Germano Junior Ferruzzi
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Germano Junior Ferruzzi has a total of 66 co-authors. Here are the top co-authors by number of shared publications:
- Gennaro Galasso
Department of Medicine, Surgery, and Dentistry, University of Salerno, 84084 Salerno, Italy
6 shared publications - Angelo Silverio
University of Salerno
4 shared publications - Carmine Vecchione
Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
3 shared publications - Michele Ciccarelli
University of Salerno
3 shared publications - Rodolfo Citro
Department of Cardiology, University of Molise, Campobasso, Italy
3 shared publications - Tiziana Attisano
University Hospital San Giovanni di Dio e Ruggi d'Aragona
3 shared publications
Latest Publications
- Open Access
- 19 May 2026
- Published by Wolters Kluwer Health in Journal of the American Heart Association
- Vol. 15 (10) , e046441
Balloon‐Expandable Versus Self‐Expanding Prostheses for Transcatheter Treatment of Patients With Low‐Flow, Low‐Gradient Aortic Stenosis
Background: The use of balloon‐expandable valves (BEVs) or self‐expanding valves (SEVs) for transcatheter aortic valve replacement (TAVR) in patients with low‐flow, low‐gradient aortic stenosis (LFLG‐AS) has been poorly investigated. Aim of this study is to evaluate the procedural and clinical outcomes of patients with severe low‐flow, low‐gradient aortic stenosis undergoing TAVR with current‐generation prostheses. Methods: This registry‐based, multicenter, cohort study included consecutive patients with low‐flow, low‐gradient aortic stenosis undergoing TAVR from January 2019 to December 2024 at 17 high‐volume Italian centers. The study population was divided into 2 groups according to the use of BEVs or SEVs. The primary outcome was all‐cause mortality up to 1 year. Results: The study involved 1380 patients; 592 (42.9%) underwent TAVR with BEVs, and 788 (57.1%) with SEVs. At discharge, BEVs were linked to higher mean transvalvular gradients ( P P <0.001) compared with SEVs. After propensity score weighting, the Cox analysis showed no difference for the risk of the primary outcome (adjusted hazard ratio [HR]:1.23; 95% CI: 0.88–1.72), cardiovascular mortality (adjusted HR:1.37; 95% CI: 0.94–1.97), stroke (adjusted HR:1.83; 95% CI: 0.85–3.95), and myocardial infarction (adjusted HR:1.03; 95% CI: 0.40–2.69) between groups; however, the use of BEVs was associated with a significantly higher risk for HF hospitalization up to 1 year (adjusted HR: 1.54; 95% CI:1.05–2.25). Conclusions: In this real‐world study on TAVR treatment for patients with low‐flow, low‐gradient aortic stenosis, there was no difference in mortality rates between BEVs and SEVs up to 1 year. However, the use of BEVs was linked to less favorable hemodynamic performance and a higher risk of HF hospitalization. Registration: URL: https://clinicaltrials.gov/ ; Unique identifier: NCT06589063.
- 19 May 2026
- Published by Wolters Kluwer Health in Journal of the American Heart Association
- Vol. 15 (10) , e046441
Open AccessBalloon‐Expandable Versus Self‐Expanding Prostheses for Transcatheter Treatment of Patients With Low‐Flow, Low‐Gradient Aortic Stenosis
Background: The use of balloon‐expandable valves (BEVs) or self‐expanding valves (SEVs) for transcatheter aortic valve replacement (TAVR) in patients with low‐flow, low‐gradient aortic stenosis (LFLG‐AS) has been poorly investigated. Aim of this study is to evaluate the procedural and clinical outcomes of patients with severe low‐flow, low‐gradient aortic stenosis undergoing TAVR with current‐generation prostheses. Methods: This registry‐based, multicenter, cohort study included consecutive patients with low‐flow, low‐gradient aortic stenosis undergoing TAVR from January 2019 to December 2024 at 17 high‐volume Italian centers. The study population was divided into 2 groups according to the use of BEVs or SEVs. The primary outcome was all‐cause mortality up to 1 year. Results: The study involved 1380 patients; 592 (42.9%) underwent TAVR with BEVs, and 788 (57.1%) with SEVs. At discharge, BEVs were linked to higher mean transvalvular gradients ( P P <0.001) compared with SEVs. After propensity score weighting, the Cox analysis showed no difference for the risk of the primary outcome (adjusted hazard ratio [HR]:1.23; 95% CI: 0.88–1.72), cardiovascular mortality (adjusted HR:1.37; 95% CI: 0.94–1.97), stroke (adjusted HR:1.83; 95% CI: 0.85–3.95), and myocardial infarction (adjusted HR:1.03; 95% CI: 0.40–2.69) between groups; however, the use of BEVs was associated with a significantly higher risk for HF hospitalization up to 1 year (adjusted HR: 1.54; 95% CI:1.05–2.25). Conclusions: In this real‐world study on TAVR treatment for patients with low‐flow, low‐gradient aortic stenosis, there was no difference in mortality rates between BEVs and SEVs up to 1 year. However, the use of BEVs was linked to less favorable hemodynamic performance and a higher risk of HF hospitalization. Registration: URL: https://clinicaltrials.gov/ ; Unique identifier: NCT06589063.
