle function with use of the CSS also resulted in less caregivers (CG) stress, greater control of their participants' breathing problems, and improvement in quality of life. Results of the caregiver burden inventory demonstrated marked reductions in caregiver burden in development items, physical health and social relationship. Overall caregiver burden fell from 43.4 ± 13.8 pre-implant to 32.4 ± 7.9 (P = 0.06), 31.7 ± 10.5 (P = 0.05), and 26.5 ± 9.3 (P = 0.01) at the 6-month, 1-year and 2-year timepoints. CONCLUSION: Use of the CSS by cervical SCI participants results in restoration of an effective cough with significant clinical benefits. While caregiver burden is very high in primary family caregivers, they derive marked improvement in caregiver burden and quality of life with implementation of this device.Trial registration: ClinicalTrials.gov identifier: NCT00116337.Trial registration: ClinicalTrials.gov identifier: NCT01659541.

Sequencing of medical therapy in heart failure with a reduced ejection fraction.

The management of heart failure with a reduced ejection fraction is a true success story of modern medicine. Evidence from randomised clinical trials provides the basis for an extensive catalogue of disease-modifying drug treatments that improve both symptoms and survival. These treatments have undergone rigorous scrutiny by licensing and guideline development bodies to make them eligible for clinical use. With an increasing number of drug therapies however, it has become a complex management challenge to ensure patients receive these treatments in a timely fashion and at recommended doses. The tragedy is that, for a condition with many life-prolonging drug therapies, there remains a potentially avoidable mortality risk associated with delayed treatment. Heart failure therapeutic agents have conventionally been administered to patients in the chronological order they were tested in clinical trials, in line with the aggregate benefit observed when added to existing background treatment. We review the evidence for simultaneous expedited initiation of these disease-modifying drug therapies and how these strategies may focus the heart failure clinician on a time-defined smart goal of drug titration, while catering for patient individuality. We highlight the need for adequate staffing levels, especially heart failure nurse specialists and pharmacists, in a structure to provide the capacity to deliver this care. Finally, we propose a heart failure clinic titration schedule and novel practical treatment score which, if applied at each heart failure patient contact, could tackle treatment inertia by a constant assessment of attainment of optimal medical therapy.

Effects of restoration of cough via spinal cord stimulation on subject quality of life.

Objectives: To determine participant quality of life before and after use of the cough stimulation system (Cough System). Design: Prospective assessment of life quality at 4 timepoints via questionnaire responses. Setting: Out-patient hospital, United States. Participants: 28 subjects with spinal cord injury (SCI) completed life quality assessment questionnaires before and at the 28- 40- and 52-week timepoints following use of the Cough System. Results: Each subject demonstrated significant clinical improvements in terms of restoration of an effective cough and ability to manage airway secretions with use of the Cough System. Positive airway pressures and peak expiratory airflows approached values associated with a normal cough. Related to cough/secretion management, use of this system also resulted less interference with family life and daily activities, less financial difficulties, less requirement for caregiver assistance, less stress, less embarrassment and greater control of their breathing problems (p < 0.01), for each comparison). There also significant improvements in that their overall health and quality of life (p < 0.01, for each comparison). Subjects also reported greater ease in breathing, restored ability to sneeze and enhanced mobility. The incidence of acute respiratory tract infections fell from 1.3 ± 0.3 to 0.2 ± 0.1 events/subject year (p < 0.01). Ten subjects developed mild hemodynamic effects consistent with autonomic dysreflexia that abated completely with continued use of the Cough System. Some subjects experienced mild leg jerks during SCS, which were well tolerated and abated completely with reduction in stimulus amplitude, No subjects reported bowel or bladder leakage. Conclusion: Use of the Cough System by SCI subjects is a safe and efficacious method which significantly improves life quality and has the potential to reduce the mortality and morbidity associated with SCI.

Phrenic-to-intercostal reflex activity in response to high frequency spinal cord stimulation (HF-SCS).

