Cardiorenal Syndrome: An Evolutionary Appraisal.

A recent American Heart Association Scientific Statement and Presidential Advisory recognized a new syndrome, the cardiovascular-kidney-metabolic syndrome. This expands our understanding of what has been called cardiorenal syndrome by incorporating the pathophysiological interrelatedness of metabolic risk factors into the previous concept of cardiorenal syndrome. Importantly, perturbation of cardiac or renal physiology combines to produce significant detrimental outcomes. The cardiorenal syndrome is a significant part of the cardiovascular-kidney-metabolic syndrome and contributes to health care cost, disability, and mortality. It is a vexing malady that has generated considerable interest. To understand the syndrome evaluation of its teleological origins is important. In life's beginning, eukaryotes acquired exocytosis for excretion, formed tubular secretory systems for clearance, and a mesenchymal nucleic acid vasoform for nutritional distribution. Those structures progressed to cardiovascular and renal systems of evolving organisms, whose migration to rivers and land imposed complex, coordinated, homeostatic roles to maintain intravascular stability. Tissue mineralization of vertebrate endoskeleton added renal calcium balance regulation, which in kidney failure results in cardiovascular calcification. Insight into cardiorenal disease can be traced to ancient Egyptian and Chinese medicine, through the Scientific Revolution, and into current insights regarding human physiology and pathophysiology. The post-World War II epidemic of cardiovascular mortality generated considerable information on cardiovascular disease, which being higher in patients with kidney disease, drew increasing health concerns. The cardiorenal syndrome was formally introduced in this setting with a focus on ultrafiltration to manage volume overload. An evolutionary review of insight into cardiorenal syndrome will help us better understand the new cardiovascular-kidney-metabolic syndrome.

Bruegel's Landscape with the Fall of Icarus.

Ovid's Metamorphoses tells the story of Icarus - his tragic flight with man-made wings, the melting of the wax that bound them, and the ensuing fall to his death. This moment has been immortalized across the arts and through several mediums, but none are more notable than Bruegel's Landscape with the Fall of Icarus. Described as a "painter for poets," Bruegel's work served as inspiration for several writers, with this piece in particular providing the basis for ekphrastic poems by W.H. Auden and William Carlos Williams. Though each of these works has a different focus, the unifying theme is that human tragedy is too often placed on the periphery of notice. They are effective reminders to physicians and other healthcare providers about the human aspect of suffering and pain in medicine.

An Obesity-Centric Approach with and Without Anti-Obesity Medications Compared to the Usual-Care Approach to Management of Patients with Obesity and Type 2 Diabetes in an Employer Setting: A Pragmatic Randomized Controlled Trial (EMPOWER-T2D).

INTRODUCTION: This study aimed to compare weight loss and glycated hemoglobin (HbA1c)-reduction effects of two obesity-centric, weight-loss management approaches (with or without anti-obesity medication) versus usual glucose-centric care in patients with obesity and type 2 diabetes. METHODS: Single-center, randomized, open-label, 3-armed, parallel-group, pragmatic, noninferiority trial, July 2020 to August 2022. Adults enrolled in the Cleveland Clinic Employee Health Plan (body mass index [BMI] ≥ 30 kg/m2, type 2 diabetes diagnosis, HbA1c > 7.5%) were randomized to usual glucose-centric management ("Usual-Care" group) or one of two obesity-centric management strategies: participation in a weight management program plus anti-obesity medication ("WMP + AOM" group), or WMP participation without anti-obesity medication ("WMP-Only" group). Primary endpoints were changes in weight and HbA1c, baseline to month 12. RESULTS: Due to enrollment and retention challenges, largely related to COVID-19, only 74/300 planned participants were randomized and the study was terminated early. Participants were predominantly female (59%), median (interquartile range [IQR]) age 53.5 (47, 60) years, 68% white, with baseline median (IQR) BMI and HbA1c of 37.4 (34.2, 42.7) kg/m2 and 8.8% (7.9%, 10.4%), respectively. At month 12, mean (90% confidence interval [CI]) percentage weight change in the Usual-Care, WMP-Only, and WMP + AOM groups was - 4.5% (- 6.5%, - 2.5%), - 6.7% (- 8.7%, - 4.7%), and - 8.7% (- 10.7%, - 6.8%), respectively; mean (90% CI) HbA1c change was - 1.7% (- 2.1%, - 1.2%), - 2.2% (- 2.7%, - 1.8%), and - 2.2% (- 2.6%, - 1.7%), respectively. WMP + AOM was superior to Usual-Care for weight change (P = 0.02); both WMP + AOM and WMP-Only were noninferior (P ≤ 0.01) to Usual-Care for change in HbA1c. CONCLUSIONS: Including anti-obesity medication was associated with superior weight loss with noninferior HbA1c reductions, warranting further evaluation in larger study populations of obesity-focused approaches to type 2 diabetes management. Graphical abstract available for this article. TRIAL REGISTRATION: ClinicalTrials.gov NCT03799198.