- Open Access
- 4 November 2024
- Published by Wolters Kluwer Health in Journal of the American Heart Association
- Vol. 13 (21) , e036239
Prevalence and Prognostic Significance of Right Ventricular Dysfunction in Patients With Severe Low‐Flow, Low‐Gradient Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement
Background: Whether the presence of right ventricular (RV) dysfunction may influence the clinical outcome of patients with low‐flow, low‐gradient aortic stenosis (LFLG‐AS) undergoing transcatheter aortic valve replacement (TAVR) has not yet been established. Methods and Results: This study included consecutive patients with LFLG‐AS undergoing TAVR at 2 high‐volume Italian centers. RV dysfunction before TAVR procedure was defined as tricuspid annular plane systolic excursion assessed by transthoracic echocardiography lower than <17 mm. The primary outcome was all‐cause death at 1 year. The propensity score weighting technique was implemented to account for potential selection bias between patients with and without RV dysfunction. A prespecified subgroup analysis was conducted to evaluate the consistency of the results in patients with classical and paradoxical LFLG‐AS forms. This study included 392 patients; of them, 97 (24.7%) patients showed RV dysfunction before TAVR. At propensity score–weighted adjusted Cox regression analysis, RV dysfunction, according to dichotomous definition, was associated with an increased risk for the primary outcome (adjusted hazard ratio [HR], 3.11 [95% CI, 1.58–6.13]), cardiovascular death (adjusted HR, 3.26 [95% CI, 1.58–6.72]), and major adverse cardiovascular and cerebrovascular events (adjusted HR, 3.39 [95% CI, 1.76–6.53]). Conversely, no difference was detected for the risk of stroke and of permanent pacemaker implantation. No significant interaction of the classical and paradoxical LFLG‐AS subgroups was detected for all the outcomes of interest. Conclusions: This study suggests that RV dysfunction echocardiographically assessed by tricuspid annular plane systolic excursion may improve the prognostic stratification of patients with LFLG‐AS undergoing TAVR.
- 4 November 2024
- Published by Wolters Kluwer Health in Journal of the American Heart Association
- Vol. 13 (21) , e036239
Open AccessPrevalence and Prognostic Significance of Right Ventricular Dysfunction in Patients With Severe Low‐Flow, Low‐Gradient Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement
Background: Whether the presence of right ventricular (RV) dysfunction may influence the clinical outcome of patients with low‐flow, low‐gradient aortic stenosis (LFLG‐AS) undergoing transcatheter aortic valve replacement (TAVR) has not yet been established. Methods and Results: This study included consecutive patients with LFLG‐AS undergoing TAVR at 2 high‐volume Italian centers. RV dysfunction before TAVR procedure was defined as tricuspid annular plane systolic excursion assessed by transthoracic echocardiography lower than <17 mm. The primary outcome was all‐cause death at 1 year. The propensity score weighting technique was implemented to account for potential selection bias between patients with and without RV dysfunction. A prespecified subgroup analysis was conducted to evaluate the consistency of the results in patients with classical and paradoxical LFLG‐AS forms. This study included 392 patients; of them, 97 (24.7%) patients showed RV dysfunction before TAVR. At propensity score–weighted adjusted Cox regression analysis, RV dysfunction, according to dichotomous definition, was associated with an increased risk for the primary outcome (adjusted hazard ratio [HR], 3.11 [95% CI, 1.58–6.13]), cardiovascular death (adjusted HR, 3.26 [95% CI, 1.58–6.72]), and major adverse cardiovascular and cerebrovascular events (adjusted HR, 3.39 [95% CI, 1.76–6.53]). Conversely, no difference was detected for the risk of stroke and of permanent pacemaker implantation. No significant interaction of the classical and paradoxical LFLG‐AS subgroups was detected for all the outcomes of interest. Conclusions: This study suggests that RV dysfunction echocardiographically assessed by tricuspid annular plane systolic excursion may improve the prognostic stratification of patients with LFLG‐AS undergoing TAVR.