OBJECTIVE: HF-SCS is a novel technique of inspiratory muscle activation which results in coincident activation of the diaphragm and inspiratory intercostal muscles via spinal cord pathways and has the potential to provide respiratory support in ventilator dependent persons with spinal cord injury. The purpose of the present study was to examine the phrenic-to-intercostal reflex during HF-SCS. METHODS: In 5 anesthetized and C2 spinalized dogs, electrical stimulation was applied via a stimulating electrode located on the ventral surface of the upper thoracic spinal cord at the T2 level. Fine wire recording electrodes were used to assess single motor unit (SMU) activity of the left and right external intercostal muscles (EI) in the 3rd interspace before and after sequential left and right phrenicotomy. RESULTS: Mean control peak firing frequency of the right EI and left EI was 11.4 ± 0.3 Hz and 10.6 ± 0.3 Hz respectively. Following unilateral right phrenic nerve section, mean SMU peak firing frequency of right EI (ipsilateral to the section) was significantly greater when compared to control (15.9 ± 0.5 Hz vs 11.4 ± 0.3 Hz; p = 0.01). Mean SMU peak firing frequency of the contralateral left EI remained unchanged (10.2 ± 0.3 Hz vs 10.6 ± 0.3 Hz, p = 0.40). Subsequent, section of the left phrenic nerve resulted in significantly higher mean SMU peak firing frequency of the left EI (16.2 ± 0.5 Hz vs 10.2 ± 0.3 Hz) when compared to before section p = 0.01). Contralateral, right EI peak firing frequency was not different if compared to before left phrenic nerve section (16.9 ± 0.4 Hz vs. 15.9 ± 0.5 Hz; p = 0.14). CONCLUSION: This study demonstrates that during HF-SCS: 1) unilateral diaphragmatic afferents reflexly inhibit motor activity to the ipsilateral EI muscles, 2) the neural circuitry mediating the phrenic-to-intercostal reflex is preserved at a spinal level and does not require supraspinal input and 3) unilateral compensatory increases were observed in EI muscle activation following ipsilateral diaphragm paralysis.

Model-Based Optimization of Spinal Cord Stimulation for Inspiratory Muscle Activation.

OBJECTIVE: High-frequency spinal cord stimulation (HF-SCS) is a potential method to provide natural and effective inspiratory muscle pacing in patients with ventilator-dependent spinal cord injuries. Experimental data have demonstrated that HF-SCS elicits physiological activation of the diaphragm and inspiratory intercostal muscles via spinal cord pathways. However, the activation thresholds, extent of activation, and optimal electrode configurations (i.e., lead separation, contact spacing, and contact length) to activate these neural elements remain unknown. Therefore, the goal of this study was to use a computational modeling approach to investigate the direct effects of HF-SCS on the spinal cord and to optimize electrode design and stimulation parameters. MATERIALS AND METHODS: We developed a computer model of HF-SCS that consisted of two main components: 1) finite element models of the electric field generated during HF-SCS, and 2) multicompartment cable models of axons and motoneurons within the spinal cord. We systematically evaluated the neural recruitment during HF-SCS for several unique electrode designs and stimulation configurations to optimize activation of these neural elements. We then evaluated our predictions by testing two of these lead designs with in vivo canine experiments. RESULTS: Our model results suggested that within physiological stimulation amplitudes, HF-SCS activates both axons in the ventrolateral funiculi (VLF) and inspiratory intercostal motoneurons. We used our model to predict a lead design to maximize HF-SCS activation of these neural targets. We evaluated this lead design via in vivo experiments, and our computational model predictions demonstrated excellent agreement with our experimental testing. CONCLUSIONS: Our computational modeling and experimental results support the potential advantages of a lead design with longer contacts and larger edge-to-edge contact spacing to maximize inspiratory muscle activation during HF-SCS at the T2 spinal level. While these results need to be further validated in future studies, we believe that the results of this study will help improve the efficacy of HF-SCS technologies for inspiratory muscle pacing.

Comparison of disc and wire electrodes to restore cough via lower thoracic spinal cord stimulation.

OBJECTIVE: To compare the safety and effectiveness of wire (WE) vs. disc (DE) electrodes to restore cough in subjects with spinal cord injury (SCI). DESIGN: Clinical trials assessing the effectiveness and clinical outcomes associated with two electrode systems to activate the expiratory muscles. SETTING: Inpatient hospital setting for DE or WE electrode insertion; outpatient evaluation of cough efficacy and instructions for home use. PARTICIPANTS: Twenty-nine subjects with SCI; 17 participants with DE and 12 with WE implants. INTERVENTION: Surgical implantation of WE or DE to restore cough. Daily application of spinal cord stimulation (SCS) at home. MAIN OUTCOME MEASURE(S): Airway pressure (P) and peak airflow (F) generation achieved with SCS; clinical parameters including ease in raising secretions, incidence of acute respiratory tract infections (RTI) and side effects. RESULTS: P and F achieved with DE and WE were not significantly different. For example, at total lung capacity (TLC) with participant effort, P was 128 ± 12 cmH2O and 118 ± 14 cmH2O, with DE and WE, respectively. The degree of difficulty in raising secretions improved markedly in both groups. The incidence of RTI per year fell from 1.3 ± 0.3 and 1.3 ± 0.5-0.3 ± 0.1 and 0.1 ± 0.1 for DE and WE groups, respectively (P < 0.01 for both when compared to pre-implant values and NS between DE and WE groups). The only significant side effect i.e. short-term autonomic dysreflexia was also similar between groups. CONCLUSIONS: The results of this investigation indicate that both DE and WE result in comparable degrees of expiratory muscle activation, clinical benefits and side effects. Importantly, SCS to restore cough can be achieved with use of WE which can be placed using minimally invasive techniques and associated reduction in cost, surgical time and overall risk.Trial registration: ClinicalTrials.gov identifier: NCT00116337., NCT01659541, FDA IDE: G980267.

