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Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called "kidney tamponade", explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium-glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice.

We report a case of intermittent dislocation of the flexor hallucis longus at its passage in the retro-malleolar area, related to a post-traumatic detachment of the retrotalar pulley from the medial tubercle of the talus. High-resolution ultrasound depicted the anterior dislocation of the tendon during dynamic stress, by asking the patient to flex his hallux against the examiner resistance, with the ankle in slight dorsiflexion. The tendon normally relocated after the dynamic maneuver. Tendon dislocation was associated with a painful snap., (© 2024. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Acute myocarditis covers a wide spectrum of clinical presentations, from uncomplicated myocarditis to severe forms complicated by hemodynamic instability and ventricular arrhythmias; however, all these forms are characterized by acute myocardial inflammation. The term "chronic inflammatory cardiomyopathy" describes a persistent/chronic inflammatory condition with a clinical phenotype of dilated and/or hypokinetic cardiomyopathy associated with symptoms of heart failure and increased risk for arrhythmias. A continuum can be identified between these two conditions. The importance of early diagnosis has grown markedly in the contemporary era with various diagnostic tools available. While cardiac magnetic resonance (CMR) is valid for diagnosis and follow-up, endomyocardial biopsy (EMB) should be considered as a first-line diagnostic modality in all unexplained acute cardiomyopathies complicated by hemodynamic instability and ventricular arrhythmias, considering the local expertise. Genetic counseling should be recommended in those cases where a genotype-phenotype association is suspected, as this has significant implications for patients' and their family members' prognoses. Recognition of the pathophysiological pathway and clinical "red flags" and an early diagnosis may help us understand mechanisms of progression, tailor long-term preventive and therapeutic strategies for this complex disease, and ultimately improve clinical outcomes.

Background: Brugada syndrome poses significant challenges in terms of risk stratification and management, particularly for asymptomatic patients who comprise the majority of individuals exhibiting Brugada ECG pattern (BrECG). The aim of this study was to evaluate the long-term prognosis of a large cohort of asymptomatic patients with BrECG., Methods: Asymptomatic patients with BrECG (1149) were consecutively collected from 2 Italian centers and followed-up at least annually for 2 to 22 years. For the 539 asymptomatic patients (men, 433 [80%]; mean age, 46±13 years) with spontaneous type 1 documented on baseline ECG (87%) or 12-lead 24-hour Holter monitoring (13%), an electrophysiologic study (EPS) was proposed; for the 610 patients with drug-induced-only type 1 (men, 420 [69%]; mean age, 44±14 years), multiple ECGs and 12-lead Holter were advised in order to detect the occurrence of a spontaneous type-1 BrECG. Arrhythmic events were defined as sudden death or documented ventricular fibrillation or tachycardia., Results: Median follow-up was 6 (4-9) years. Seventeen (1.5%) arrhythmic events occurred in the overall asymptomatic population (corresponding to an event-rate of 0.2% per year), including 16 of 539 (0.4% per year) in patients with spontaneous type-1 BrECG and 1 of 610 in those with drug-induced type-1 BrECG (0.03% per year; P <0.001). EPS was performed in 339 (63%) patients with spontaneous type-1 BrECG. Patients with spontaneous type-1 BrECG and positive EPS had significantly higher event rates than patients with negative EPS (7 of 103 [0.7% per year] versus 4 of 236 [0.2% per year]; P =0.025). Among 200 patients who declined EPS, 5 events (0.4% per year) occurred. There was 1 device-related death., Conclusions: The entire population of asymptomatic patients with BrECG exhibits a relatively low event rate per year, which is important in view of the long life expectancy of these young patients. The presence of spontaneous type-1 BrECG associated with positive EPS identifies a subgroup at higher risk. Asymptomatic patients with drug-induced-only BrECG have a minimal arrhythmic risk, but ongoing follow-up with 12-lead Holter monitoring is recommended to detect the appearance of spontaneous type-1 BrECG pattern., Competing Interests: Disclosures None.