- Open Access
- 5 September 2023
- Published by Wolters Kluwer Health in Journal of the American Heart Association
- Vol. 12 (17) , e029553
Prognostic Impact of Mitral Regurgitation Before and After Transcatheter Aortic Valve Replacement in Patients With Severe Low‐Flow, Low‐Gradient Aortic Stenosis
Background: There is little evidence about the prognostic role of mitral regurgitation (MR) in patients with low‐flow, low‐gradient aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). The aim of this study was to assess the prevalence and outcome implications of MR severity in patients with low‐flow, low‐gradient aortic stenosis undergoing TAVR, and to evaluate whether MR improvement after TAVR could influence clinical outcome. Methods and Results: This study included consecutive patients with low‐flow, low‐gradient aortic stenosis undergoing TAVR at 2 Italian high‐volume centers. The study population was categorized according to the baseline MR severity and to the presence of MR improvement at discharge. The primary outcome was the composite of all‐cause death and hospitalization for worsening heart failure up to 1 year. The study included 268 patients; 57 (21%) patients showed MR >2+. Patients with MR >2+ showed a lower 1‐year survival free from the primary outcome ( P P P 2+ was an independent predictor of the primary outcome ( P 2+, MR improvement was reported in 24 (44%) cases after TAVR. The persistence of MR was associated with a significantly reduced survival free from the primary outcome, all‐cause death, and heart failure hospitalization up to 1 year. Conclusions: In this study, the presence of moderately severe to severe MR in patients with low‐flow, low‐gradient aortic stenosis undergoing TAVR portends a worse clinical outcome at 1 year. TAVR may improve MR severity in nearly half of the patients, resulting in a potential outcome benefit after discharge.
- 5 September 2023
- Published by Wolters Kluwer Health in Journal of the American Heart Association
- Vol. 12 (17) , e029553
Open AccessPrognostic Impact of Mitral Regurgitation Before and After Transcatheter Aortic Valve Replacement in Patients With Severe Low‐Flow, Low‐Gradient Aortic Stenosis
Background: There is little evidence about the prognostic role of mitral regurgitation (MR) in patients with low‐flow, low‐gradient aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). The aim of this study was to assess the prevalence and outcome implications of MR severity in patients with low‐flow, low‐gradient aortic stenosis undergoing TAVR, and to evaluate whether MR improvement after TAVR could influence clinical outcome. Methods and Results: This study included consecutive patients with low‐flow, low‐gradient aortic stenosis undergoing TAVR at 2 Italian high‐volume centers. The study population was categorized according to the baseline MR severity and to the presence of MR improvement at discharge. The primary outcome was the composite of all‐cause death and hospitalization for worsening heart failure up to 1 year. The study included 268 patients; 57 (21%) patients showed MR >2+. Patients with MR >2+ showed a lower 1‐year survival free from the primary outcome ( P P P 2+ was an independent predictor of the primary outcome ( P 2+, MR improvement was reported in 24 (44%) cases after TAVR. The persistence of MR was associated with a significantly reduced survival free from the primary outcome, all‐cause death, and heart failure hospitalization up to 1 year. Conclusions: In this study, the presence of moderately severe to severe MR in patients with low‐flow, low‐gradient aortic stenosis undergoing TAVR portends a worse clinical outcome at 1 year. TAVR may improve MR severity in nearly half of the patients, resulting in a potential outcome benefit after discharge.
