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Open Access Publications from the University of California

Scholarly Works (10 results)

  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2021)
    Cover page: Cardiac Magnetic Resonance Imaging in Danon Disease CardiomyopathyCreative Commons 'BY-NC-ND' version 4.0 license
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)
    Targeting angiotensinogen (AGT) may provide a novel approach to more optimally inhibit the renin-angiotensin-aldosterone system pathway. Double-blind, placebo-controlled clinical trials were performed in subjects with hypertension as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with IONIS-AGT-LRx versus placebo up to 2 months. IONIS-AGT-LRx was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function. IONIS-AGT-LRx significantly reduced AGT levels compared with placebo in all 3 studies. Although not powered for this endpoint, trends were noted in blood pressure reduction. In conclusion, IONIS-AGT-LRx significantly reduces AGT with a favorable safety, tolerability, and on-target profile. (A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx; NCT04083222; A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure; NCT03714776; Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ionis AGT-LRx in Healthy Volunteers; NCT03101878).
      Cover page: Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx Results of Phase 1 and Phase 2 Studies
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2021)

      Rationale & objective

      Nearly half the patients with heart failure have chronic kidney disease. Implantation of a left ventricular assist device (LVAD) improves kidney function in some but not all patients, and lack of improvement is associated with worse outcomes. Preimplantation factors that predict change in kidney function after LVAD placement are not well described.

      Study design

      Single-center observational study.

      Setting & participants

      Consecutive patients undergoing LVAD implantation.

      Predictors

      48 diverse preimplantation variables including demographic, clinical, laboratory, hemodynamic, and echocardiographic variables.

      Outcomes

      The primary outcome was change in estimated glomerular filtration rate (eGFR) at 1 month after implantation. Secondary outcomes included eGFR changes at 3, 6, and 12 months.

      Analytic approach

      Univariable and multivariable linear regression.

      Results

      Among 131 patients, average age was 60 ± 13 years, 83% were men, 47% had pre-existing chronic kidney disease, and mean preimplantation eGFR was 57 ± 23 mL/min/1.73 m2. At 1-month following LVAD implantation, eGFR improved in 98 (75%) patients. Variables associated with 1-month increases in eGFR were younger age, absence of diabetes mellitus (DM), use of inotropes, lower implantation eGFR, and higher implantation serum urea nitrogen, alanine aminotransferase, bilirubin, and creatinine levels. In multivariable models, younger age (β = 7.14 mL/min/1.73 m2 per SD; 95% CI, 3.17-11.10), lower eGFR (β = 7.72 mL/min/1.73 m2 per SD; 95% CI, 3.10-12.34), and absence of DM (β = 10.36 mL/min/1.73 m2; 95% CI, 2.99-17.74) were each independently associated with 1-month improvement in eGFR. Only younger age and lower eGFR were associated with improvements in eGFR at later months.

      Limitations

      Single-center study. Loss to follow-up from heart transplantation and death over duration of study.

      Conclusions

      Only younger age, lower eGFR, and absence of DM were associated with improvement in eGFR at 1 month. Thus, prediction of eGFR change at 1 month and beyond is limited by using preimplantation variables.
        Cover page: Kidney Function Following Left Ventricular Assist Device Implantation: An Observational Cohort Study
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2020)

        Ventricular arrhythmias (VAs) are common in patients after left ventricular assist device (LVAD) implant and are associated with worse outcomes. However, the prevalence and impact of VA in patients with durable biventricular assist device (BIVAD) is unknown. We performed a retrospective cohort study of patients with BIVADs to evaluate the prevalence of VA and their clinical outcomes.

        Consecutive patients who received a BIVAD between June 2014 and July 2017 at our medical center were included. The prevalence of VA, defined as sustained ventricular tachycardia or fibrillation requiring defibrillation or ICD therapy, was compared between BIVAD patients and a propensity-matched population of patients with LVAD from our center. The occurrence of adverse clinical events was compared between BIVAD patients with and without VA.

        Of the 13 patients with BIVADs, 6 patients (46%) experienced clinically significant VA, similar to a propensity-matched LVAD population (38%, p = 1.00). There were no differences in baseline characteristics between the two cohorts, except patients in the non-VA group who had worse hemodynamics (mitral regurgitation and right-sided indices), had less history of VA, and were younger. BIVAD patients with VA had a higher incidence of major bleeding (MR 3.05 (1.07-8.66), p = 0.036) and worse composite outcomes (log-rank test, p = 0.046). The presence of VA was associated with worse outcomes in both LVAD and BIVAD groups.

        Ventricular arrhythmias are common in patients with BIVADs and are associated with worse outcomes. Future work should assess whether therapies such as ablation improve the outcome of BIVAD patients with VA.

          Cover page: Ventricular arrhythmias in patients with biventricular assist devices.
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2020)

          Ventricular arrhythmias (VAs) are common in patients after left ventricular assist device (LVAD) implant and are associated with worse outcomes. However, the prevalence and impact of VA in patients with durable biventricular assist device (BIVAD) is unknown. We performed a retrospective cohort study of patients with BIVADs to evaluate the prevalence of VA and their clinical outcomes.

          Consecutive patients who received a BIVAD between June 2014 and July 2017 at our medical center were included. The prevalence of VA, defined as sustained ventricular tachycardia or fibrillation requiring defibrillation or ICD therapy, was compared between BIVAD patients and a propensity-matched population of patients with LVAD from our center. The occurrence of adverse clinical events was compared between BIVAD patients with and without VA.