Comparison of wire and disc electrodes to electrically activate the inspiratory muscles in dogs.

OBJECTIVE: To compare the effectiveness of wire versus disc electrodes to activate the inspiratory muscles via high frequency spinal cord stimulation. DESIGN: Animal study. SETTING: Research laboratory. ANIMALS: Dogs (n = 5) INTERVENTIONS: In separate trials, spinal cord stimulation (SCS) was applied via disc (DE) and two parallel wire electrodes (WE) on the ventral epidural space at the T2-T3 spinal region. MAIN OUTCOME MEASURE(S): Airway pressure (P) and inspired volume (V) generation following stimulation with DE and WE were compared. Given our previous success with (DE), outcome variables with this electrode were used as our gold standard to which all comparisons were made. RESULTS: Two configurations of WE using monopolar stimulation (MS) resulted in P and V that were similar to those generated with MS with DE. For example, MS with parallel WE connected together to function as a common cathode (Y-connection) and a 2-channel system (separate cathodes with a remote ground), resulted in P that were 91 ±â€¯6 and 92 ±â€¯4%, respectively, of those achieved with DE (NS for both). Bipolar stimulation with parallel WE using a Y-connection and with a 2-channel system, resulted in P that were 96 ±â€¯4 and 94 ±â€¯4%, of the P achieved with DE (NS for both). CONCLUSION(S): These results suggest that specific configurations of WE, which can be placed via minimally invasive techniques, provide comparable activation of the inspiratory muscles compared to DE and may be a useful technique to restore ventilatory support in persons with spinal cord injury.

Effects of Lower Thoracic Spinal Cord Stimulation on Bowel Management in Individuals With Spinal Cord Injury.

OBJECTIVE: To systematically determine whether use of the spinal cord stimulation (SCS) system to restore cough may improve bowel management (BM) in individuals with spinal cord injury (SCI). DESIGN: Experimental studies (clinical trial). SETTING: Inpatient hospital setting for electrode insertion; outpatient setting for measurement of respiratory pressures; home setting for application of SCS. PARTICIPANTS: Participants (N=5) with cervical SCI. INTERVENTION: A fully implantable SCS cough system was surgically placed in each subject. SCS was applied at home, 2-3 times/d, on a chronic basis, every time bowel regimen was performed and as needed for secretion management. Stimulus parameters were set at values resulting in near maximum airway pressure generation, which was used as an index of expiratory muscle strength. Participants also used SCS during their bowel routine. MAIN OUTCOME MEASURES: Airway pressure generation achieved with SCS. Weekly completion of Bowel Routine Log including BM time, mechanical measures, and medications used. RESULTS: Mean pressure during spontaneous efforts was 30±8 cmH2O. After a period of reconditioning, SCS resulted in pressure of 146±21 cmH2O. The time required for BM routines was reduced from 118±34 minutes to 18±2 minutes (P<.05) and was directly related to the magnitude of pressure development during SCS. Mechanical methods for BM were completely eliminated in 4 patients. No patients experienced fecal incontinence as result of SCS. Each participant also reported marked overall improvement associated with BM. CONCLUSIONS: Our results of this pilot study suggest that SCS to restore cough may be a useful method to improve BM and life quality for both patients with SCI and their caregivers. Our results indicate that the improvement in BM is secondary to restoration of intra-abdominal pressure development.

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

Activation of the expiratory muscles via lower thoracic high frequency spinal cord stimulation in awake animals.

Lower thoracic spinal cord stimulation is an effective method of restoring an effective cough in participants with complete spinal cord injury. The high voltage requirements however significantly limits this application in subjects with intact lower chest wall sensation. In anesthetized animals, we have shown that the expiratory muscles can also be effectively activated with low stimulus currents (1 mA) but with high stimulus frequencies (HF-SCS -500 Hz). In 3 intact, awake pigs the responses to HF-SCS, were evaluated. HF-SCS was associated with marked expansion of the abdominal wall and external oblique EMG activity without any associated changes in heart rate or vocalization. During a terminal procedure under general anesthesia, responses to HF-SCS were re-assessed. Abdominal movement and EMG were similar to that observed in the awake state. HF-SCS (1.5 mA) resulted in an airway pressure of 65 ± 2cmH2O. Our results indicate that lower thoracic HF-SCS may be a useful method to restore an effective cough in patients with intact chest wall sensation.

Initial assessment and management of respiratory infections in persons with spinal cord injuries and disorders in the COVID-19 era.