When I Am Asked: Lisel Mueller's Beginning in Poetry.

Why does anyone write poetry? Lisel Mueller (1924-2020) was a poet, author, and translator with a long and much-decorated career. She and her family fled Nazi Germany in the 1930s and emigrated to the United States, where she would establish herself as a writer. The poem "When I Am Asked" describes the beginning of her journey into poetry, undertaken during a period of grief after the death of her mother. Her writing would come to include nine collections of poetry and myriad accolades, including the 1981 National Book Award and the 1997 Pulitzer Prize for Poetry. Though her ouvre is filled with evocative works, this piece stands out as particularly relevant to physicians and other writers who find solace by expressing themselves through the art of poetry.

Bulk Depolymerization of Methacrylate Polymers via Pendent Group Activation.

In this study, we present an efficient approach for the depolymerization of poly(methyl methacrylate) (PMMA) copolymers synthesized via conventional radical polymerization. By incorporating low mol % phthalimide ester-containing monomers during the polymerization process, colorless and transparent polymers closely resembling unfunctionalized PMMA are obtained, which can achieve >95% reversion to methyl methacrylate (MMA). Notably, our catalyst-free bulk depolymerization method exhibits exceptional efficiency, even for high-molecular-weight polymers, including ultrahigh-molecular-weight (106-107 g/mol) PMMA, where near-quantitative depolymerization is achieved. Moreover, this approach yields polymer byproducts of significantly lower molecular weight, distinguishing it from bulk depolymerization methods initiated from chain ends. Furthermore, we extend our investigation to polymethacrylate networks, demonstrating high extents of depolymerization. This innovative depolymerization strategy offers promising opportunities for the development of sustainable polymethacrylate materials, holding great potential for various applications in polymer science.

Selective Electrochemical Modification and Degradation of Polymers.

We demonstrate that electrochemical-induced decarboxylation enables reliable post-polymerization modification and degradation of polymers. Polymers containing N-(acryloxy)phthalimides were subjected to electrochemical decarboxylation under mild conditions, which led to the formation of transient alkyl radicals. By installing these redox-active units, we systematically modified the pendent groups and chain ends of polyacrylates. This approach enabled the production of poly(ethylene-co-methyl acrylate) and poly(propylene-co-methyl acrylate) copolymers, which are difficult to synthesize by direct polymerization. Spectroscopic and chromatographic techniques reveal these transformations are near-quantitative on several polymer systems. Electrochemical decarboxylation also enables the degradation of all-methacrylate poly(N-(methacryloxy)phthalimide-co-methyl methacrylate) copolymers with a degradation efficiency of >95 %. Chain cleavage is achieved through the decarboxylation of the N-hydroxyphthalimide ester and subsequent ß-scission of the backbone radical. Electrochemistry is thus shown to be a powerful tool in selective polymer transformations and controlled macromolecular degradation.

Truman Capote as a Poet.

Truman Capote (1924-1984) was a fascinating, entertaining, and much ballyhooed American character who came of age in the mid-Twentieth Century. Some would say he led a tragic life. Often described as a notable novelist, he was more generally a polymath dabbling in nonfiction between his parties. He also was a screenwriter, playwright, actor, and short-story writer. His literary classics include the novella Breakfast at Tiffany's (1958, movie 1961) and true crime nonfiction "novel" (as Capote described it) In Cold Blood (1965, movie 1967). These two efforts became his most famous. But what about his poetry? Was this one of his creative passions?