- Open Access
- 7 July 2023
- Published by MDPI AG in Journal of Clinical Medicine
- Vol. 12 (13) , 4550
Moving toward Precision Medicine in Acute Coronary Syndromes: A Multimodal Assessment of Non-Culprit Lesions
Patients with acute coronary syndrome and multivessel disease experience several recurrent adverse events that lead to poor outcomes. Given the complexity of treating these patients, and the extremely high risk of long-term adverse events, the assessment of non-culprit lesions becomes crucial. Recently, two trials have shown a possible clinical benefit into treat non-culprit lesions using a fraction flow reserve (FFR)-guided approach, compared to culprit-lesion-only PCI. However, the most recent FLOW Evaluation to Guide Revascularization in Multivessel ST-elevation Myocardial Infarction (FLOWER-MI) trial did not show a benefit of the use of FFR-guided PCI compared to an angiography-guided approach. Otherwise, intracoronary imaging using optical coherence tomography (OCT), intravascular ultrasound (IVUS), or near-infrared spectroscopy (NIRS) could provide both quantitative and qualitative assessments of non-culprit lesions. Different studies have shown how the characterization of coronary lesions with intracoronary imaging could lead to clinical benefits in these peculiar group of patients. Moreover, non-invasive evaluations of NCLs have begun to take ground in this context, but more insights through adequately powered and designed studies are needed. The aim of this review is to outline the available techniques, both invasive and non-invasive, for the assessment of multivessel disease in patients with STEMI, and to provide a systematic guidance on the assessment and approach to these patients.
- 7 July 2023
- Published by MDPI AG in Journal of Clinical Medicine
- Vol. 12 (13) , 4550
Open AccessMoving toward Precision Medicine in Acute Coronary Syndromes: A Multimodal Assessment of Non-Culprit Lesions
Patients with acute coronary syndrome and multivessel disease experience several recurrent adverse events that lead to poor outcomes. Given the complexity of treating these patients, and the extremely high risk of long-term adverse events, the assessment of non-culprit lesions becomes crucial. Recently, two trials have shown a possible clinical benefit into treat non-culprit lesions using a fraction flow reserve (FFR)-guided approach, compared to culprit-lesion-only PCI. However, the most recent FLOW Evaluation to Guide Revascularization in Multivessel ST-elevation Myocardial Infarction (FLOWER-MI) trial did not show a benefit of the use of FFR-guided PCI compared to an angiography-guided approach. Otherwise, intracoronary imaging using optical coherence tomography (OCT), intravascular ultrasound (IVUS), or near-infrared spectroscopy (NIRS) could provide both quantitative and qualitative assessments of non-culprit lesions. Different studies have shown how the characterization of coronary lesions with intracoronary imaging could lead to clinical benefits in these peculiar group of patients. Moreover, non-invasive evaluations of NCLs have begun to take ground in this context, but more insights through adequately powered and designed studies are needed. The aim of this review is to outline the available techniques, both invasive and non-invasive, for the assessment of multivessel disease in patients with STEMI, and to provide a systematic guidance on the assessment and approach to these patients.
- Open Access
Sacubitril/Valsartan vs. Standard Medical Therapy on Exercise Capacity in HFrEF Patients
Sacubitril/valsartan (Sac/Val) reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) compared to enalapril. However, its effects on functional capacity remain uncertain; consequently, we sought to compare Sac/Val vs. standard medical therapy, in terms of effects on prognostically significant CPET parameters, in HFrEF patients during a long follow-up period. We conducted a single-center, observational study in an HF clinic; specifically, we retrospectively identified that 12 patients switched to Sac/Val and 13 patients that managed with standard, optimal medical therapy (control group). At each visit, baseline, and follow-up (median time: 16 months; IQ range: 11.5–22), we collected demographic information, medical history, vital signs, cardiopulmonary exercise testing, standard laboratory data, pharmacological treatment information, and echocardiographic parameters. The study’s primary end-point was the change from baseline in peak VO2 (adjusted to body weight). We did not observe significant differences between the two study groups at baseline. Similarly, we did not observe any significant differences during the follow-up in mean values of peak VO2 corrected for body weight: Sac/Val baseline: 12.2 ± 4.6 and FU: 12.7 ± 3.3 vs. control group: 13.1 ± 4.2 and 13.0 ± 4.2 mL/kg/min; p = 0.49. No significant treatment differences were observed for changes in VE/VCO2 slope: Sac/Val baseline: 35.4 ± 7.4 and FU: 37.2 ± 13.1 vs. control group: 34.6 ± 9.1 and 34.0 ± 7.3; p = 0.49. In conclusion, after a median follow-up period of 16 months, there was no significant benefit of Sac/Val on peak VO2 and other measures of CPET compared with standard optimal therapy in patients with HFrEF.