Background: The current understanding of the clinical course and long-term outcome of patients with hypertrophic cardiomyopathy (HCM) has been extrapolated from cohorts with relatively short follow-up, usually <10 years. Extended assessments more closely reflecting HCM lifetime burden are not available., Objectives: The purpose of this study was to report the lifetime clinical course of HCM., Methods: We analyzed the clinical course of HCM patients diagnosed at our center from 1970 to 1992 and followed annually to the present. Cumulative incidence functions were used to estimate the incidence of HCM-related mortality (including heart failure [HF]/stroke related, sudden cardiac death [SCD]) and non-HCM related., Results: A total of 202 patients (age 41 ± 17 years; 63% male) were followed 27 ± 6 [range: 3-50] years. Overall, 97 (48%) survived and 105 (52%) died during the particularly long follow-up; 69 deaths were related to HCM, including 53 HF related, 11 fatal embolic strokes, and 16 SCDs. Annual overall HCM-related mortality was 1.3%/y, increasing from 0.7% during the first decade to 1.8% in the second/third decade ( P  < 0.01), mainly driven by increase in HF-/stroke-related events (from 0.6% to 1.3%). The SCD mortality rate was similar in the 2 periods (0.1% vs 0.44%, P  = 0.10). Of the 69 HCM deaths, 29 (42%) occurred before the widespread availability of effective contemporary treatment strategies and are considered potentially preventable., Conclusions: In this unique HCM cohort followed for up to 50 years, often before contemporary therapies became widely implemented for HCM, HF frequently progressed over time, while arrhythmic SCD events were less common and remained constant over time. Despite spanning different management eras over 5 decades, HCM-related mortality remained relatively low (1.3%/y)., Competing Interests: Dr Olivotto was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement no. 777204: “SILICOFCM - In Silico trials for drug tracing the effects of sarcomeric protein mutations leading to familial cardiomyopathy”; has received grants from 10.13039/100002491Bristol Myers Squibb, 10.13039/100014941Cytokinetics, 10.13039/100015362Amicus, 10.13039/100004329Genzyme, 10.13039/100007343Shire, 10.13039/100004326Bayer, 10.13039/100008497Boston Scientific, Menarini International; fees (honoraria or consulting) from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire, and Boston Scientific; and served or currently serving as PI on EXPLORER-HCM, MAVA-LTE, REDWOOD-HCM, REDWOOD-OLE, and SEQUOIA-HCM trial. Dr M. S. Maron is a consultant for Cytokinetics and Steering Committee Chair for REDWOOD-HCM phase 2 trial; consultant for Imbria Pharmaceuticals; and is a consultant and has a research grant from 10.13039/100007723Takeda Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN PATIENT CARE: Current understanding of the clinical course and long-term outcome of patients with HCM has been extrapolated from cohorts with relatively short follow-up, usually <10 years. In this unique HCM cohort followed for up to 50 years, often before contemporary therapies became widely implemented for HCM, annual overall HCM-related mortality was 1.3%/y, increasing from 0.7% during the first decade to 1.8% in the second/third decade, mainly driven by increase in HF-/stroke-related events (from 0.6% to 1.3%). However, sudden death mortality rate was similar during the 2 periods (0.1% vs 0.44%). TRANSLATIONAL OUTLOOK: These data support the recognition that contemporary management options can substantially impact mortality directly attributable to HCM. Indeed, >40% of our patients would have benefited importantly by treatment options not fully available >20 years ago., (© 2023 The Authors.)

Cardiac Contractility Modulation (CCM) has been proposed for inpatients affected by heart failure with reduced ejection fraction (HFrEF), with relapsing HF symptoms. We present a case of a patient treated with percutaneous coronary intervention (PCI) in the setting of acute coronary syndrome without persistent ST-segment elevation, with the best medical therapy for decompensated HF. The patient refused the implantable cardioverter-defibrillator (ICD), and to reduce the increasing number of hospitalizations for HF exacerbations, we proposed the use of the cardiac contractility modulation device. After the implant, the patient demonstrated a marked improvement in exercise effort and quality of life (QOL) with a six-minute walk test (SMWT), Minnesota Living with Heart Failure Questionnaire (MLWHFQ), and echocardiographic parameters. At 9 months after discharge, no hospital admissions for HF were recorded. We showed with the speckle tracking imaging how the improvement in global longitudinal strain (GLS) correlates with the remodeling effects on myocardial cells.

Syndesmotic injuries, also referred as high ankle sprains, may cause significant ankle instability and chronic pain. Ultrasound (US) is a well-proven imaging modality to evaluate the ligaments of the ankle, due to its high spatial resolution and the possibility to perform dynamic examinations. However, considering the syndesmosis complex, the sonographic appearance of the posterior inferior tibiofibular ligament (PITFL) is not well described in the pertinent literature and, to the best of our knowledge, we found no report of PITFL avulsion demonstrated at US, as in the case presented.

The hamstring muscle complex is made by a group of posterior biarticular thigh muscles, originating at the ischial tuberosity, which extend the hip and flex the knee joint. Proximal hamstring injuries are frequent among athletes, commonly involving their long myotendinous junction during an eccentric contraction. In this pictorial essay, we describe the ultrasound technique to visualize the normal anatomy of the proximal hamstring muscle-tendon-bone complex and present ultrasound findings in patients with traumatic injuries and tendinopathies., (© 2018 by the American Institute of Ultrasound in Medicine.)

Killian-Jamieson diverticulum (KJD) is a pharyngoesophageal diverticulum that can be observed during a neck ultrasound examination. Because of its position, it is frequently misinterpreted as a thyroid nodule. We present a case of an incidental finding of KJD, where changes in shape during dynamic scanning led to the correct diagnosis, preventing from invasive procedures such as fine needle aspiration., Competing Interests: The authors have no conflict of interest. Informed consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. All patients provided written informed consent for enrolment in the study and for the inclusion in this article of information that could potentially lead to their identification. Human and animal studies The study was conducted in accordance with all institutional and national guidelines for the care and use of laboratory animals.