          Of the 13 patients with BIVADs, 6 patients (46%) experienced clinically significant VA, similar to a propensity-matched LVAD population (38%, p = 1.00). There were no differences in baseline characteristics between the two cohorts, except patients in the non-VA group who had worse hemodynamics (mitral regurgitation and right-sided indices), had less history of VA, and were younger. BIVAD patients with VA had a higher incidence of major bleeding (MR 3.05 (1.07-8.66), p = 0.036) and worse composite outcomes (log-rank test, p = 0.046). The presence of VA was associated with worse outcomes in both LVAD and BIVAD groups.

          Ventricular arrhythmias are common in patients with BIVADs and are associated with worse outcomes. Future work should assess whether therapies such as ablation improve the outcome of BIVAD patients with VA.

            Cover page: Ventricular arrhythmias in patients with biventricular assist devices.
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2020)
            PURPOSE: Ventricular arrhythmias (VAs) are common in patients after left ventricular assist device (LVAD) implant and are associated with worse outcomes. However, the prevalence and impact of VA in patients with durable biventricular assist device (BIVAD) is unknown. We performed a retrospective cohort study of patients with BIVADs to evaluate the prevalence of VA and their clinical outcomes. METHODS: Consecutive patients who received a BIVAD between June 2014 and July 2017 at our medical center were included. The prevalence of VA, defined as sustained ventricular tachycardia or fibrillation requiring defibrillation or ICD therapy, was compared between BIVAD patients and a propensity-matched population of patients with LVAD from our center. The occurrence of adverse clinical events was compared between BIVAD patients with and without VA. RESULTS: Of the 13 patients with BIVADs, 6 patients (46%) experienced clinically significant VA, similar to a propensity-matched LVAD population (38%, p = 1.00). There were no differences in baseline characteristics between the two cohorts, except patients in the non-VA group who had worse hemodynamics (mitral regurgitation and right-sided indices), had less history of VA, and were younger. BIVAD patients with VA had a higher incidence of major bleeding (MR 3.05 (1.07-8.66), p = 0.036) and worse composite outcomes (log-rank test, p = 0.046). The presence of VA was associated with worse outcomes in both LVAD and BIVAD groups. CONCLUSIONS: Ventricular arrhythmias are common in patients with BIVADs and are associated with worse outcomes. Future work should assess whether therapies such as ablation improve the outcome of BIVAD patients with VA.
              Cover page: Ventricular arrhythmias in patients with biventricular assist devices.
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2020)
              Left ventricular assist devices (LVADs) have dramatically improved short-term outcomes among patients with advanced heart failure. While neurohormonal blockade (NHB) is the cornerstone of treatment for patients with heart failure with reduced ejection fraction, its effect after LVAD placement has not been established. We reviewed medical records of 307 patients who underwent primary LVAD implantation from January 2006 to September 2015 at two institutions in the United States. Patients were followed for at least 2 years post-LVAD implantation or until explantation, heart transplantation, or death. Cox regression analysis stratifying on center was used to assess associations with mortality. Neurohormonal blockade use was treated as a time-dependent predictor. Stepwise selection indicated treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) (hazard ratio [HR] = 0.53 [0.30-0.95], p = 0.03), age at the time of implantation (HR = 1.28 [1.05-1.56] per decade, p = 0.02), length of stay postimplantation (HR = 1.16 [1.11-1.21] per week, p < 0.01) and INTERMACS profile of 1 or 2 (HR = 1.86 [1.17-2.97], p < 0.01) were independent predictors of mortality. In this large, retrospective study, treatment with ACEIs or ARBs was an independent factor associated with decreased mortality post-LVAD placement.
                Cover page: Benefits of Neurohormonal Therapy in Patients With Continuous-Flow Left Ventricular Assist Devices.
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2023)

                Background

                Angiotensinogen is the proximal precursor of the angiotensin peptide hormones of the renin-angiotensin-aldosterone system (RAAS). Clinical trials are ongoing targeting angiotensinogen for the treatment of hypertension and heart failure. The epidemiology of angiotensinogen is not well defined, particularly its relationship to ethnicity, sex, and blood pressure (BP)/hypertension.

                Objectives

                The authors sought to determine the relationship of circulating angiotensinogen levels to ethnicity, sex, BP, incident hypertension, and prevalent hypertension in a modern sex-balanced ethnically diverse cohort.

                Methods

                Plasma angiotensinogen levels were measured in 5,786 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). Linear, logistic, and Cox proportional hazards models were utilized to examine the associations of angiotensinogen with BP, prevalent hypertension, and incident hypertension, respectively.

                Results

                Angiotensinogen levels were significantly higher in females than males and differed across self-reported ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. Higher levels were associated with higher BP and odds of prevalent hypertension, after adjusting for other risk factors. Equivalent relative differences in angiotensinogen were associated with greater differences in BP in males vs females. In males not taking RAAS-blocking medications, a standard deviation increment in log-angiotensinogen was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49-3.80), while in females the same increment in angiotensinogen was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30-1.65).

                Conclusions

                Significant differences in angiotensinogen levels are present between sexes and ethnicities. A positive association is present between levels and prevalent hypertension and BP, which differs between sexes.
                  Cover page: Blood Levels of Angiotensinogen and Hypertension in the Multi-Ethnic Study&nbsp;of&nbsp;Atherosclerosis (MESA)
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2020)
                  Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.
                    Cover page: Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2021)

                    Introduction

                    AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients.

                    Methods/design

                    Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire.

                    Conclusion

                    NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN.

                    Trial registration

                    The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).
                      Cover page: Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
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