Open AccessSacubitril/Valsartan vs. Standard Medical Therapy on Exercise Capacity in HFrEF Patients
Sacubitril/valsartan (Sac/Val) reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) compared to enalapril. However, its effects on functional capacity remain uncertain; consequently, we sought to compare Sac/Val vs. standard medical therapy, in terms of effects on prognostically significant CPET parameters, in HFrEF patients during a long follow-up period. We conducted a single-center, observational study in an HF clinic; specifically, we retrospectively identified that 12 patients switched to Sac/Val and 13 patients that managed with standard, optimal medical therapy (control group). At each visit, baseline, and follow-up (median time: 16 months; IQ range: 11.5–22), we collected demographic information, medical history, vital signs, cardiopulmonary exercise testing, standard laboratory data, pharmacological treatment information, and echocardiographic parameters. The study’s primary end-point was the change from baseline in peak VO2 (adjusted to body weight). We did not observe significant differences between the two study groups at baseline. Similarly, we did not observe any significant differences during the follow-up in mean values of peak VO2 corrected for body weight: Sac/Val baseline: 12.2 ± 4.6 and FU: 12.7 ± 3.3 vs. control group: 13.1 ± 4.2 and 13.0 ± 4.2 mL/kg/min; p = 0.49. No significant treatment differences were observed for changes in VE/VCO2 slope: Sac/Val baseline: 35.4 ± 7.4 and FU: 37.2 ± 13.1 vs. control group: 34.6 ± 9.1 and 34.0 ± 7.3; p = 0.49. In conclusion, after a median follow-up period of 16 months, there was no significant benefit of Sac/Val on peak VO2 and other measures of CPET compared with standard optimal therapy in patients with HFrEF.
- Top Cited PapersOpen Access
- 20 January 2022
- Published by MDPI AG in Journal of Clinical Medicine
- Vol. 11 (3) , 524
Post-COVID-19 Syndrome: Involvement and Interactions between Respiratory, Cardiovascular and Nervous Systems
Though the acute effects of SARS-CoV-2 infection have been extensively reported, the long-term effects are less well described. Specifically, while clinicians endure to battle COVID-19, we also need to develop broad strategies to manage post-COVID-19 symptoms and encourage those affected to seek suitable care. This review addresses the possible involvement of the lung, heart and brain in post-viral syndromes and describes suggested management of post-COVID-19 syndrome. Post-COVID-19 respiratory manifestations comprise coughing and shortness of breath. Furthermore, arrhythmias, palpitations, hypotension, increased heart rate, venous thromboembolic diseases, myocarditis and acute heart failure are usual cardiovascular events. Among neurological manifestations, headache, peripheral neuropathy symptoms, memory issues, lack of concentration and sleep disorders are most commonly observed with varying frequencies. Finally, mental health issues affecting mental abilities and mood fluctuations, namely anxiety and depression, are frequently seen. Finally, long COVID is a complex syndrome with protracted heterogeneous symptoms, and patients who experience post-COVID-19 sequelae require personalized treatment as well as ongoing support.