Up-Hill: An Allegory.

The Christina Rossetti poem "Up-Hill" (1862) is an exemplary poem of the Victorian era by one of the rare female poets of the time, including Emily Brontë, Elizabeth Browning, Katherine Tynan, and Alice Meynell. Rossetti, typical of the era and the Victorian genre, wrote allegories about faith and love. She came from a distinguished literary family. "Up-Hill" was one of her better-known works.

Old Ironsides.

Dr. Oliver Wendell Holmes Sr. was a 19th century elite physician, curmudgeon, essayist, and poet. His works were numerous, insightful, entertaining, and characteristic of the pre-Civil War, Civil War, and Gilded age eras. Many of his shorter poems are taught in high school as examples of late 19th century works, as they are relatively easy to memorize and understand. Holmes and the Fireside Poets (Emerson, Longfellow, and Lowell, among others) created works that, in their time, were read aloud by fathers and mothers to their family because the poems often centered around values, morals, and historic events. "Old Ironsides" is characteristic of the type of work for which the Fireside Poets became famous. It is an entertaining poem to read, study, and hear, particularly when linking it to the oldest ship in the world, still afloat and sailing around Boston Bay.

Constantly Bombarded with New Drugs: What's a Cardiologist to Do?

Every physician encounters a barrage of direct-to-consumer and direct-to-physician advertising and is faced with the daunting task of deciding which drugs to add to their clinical armamentarium and how and when to add them. The purpose of this Points to Remember is to present a commonsense approach to incorporating newer drugs, or perhaps new indications for older drugs, into our clinical practice. To illustrate these points, this article focuses on a single drug, empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor that has been highly marketed in lay and medical media and hence has been incorporated into professional society treatment guidelines.

How a New Understanding of Drug or Drug Class Pharmacology Often Drives Drug Development: A Conversation with Steven E. Nissen, MD.

This video interview features Steven Nissen, MD, telling his 2007 story of revealing that the number-1 diabetes drug, rosiglitazone, led to more cardiovascular events than placebo or a variety of competitors. The discovery resulted in new requirements for clinical trials to rule out harm. It focuses on how a new understanding of drug or drug class pharmacology often drives drug development, and includes a discussion of the approval process, which may bring a different result than was originally intended. View the video at https://youtu.be/aFtCfZyd54E.

The Noncompliant Patient.

This issue's Poet's Pen is an experiential work submitted by Captain Justin C. Cordova, MD, from the Department of Anesthesiology at Walter Reed National Military Medical Center in Bethesda, Maryland. The submission was a response to an invitation for our readers to submit poems for consideration of publication. Captain Cordova's work, "Against Medical Advice," is an engaging and provocative poem that focuses on a disturbing healthcare provider challenge-attempting to deliver "best care" to patients who, for countless reasons, choose a pathway we label as noncompliance or against medical advice.

Does Osler's Aequanimitas Inform Our Contemporary Pursuit of Stillness?

William Osler (1849-1919) was an academic physician who has been revered by many as an accomplished internist of his time. His contributions to the philosophy and practice of medicine foreground characteristics of a compassionate caregiver, including imperturbability and equanimity. This article defines these qualities, argues that Osler demonstrated both, and suggests how today's clinicians can apply these qualities to their own pursuits of stillness in their practices and relationships with patients.

Photoassisted Radical Depolymerization.

Controlled radical polymerization techniques enable the synthesis of polymers with predetermined molecular weights, narrow molecular weight distributions, and controlled architectures. Moreover, these polymerization approaches have been routinely shown to result in retained end-group functionality that can be reactivated to continue polymerization. However, reactivation of these end groups under conditions that instead promote depropagation is a viable route to initiate depolymerization and potentially enable closed-loop recycling from polymer to monomer. In this report, we investigate light as a trigger for thermal depolymerization of polymers prepared by reversible-addition-fragmentation chain-transfer (RAFT) polymerization. We study the role of irradiation wavelength by targeting the n → π* and π → π* electronic transitions of the thiocarbonylthio end-groups of RAFT-generated polymers to enhance depolymerization via terminal bond homolysis. Specifically, we explore depolymerization of polymers with trithiocarbonate, dithiocarbamate, and p-substituted dithiobenzoate end groups with the purpose of increasing depolymerization efficiency with light. As the wavelength decreases from the visible range to the UV range, the rate of depolymerization is dramatically increased. This method of photoassisted depolymerization allows up to 87% depolymerization efficiency within 1 h, results that may further the advancement of recyclable materials and life-cycle circularity.