Calcific tendinopathy of the shoulder is a common condition caused by calcium hydroxyapatite crystals, affecting the tendons of the rotator cuff. Among uncommon complication, one is the migration of the calcium in the subacromion-subdeltoid bursa. More rare is the intraosseous migration. We present four cases of an even more rare condition, not well described in literature yet, the intramuscular migration of calcium., Competing Interests: The authors have no conflict of interest. Informed consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. All patients provided written informed consent for enrolment in the study and for the inclusion in this article of information that could potentially lead to their identification. Human and animal studies The study was conducted in accordance with all institutional and national guidelines for the care and use of laboratory animals.

The fractures of sesamoid bones of the hand are rare, sometimes the diagnosis is missed. We report a case of fracture of both the ulnar and radial sesamoids of the metacarpophalangeal (MCP) joint of the thumb. The trauma (hyperextension of the thumb during a soccer match) also caused a lesion of the volar plate. The diagnosis was made by ultrasound (US) and confirmed by CT scan.

7-[(2,2-Dimethyl)propyl]-1-methyl xanthine (CAS 155006-67-0, MX2/120) is a new potent antibronchospastic agent with negligible side effects. The synthesis involves the alkylation of 3-benzyl-1-methyl xanthine with neopentyl bromide followed by removal of the benzyl protecting group. Main physico-chemical properties were determined using NMR, MS, IR, UV spectra and X-ray crystal structure. A quantitative determination of substances related to MX2/120 and of residual solvents by means of HPLC and GC, respectively, is described. MX2/120 is safely stored at room temperature for a long time.

A series of 7-(2,2-dimethyl)propyl substituted xanthines were synthesized and tested for their antibronchospastic activity in comparison with theophylline. In vitro, the inhibition of carbachol-induced increase in bronchial tone was determined. In vivo, the inhibition of antigen-induced bronchoconstriction in guinea pigs was determined 1, 3 and 5 h after oral administration. Central side effects were evaluated. In vitro, the majority of compounds were more effective than theophylline. In vivo, three compounds 2, 14 and 15 showed an effect comparable to theophylline but longer lasting. A mild sedative effect was generally observed. Compound 2, 7-(2,2-dimethyl)propyl-1-methyl xanthine, coded MX2/120, was selected for a deeper evaluation.

Isbufylline metabolism after oral administration to humans was studied. The main metabolites detected by the HPLC method, in plasma, were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-hydroxy-2-methyl-propyl) xanthine (II), and 1-methyl-7-(2-methyl-propyl) xanthine (III). The main metabolites detected in urine were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-carboxy-propyl) xanthine (IV), and 1,3-dimethyl-7-(2-hydroxymethyl-propyl) xanthine glucuronic acid (V)-Gluc. They were isolated by HPLC, identified by GC/MS, HPLC/MS, or HPLC/MS/MS, and finally synthesized. Recovery of these metabolites, along with the absence of unmetabolized isbufylline in the urine, indicated biotransformation and renal excretion as the main routes of isbufylline elimination in humans. HPLC quantitation of the characterized urine metabolites revealed that 49% of the drug was eliminated as (I), 9% as (V)-Gluc, and 5% as (IV).

Physico-chemical properties, i.e. elemental analysis, spectra (NMR, MS, IR, UV), X-ray crystal structure, solubilities, partition coefficient, melting point, HPLC, GC, and data about purity and stability of 1,3-dimethyl-7-isobutyl xanthine (isbufylline, TE/06, CAS 90162-60-0), a new drug with antibronchospastic properties, are reported.

An investigation was carried out to ascertain whether erythro- and threo-alpha-methyl-dihydroxy-phenyl-serine were able of depleting cerebral and peripheral norepinephrine (NE) through their metabolization to alpha-mNE. The results show that the alpha-methyl-aminoacids were decarboxylated only at the periphery and that the threo-form caused depletion in cardiac NE. In any case, both isomers were unable to cross the blood-brain barrier leaving the cerebral NE unaffected. Consequently the use of alpha-mDOPS as alternative tool to alpha-mDOPA in the therapy for hypertension seems unlikely to occur. The results also provide evidence for differences in the pharmacokinetics of the two isomers.

Resolution of the optical isomers of the alpha-adrenoceptor antagonist IP-66 (1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine) and its intermediate IP-30 (1-[2-hydroxy-2-(3'-pyridyl)ethyl]-4- (2'-methoxy-phenyl)piperazine have been carried out. Optical purity was assayed by high-pressure liquid chromatography. The antagonistic potencies of racemic mixtures and stereoisomers toward phenylephrine- and norepinephrine-induced contraction in isolated rat aortic strips have been compared. (+)-IP-66 and (+)-IP-30 were resp. 363 and 170 times more potent than respective (-) isomers in eliciting competitive alpha 1-adrenoceptor blockade. Similarly IP-66 (+) or (+/-) were extremely more effective than the (-) isomer in antagonizing norepinephrine-induced pressor responses in pithed rat.