As the COVID-19 pandemic unfolds, emergency department (ED) personnel will face a higher caseload, including those with special medical needs such as persons living with spinal cord injuries and disorders (SCI/D). Individuals with SCI/D who develop COVID-19 are at higher risk for rapid decompensation and development of acute respiratory failure during respiratory infections due to the combination of chronic respiratory muscle paralysis and autonomic dysregulation causing neurogenic restrictive/obstructive lung disease and chronic immune dysfunction. Often, acute respiratory infections will lead to significant mucus production in individuals with SCI/D, and aggressive secretion management is an important component of successful medical treatment. Secretion management techniques include nebulized bronchodilators, chest percussion/drainage techniques, manually assisted coughing techniques, nasotracheal suctioning, and mechanical insufflation-exsufflation. ED professionals, including respiratory therapists, should be familiar with the significant comorbidities associated with SCI/D and the customized secretion management procedures and techniques required for optimal medical management and prevention of respiratory failure. Importantly, protocols should also be implemented to minimize potential COVID-19 spread during aerosol-generating procedures.

Restoration of cough via spinal cord stimulation improves pulmonary function in tetraplegics.

Background: Spinal cord injury (SCI) results in significant loss in pulmonary function secondary to respiratory muscle paralysis. Retention of secretions and atelectasis and, recurrent respiratory tract infections may also impact pulmonary function. Objective: To determine whether usage of lower thoracic spinal cord stimulation (SCS) to restore cough may improve spontaneous pulmonary function in individuals with chronic SCI. Design/Methods: 10 tetraplegics utilized SCS system on a regular daily basis. Spontaneous inspiratory capacity (IC), maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) were measured at baseline prior to usage of the device and repeated every 4-5 weeks over a 20-week period. Maximum airway pressure generation (P) during SCS (40 V, 50 Hz, 0.2 ms) at total lung capacity (TLC) with subject maximal expiratory effort, at the same timepoints were determined, as well. Results: Following daily use of SCS, mean IC improved from 1636 ± 229 to 1932 ± 239 ml (127 ± 8% of baseline values) after 20 weeks (P < 0.05). Mean MIP increased from 40 ± 7, to 50 ± 8 cmH2O (127 ± 6% of baseline values) after 20 weeks, respectively (P < 0.05). MEP also improved from 27 ± 3.7 to 33 ± 5 (127 ± 14% of baseline values) (NS). During SCS, P increased from baseline in all participants from mean 87 ± 8 cmH2O to 117 ± 14 cmH2O at weeks 20, during TLC with subject maximal expiratory effort, respectively (P < 0.05). Each subject stated that they experienced much greater ease in raising secretions with use of SCS. Conclusion: Our findings indicate that use of SCS not only improves expiratory muscle function to restore cough but also results in improvement inspiratory function, as well.

High-frequency spinal cord stimulation in a subacute animal model of spinal cord injury.

High-frequency spinal cord stimulation (HF-SCS) applied at the T2 spinal level results in physiologic activation of the inspiratory muscles in C2 spinal-sectioned dogs. Although the bulbo-spinal fibers were cut, they likely survived the duration of acute experiments, and inspiratory muscle activation may have involved stimulation of these fibers. In two anesthetized, C2 paralyzed, intubated, and mechanically ventilated dogs, HF-SCS (300 Hz) was applied at the T2 level. The effectiveness of HF-SCS in generating inspired volume (V) and negative airway pressures (P) was evaluated over a period of 5 days during which time the bulbo-spinal fibers would have degenerated. Because the effectiveness of HF-SCS may be adversely affected by deterioration of these fibers and/or the condition of the animal, low-frequency (50 Hz) SCS (LF-SCS) was also performed and served as a control. All vital signs, oxygen saturation, and end-tidal Pco2 remained stable over the 5-day period. V and P also remained stable over the study period. For example, mean V and P were 771 ± 25 ml and 64 ± 1 cmH2O with HF-SCS (3 mA) during the initial and 674 ± 59 ml and 63 ± 5 cmH2O on the final day. Comparable values during LF-SCS (8 mA) were 467 ± 12 ml and 48 ± 1 cmH2O during the initial and 397 ± 20 ml and 42 ± 2 cmH2O on the final day. Because V and P in response to HF-SCS remained stable over a 5-day period following which the bulbo-spinal fibers would have degenerated, the mechanism of HF-SCS does not depend upon the viability of these tracts. HF-SCS therefore may be a useful method to restore ventilation in chronic ventilator dependent tetraplegics. NEW & NOTEWORTHY This study indicates that the respiratory responses to high-frequency spinal cord stimulation applied at the T2 level results in activation of the inspiratory motoneuron pools via interneuronal circuits and/or the inspiratory motoneurons directly and does not depend upon activation of long descending inspiratory bulbo-spinal fibers. This method therefore, may provide an alternative method to restore ventilation in ventilator dependent spinal cord injured patients.