- 20 January 2022
- Published by MDPI AG in Journal of Clinical Medicine
- Vol. 11 (3) , 524
Top Cited PapersOpen AccessPost-COVID-19 Syndrome: Involvement and Interactions between Respiratory, Cardiovascular and Nervous Systems
Though the acute effects of SARS-CoV-2 infection have been extensively reported, the long-term effects are less well described. Specifically, while clinicians endure to battle COVID-19, we also need to develop broad strategies to manage post-COVID-19 symptoms and encourage those affected to seek suitable care. This review addresses the possible involvement of the lung, heart and brain in post-viral syndromes and describes suggested management of post-COVID-19 syndrome. Post-COVID-19 respiratory manifestations comprise coughing and shortness of breath. Furthermore, arrhythmias, palpitations, hypotension, increased heart rate, venous thromboembolic diseases, myocarditis and acute heart failure are usual cardiovascular events. Among neurological manifestations, headache, peripheral neuropathy symptoms, memory issues, lack of concentration and sleep disorders are most commonly observed with varying frequencies. Finally, mental health issues affecting mental abilities and mood fluctuations, namely anxiety and depression, are frequently seen. Finally, long COVID is a complex syndrome with protracted heterogeneous symptoms, and patients who experience post-COVID-19 sequelae require personalized treatment as well as ongoing support.
- 15 October 2021
- Published by Bentham Science Publishers Ltd. in Current Medicinal Chemistry
- Vol. 28 (32) , 6569-6590
Artificial Intelligence as a Business Partner in Cardiovascular Precision Medicine: An Emerging Approach for Disease Detection and Treatment Optimization
Background: In the real world, medical practice is changing hand in hand with the development of new Artificial Intelligence (AI) systems and problems from different areas have been successfully solved using AI algorithms. Specifically, the use of AI techniques in setting up or building precision medicine is significant in terms of the accuracy of disease discovery and tailored treatment. Moreover, with the use of technology, clinical personnel can deliver a very much efficient healthcare service. Objective: This article reviews AI state-of-the-art in cardiovascular disease management, focusing on diagnostic and therapeutic improvements. Methods: To that end, we conducted a detailed PubMed search on AI application from distinct areas of cardiology: heart failure, arterial hypertension, atrial fibrillation, syncope and cardiovascular rehabilitation. Particularly, to assess the impact of these technologies in clinical decision-making, this research considers technical and medical aspects. Results: : On one hand, some devices in heart failure, atrial fibrillation and cardiac rehabilitation represent an inexpensive, not invasive or not very invasive approach to long-term surveillance and management in these areas. On the other hand, the availability of large datasets (big data) is a useful tool to predict the development and outcome of many cardiovascular diseases. In summary, with this new guided therapy, the physician can supply prompt, individualised, and tailored treatment and the patients feel safe as they are continuously monitored, with a significant psychological effect. Conclusion: Soon, tailored patient care via telemonitoring can improve clinical practice because AI-based systems support cardiologists in daily medical activities, improving disease detection and treatment. However, the physician-patient relationship remains a pivotal step.
- 15 October 2021
- Published by Bentham Science Publishers Ltd. in Current Medicinal Chemistry
- Vol. 28 (32) , 6569-6590
Artificial Intelligence as a Business Partner in Cardiovascular Precision Medicine: An Emerging Approach for Disease Detection and Treatment Optimization
Background: In the real world, medical practice is changing hand in hand with the development of new Artificial Intelligence (AI) systems and problems from different areas have been successfully solved using AI algorithms. Specifically, the use of AI techniques in setting up or building precision medicine is significant in terms of the accuracy of disease discovery and tailored treatment. Moreover, with the use of technology, clinical personnel can deliver a very much efficient healthcare service. Objective: This article reviews AI state-of-the-art in cardiovascular disease management, focusing on diagnostic and therapeutic improvements. Methods: To that end, we conducted a detailed PubMed search on AI application from distinct areas of cardiology: heart failure, arterial hypertension, atrial fibrillation, syncope and cardiovascular rehabilitation. Particularly, to assess the impact of these technologies in clinical decision-making, this research considers technical and medical aspects. Results: : On one hand, some devices in heart failure, atrial fibrillation and cardiac rehabilitation represent an inexpensive, not invasive or not very invasive approach to long-term surveillance and management in these areas. On the other hand, the availability of large datasets (big data) is a useful tool to predict the development and outcome of many cardiovascular diseases. In summary, with this new guided therapy, the physician can supply prompt, individualised, and tailored treatment and the patients feel safe as they are continuously monitored, with a significant psychological effect. Conclusion: Soon, tailored patient care via telemonitoring can improve clinical practice because AI-based systems support cardiologists in daily medical activities, improving disease detection and treatment. However, the physician-patient relationship remains a pivotal step.