Gertrude Stein: A Physician Who Wasn't to Be.

After a tumultuous time in the United States, including flunking out of medical school in 1901, Gertrude Stein, an iconic American author, art lover, and critic, moved to Paris in 1903 as an avant garde modernist who became a leading and legendary guru in the Parisian art and literature world.

Do Not Go Gentle Into That Good Night.

Do not go gentle into that good night,Old age should burn and rave at close of day;Rage, rage against the dying of the light. Though wise men at their end know dark is right,Because their works had forked no lightning theyDo not go gentle into that good night. Good men, the last wave by, crying how brightTheir frail deeds might have danced in a green bay,Rage, rage against the dying of the light. Wild men who caught and sang the sun in flight,And learn, too late, they grieved it on its way,Do not go gentle into that good night. Grave men, near death, who see with blinding sightBlind eyes could blaze like meteors and be gay,Rage, rage against the dying of the light. And you, my father, there on the sad height,Curse, bless, me now with your fierce tears, I pray.Do not go gentle into that good night.Rage, rage against the dying of the light. Dylan ThomasThe Poems of Dylan Thomas, New Directions Publishing 1971. This poem is in the public domain.

Postimplant Phosphodiesterase-5 Inhibitor Use in Centrifugal Flow Left Ventricular Assist Devices.

OBJECTIVES: This study examined the association between phosphodiesterase-5 inhibitor (PDE-5i) use and outcomes in patients with contemporary centrifugal flow left ventricular assist devices (LVADs). BACKGROUND: PDE-5i use may affect outcomes in patients with continuous flow LVADs. METHODS: Patients enrolled in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support), with HeartMate 3 (n = 4,628) or HeartWare Ventricular Assist Device (HVAD) (n = 2,601) implant were included in the analysis. The mean duration of follow-up was 11.94 ± 8.65 months. PDE-5is were used in 2,173 patients. The primary endpoint was the composite of all-cause mortality, ischemic stroke, and pump thrombosis. Propensity matching and stabilized inverse probability of treatment weights were used to adjust for baseline differences between patients receiving and not receiving PDE-5i. Adjusted Cox proportional hazards analysis was performed for each outcome. RESULTS: The primary endpoint was lower in the PDE-5i group (adjusted HR: 0.77; 95% CI: 0.69-0.86; P < 0.0001; HeartMate 3: adjusted HR: 0.77; 95% CI: 0.64-0.92; P = 0.0044; HVAD: adjusted HR: 0.76; 95% CI: 0.66-0.88; P = 0.0002). All-cause mortality was lower with PDE-5is (adjusted HR: 0.75; 95% CI: 0.65-0.86; P < 0.0001; HeartMate 3: adjusted HR: 0.70; 95% CI: 0.57-0.86; P = 0.0007; HVAD: adjusted HR: 0.78; 95% CI: 0.65-0.94; P = 0.0098) and fewer ischemic strokes with PDE-5is were observed (adjusted HR: 0.71; 95% CI: 0.56-0.89; P = 0.003; HeartMate 3: adjusted HR: 0.67; 95% CI: 0.45-0.99; P = 0.045; HVAD: adjusted HR: 0.73; 95% CI: 0.56-0.97; P = 0.03). LVAD thrombosis was unchanged with PDE-5is, with overall low event rates observed. CONCLUSIONS: Postimplant PDE-5i use was associated with lower mortality and ischemic strokes in patients with centrifugal flow LVADs.

Growth differentiation factor 15 predicts poor prognosis in patients with heart failure and reduced ejection fraction and anemia: results from RED-HF.

AIMS: We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia METHODS AND RESULTS: Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23-1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38-2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin. CONCLUSIONS: In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients.